Osteocyte-derived sclerostin impairs cognitive function during ageing and Alzheimer's disease progression.

Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-ß-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-ß-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-ß-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid ß (Aß) production through ß-catenin-ß-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αß production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD.

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer's disease therapy.

RATIONALE: The ß-secretase BACE1 initiates amyloid-ß (Aß) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aß reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. OBJECTIVES: We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. METHODS: The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aß deposition. RESULTS: Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12 months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the ß-amyloidogenic processing of amyloid precursor protein or Aß levels in 5XFAD mouse brains. CONCLUSIONS: A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.

Asthma aggravates alzheimer's disease by up-regulating NF- κB signaling pathway through LTD4.

Clinical studies have shown that asthma is a risk factor for dementia or Alzheimer's disease (AD). To investigate whether asthma aggravates AD in APP/PS1 mice and explore the potential mechanisms, an asthma model was established using six-month-old APP/PS1 mice, and montelukast was used as a therapeutic agent in APP/PS1 mice with asthma. The Morris water maze test showed that asthma aggravates spatial learning and memory abilities. Asthma also upregulates the NF-κB inflammatory pathway in APP/PS1 mice and promotes the expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid-ß (Aß) deposition, neuronal damage, synaptic plasticity deficiency, activation of microglia and astrocytes. The level of LTD4 and its receptor CysLT1R in the hippocampus of APP/PS1 mice after the asthma modeling was established was higher than that in APP/PS1 mice, suggesting that asthma may affect the pathology of AD through LTD4 and its receptor Cys-LT1R. Montelukast ameliorates these pathological changes and cognitive impairment. These results suggest that asthma aggravates AD pathology and cognitive impairment of APP/PS1 mice via upregulation of the NF-κB inflammatory pathway, and montelukast ameliorates these pathological changes.

PCSK9 ablation attenuates Aß pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice.

BACKGROUND: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aß pathology, neuroinflammation, and brain lipids. METHODS: For in vitro studies, U373 human astrocytoma cells were treated with Aß fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFADHet with PCSK9KO mice - was tested by the Morris water maze test. After sacrifice, immunohistochemical analyses were performed to evaluate Aß plaque deposition, distribution and composition, BACE1 immunoreactivity, as well as microglia and astrocyte reactivity. Cholesterol and hydroxysterols levels in mouse brains were quantified by fluorometric and LC-MS/MS analyses, respectively. Statistical comparisons were performed according to one- or two-way ANOVA, two-way repeated measure ANOVA or Chi-square test. RESULTS: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aß fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aß burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels. CONCLUSIONS: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aß pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD.

Desmoid-type fibromatosis: Current therapeutic strategies and future perspectives.

Desmoid tumors (DT) are rare, slow-growing, locally invasive soft tissue tumors that often pose significant therapeutic challenges. Traditional management strategies including active surveillance, surgery, radiotherapy, and systemic therapy which are associated with varying recurrence rates and high morbidity. Given the challenging nature of DT and the modest outcomes associated with current treatment strategies, there has been a growing interest in the field of γ-secretase inhibitors as a result of its action on the Wnt/ß-catenin signaling pathway. In this review article, we will shed the light on the pathogenesis and molecular biology of DT, discuss its symptoms and diagnosis, and provide a comprehensive review of the traditional therapeutic approaches. We will also delve into the mechanisms of action of γ-secretase inhibitors, its efficacy, and the existing preclinical and clinical data available to date on the use of these agents, as well as the potential challenges and future prospects in the treatment landscape of these tumors.

Enhanced Nose-to-Brain Delivery of Combined Small Interfering RNAs Using Lesion-Recognizing Nanoparticles for the Synergistic Therapy of Alzheimer's Disease.

Gene therapy has great potential in treating neurodegenerative diseases with complex pathologies. The combination of small interfering RNAs (siRNAs) targeting ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) and caspase-3 will provide an effective treatment option for Alzheimer's disease (AD). To overcome the multiple physiological barriers and improve the therapeutic efficacy of siRNAs, lesion-recognizing nanoparticles (NPs) are constructed in this study for the synergistic treatment of AD. The lesion-recognizing NPs contain rabies virus glycoprotein peptide-modified mesenchymal stem cell-derived exosomes as the shell and a reactive oxygen species (ROS)-responsive polymer loaded with siRNAs as the core. After intranasal administration, the lesion-recognizing NPs cross the nasal mucosa and migrate to the affected brain areas. Furthermore, the NPs recognize the target cells and fuse with the cell membranes of neurons. The cores of NPs directly enter into the cytoplasm and achieve the controlled release of siRNAs in a high-ROS environment to downregulate the level of BACE1 and caspase-3 to ameliorate neurologic injury. In addition, lesion-recognizing NPs can significantly reduce the number of reactive astrocytes. Lesion-recognizing NPs have a positive effect on regulating the phase of neurons and astrocytes, which results in better restoration of memory deficits in 3 × Tg-AD mice. Therefore, this work provides a promising platform for neurodegenerative disease treatment.

Preferential Regulation of Γ-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease.

A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains ß-amyloid peptides (Aß). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aß processing is rarely known. Aß levels are detected by using Immunohistochemistry (IHC) and enzyme-linked immune-sorbent assay (ELISA). Cryo-electron microscopy (Cryo-EM) is used to determine the structure of γ-secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ-secretase structure and specifically accelerates γ-secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N-terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aß generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ-secretase activity and the pathogenesis of AD.

The citrus flavonoid "Nobiletin" impedes STZ-induced Alzheimer's disease in a mouse model through regulating autophagy mastered by SIRT1/FoxO3a mechanism.

The prominence of autophagy in the modulation of neurodegenerative disorders has sparked interest to investigate its stimulation in Alzheimer's disease (AD). Nobiletin possesses several bioactivities such as anti-inflammation, antioxidation, and neuroprotection. Consequently, the study's aim was to inspect the possible neurotherapeutic impact of Nobiletin in damping AD through autophagy regulation. Mice were randomly assigned into: Group I which received DMSO, Groups II, III, and IV obtained STZ (3 mg/kg) intracerebroventricularly once with Nobiletin (50 mg/kg/day; i.p.) in Group III and Nobiletin with EX-527 (2 mg/kg, i.p.) in Group IV. Interestingly, Nobiletin ameliorated STZ-induced AD through enhancing the motor performance and repressing memory defects. Moreover, Nobiletin de-escalated hippocampal acetylcholinesterase (AChE) activity and enhanced acetylcholine level while halting BACE1 and amyloid-ß levels. Meanwhile, Nobiletin stimulated the autophagy process through activating the SIRT1/FoxO3a, LC3B-II, and ATG7 pathway. Additionally, Nobiletin inhibited Akt pathway and controlled the level of NF-κB and TNF-α. Nobiletin amended the oxidative stress through enhancing GSH and cutting down MDA levels. However, EX527, SIRT1 inhibitor, counteracted the neurotherapeutic effects of Nobiletin. Therefore, the present study provides a strong verification for the therapeutic influence of Nobiletin in AD. This outcome may be assigned to autophagy stimulation through SIRT1/FoxO3a, inhibiting AChE activity, reducing neuroinflammation and oxidative stress.

γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.

Zinc Ortho Methyl Carbonodithioate Improved Pre and Post-Synapse Memory Impairment via SIRT1/p-JNK Pathway against Scopolamine in Adult Mice.

Alzheimer's disease (AD) is globally recognized as a prominent cause of dementia for which efficient treatment is still lacking. New candidate compounds that are biologically potent are regularly tested. We, therefore, hypothesized to study the neuroprotective potential of Zinc Ortho Methyl Carbonodithioate (thereafter called ZOMEC) against Scopolamine (SCOP) induced Alzheimer's disease (AD) model using adult albino mice. We post-administered ZOMEC (30 mg/Kg) into two group of mice for three weeks on daily basis that received either 0.9% saline or SCOP (1 mg/Kg) for initial two weeks. The other two groups of mice received 0.9% saline and SCOP (1 mg/Kg) respectively. After memory related behavioral analysis the brain homogenates were evaluated for the antioxidant potential of ZOMEC and multiple protein markers were examined through western blotting. Our results provide enough evidences that ZOMEC decrease oxidative stress by increasing catalase (CAT) and glutathione S transferase (GST) and decreasing the lipid peroxidation (LPO). The SIRT1 and pre and post synaptic marker proteins, synaptophysin (SYP) as well as post synaptic density protein (PSD-95) expression were also enhanced upon ZOMEC treatment. Furthermore, memory impairment was rescued and ZOMEC appreciably abrogated the Aß accumulation, BACE1 expression C and the p-JNK pathway. The inflammatory protein markers, NF-kß and IL-1ß in ZOMEC treated mice were also comparable with control group. The predicted interaction of ZOMEC with SIRT1 was further confirmed by molecular docking. These findings thus provide initial reports on efficacy of ZOMEC in SCOP induced AD model.

High throughput and targeted screens for prepilin peptidase inhibitors do not identify common inhibitors of eukaryotic gamma-secretase.

INTRODUCTION: Prepilin peptidases (PPP) are essential enzymes for the biogenesis of important virulence factors, such as type IV pili (T4P), type II secretion systems, and other T4P-related systems of bacteria and archaea. PPP inhibitors could be valuable pharmaceuticals, but only a few have been reported. Interestingly, PPP share similarities with presenilin enzymes from the gamma-secretase protease complex, which are linked to Alzheimer's disease. Numerous gamma-secretase inhibitors have been reported, and some have entered clinical trials, but none has been tested against PPP. OBJECTIVE: The objective of this study is to develop a high-throughput screening (HTS) method to search for inhibitors of PPP from various chemical libraries and reported gamma-secretase inhibitors. METHOD: More than 15,000 diverse compounds, including 13 reported gamma-secretase inhibitors and other reported peptidase inhibitors, were screened to identify potential PPP inhibitors. RESULTS: The authors developed a novel screening method and screened 15,869 compounds. However, the screening did not identify a PPP inhibitor. Nevertheless, the study suggests that gamma-secretase is sufficiently different from PPP that specific inhibitors may exist in a larger chemical space. CONCLUSION: The authors believe that the HTS method that they describe has numerous advantages and encourage others to consider its application in the search for PPP inhibitors.

Gamma secretase inhibition: Effects on fertility and embryo-fetal development in rats.

Avagacestat inhibits γ-secretase, a protease that cleaves the amyloid precursor protein (APP) to produce amyloid beta (Aß). Aß plaques, a predominant lesion in Alzheimer's patient's brain, is considered a mechanism driving neurodegeneration. As part of the nonclinical reproductive safety assessment, avagacestat effects on fertility and early embryonic development and embryo-fetal development were evaluated in rats. In the embryo-fetal development study, avagacestat was a selective developmental toxicant with dose-related increased fetal mortality, decreased fetal growth, and increased fetal malformations and variations (primarily affecting the axial and appendicular skeletal system) at ≥3 mg/kg/day. In the female fertility and early embryonic development study, avagacestat-related reductions in female fecundity at ≥5 mg/kg/day were attributed to impaired ovarian follicular development that was reflected in dose-dependent reductions in implantation sites, litter size, and gravid uterine weights. In the male fertility and early embryonic development study, avagacestat-related effects on reproduction could not be fully assessed because of low systemic exposures achieved due to extensive metabolism and clearance of the drug. The results obtained in these studies were consistent with pharmacologically mediated inhibition of γ-secretase and resulting inhibition of Notch processing and signaling that are key for embryonic development and ovary folliculogenesis. These findings are not considered a risk for late-onset AD where the patient population is ≥65 years old most with women who are post-menopausal. However, for treatment of early onset AD with a younger patient population, there are risks for reproductive or developmental toxicities with treatment with gamma secretase inhibitors like avagacestat.

Vitamin D alleviates cognitive dysfunction and brain damage induced by copper sulfate intake in experimental rats: focus on its combination with donepezil.

This study aimed to demonstrate the potential benefits of donepezil (DPZ) and vitamin D (Vit D) in combination to counteract the neurodegenerative disorders induced by CuSO4 intake in experimental rats. Neurodegeneration (Alzheimer-like) was induced in twenty-four male Wistar albino rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. AD rats were divided into four groups: untreated AD group (Cu-AD) and three treated AD groups; orally treated for 4 weeks with either DPZ (10 mg/kg/day), Vit D (500 IU/kg/day), or DPZ + Vit D starting from the 10th week of CuSO4 intake. Another six rats were used as normal control (NC) group. The hippocampal tissue content of ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 and the cortical content of acetylcholine (Ach), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured. Cognitive function tests (Y-maze) and histopathology studies (hematoxylin and eosin and Congo red stains) and immunohistochemistry for neurofilament. Vit D supplementation alleviated CuSO4-induced memory deficits including significant reduction hippocampal BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α and cortical AChE and MDA. Vit D remarkably increased cortical Ach, TAC, and hippocampal Bcl-2. It also improved neurobehavioral and histological abnormalities. The effects attained by Vit D treatment were better than those attained by DPZ. Furthermore, Vit D boosted the therapeutic potential of DPZ in almost all AD associated behavioral and pathological changes. Vit D is suggested as a potential therapy to retard neurodegeneration.

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Repurposing of phyto-ligand molecules from the honey bee products for Alzheimer's disease as novel inhibitors of BACE-1: small molecule bioinformatics strategies as amyloid-based therapy.

Alzheimer's disease (AD) is one of the neurodegenerative diseases, manifesting dementia, spatial disorientation, language, cognitive, and functional impairment, mainly affects the elderly population with a growing concern about the financial burden on society. Repurposing can improve the traditional progress of drug design applications and could speed up the identification of innovative remedies for AD. The pursuit of potent anti-BACE-1 drugs for AD treatment has become a pot boiler topic in the recent past and to instigate the design of novel improved inhibitors from the bee products. Drug-likeness characteristics (ADMET: absorption, distribution, metabolism, excretion, and toxicity), docking (AutoDock Vina), simulation (GROMACS), and free energy interaction (MM-PBSA, molecular mechanics Poisson-Boltzmann surface area) analyses were performed to identify the lead candidates from the bee products (500 bioactives from the honey, royal jelly, propolis, bee bread, bee wax, and bee venom) for Alzheimer's disease as novel inhibitors of BACE-1 (beta-site amyloid precursor protein cleaving enzyme (1) receptor using appropriate bioinformatics tools. Forty-four bioactive lead compounds were screened from the bee products through high throughput virtual screening on the basis of their pharmacokinetic and pharmacodynamics characteristics, showing favorable intestinal and oral absorption, bioavailability, blood brain barrier penetration, less skin permeability, and no inhibition of cytochrome P450 inhibitors. The docking score of the forty-four ligand molecules was found to be between -4 and -10.3 kcal/mol, respectively, exhibiting strong binding affinity to BACE1 receptor. The highest binding affinity was observed in the rutin (-10.3 kcal/mol), 3,4-dicaffeoylquinic acid (-9.5 kcal/mol), nemorosone (-9.5 kcal/mol), and luteolin (-8.9 kcal/mol). Furthermore, these compounds demonstrated high total binding energy -73.20 to -105.85 kJ/mol), and low root mean square deviation (0.194-0.202 nm), root mean square fluctuation (0.0985-0.1136 nm), radius of gyration (2.12 nm), number of H-bonds (0.778-5.436), and eigenvector values (2.39-3.54 nm2) in the molecular dynamic simulation, signifying restricted motion of Cα atoms, proper folding and flexibility, and highly stable with compact of the BACE1 receptor with the ligands. Docking and simulation studies concluded that rutin, 3,4-dicaffeoylquinic acid, nemorosone, and luteolin are plausibly used as novel inhibitors of BACE1 to combat AD, but further in-depth experimental investigations are warranted to prove these in silico findings.

BACE1 Aptamer-Modified Tetrahedral Framework Nucleic Acid to Treat Alzheimer's Disease in an APP-PS1 Animal Model.

Alzheimer's disease is a neurodegenerative disease caused by excessive amyloid ß protein-induced neurotoxicity. However, drugs targeting amyloid ß protein production face many problems, such as the low utilization rate of drugs by cells and the difficulty of drugs in penetrating the blood-brain barrier. A tetrahedral framework nucleic acid is a new type of nanonucleic acid structure that functions as a therapy and drug carrier. Here, we synthesized a BACE1 aptamer-modified tetrahedral framework nucleic acid and tested its therapeutic effect on Alzheimer's disease in vitro and in vivo. Our results demonstrated that the tetrahedral framework nucleic acid could be used as a carrier to deliver the BACE1 aptamer to the brain to reduce the production of amyloid ß proteins. It also played an antiapoptotic role by reducing the production of reactive oxygen species. Thus, this nanomaterial is a potential drug for Alzheimer's disease.

Differential neuroprotective effect of curcuminoid formulations in aluminum chloride-induced Alzheimer's disease.

Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1ß, acetylcholinesterase, and ß-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways.

Current management and recent progress in desmoid tumors.

Desmoid tumors are rare soft tissue tumors that can have aggressive infiltrative growth and relapse locally. Desmoid tumors can impact functionality and cause treatment-related morbidity and mortality. Here, the authors review current management strategies and avenues for further investigation. As part of the evolution of therapy away from primary surgical approaches to less invasive options, image-guided ablation has been accepted as less morbid and include cryoablation and high-intensity focused ultrasound. Systemic therapy options currently include hormonal agents, nonsteroidal anti-inflammatory drugs, tyrosine kinase inhibitors, and anthracycline-based regimens. Hormonal agents and nonsteroidal anti-inflammatory drugs have benign side effect profiles but generally limited efficacy. Anthracycline-based therapies are limited by the risk of secondary malignancies and cardiomyopathy. Tyrosine kinase inhibitors are well studied, and sorafenib is now one of the most utilized therapies, though limited by its side effect profile. Nirogacestat (PF-0308401) is an investigational small molecule gamma-secretase (GS) inhibitor that has demonstrated efficacy in phase 1 and II trials. A phase III trial investigating patients with desmoid tumors or aggressive fibromatosis is estimated to be completed December 2021 (NCT03785964). In addition to nirogacestat, the gamma-secretase inhibitor AL102 is being investigated for the treatment of patients with progressing desmoid tumors in the phase II/III RINGSIDE trial. Finally, the beta-catenin inhibitor Tegavivint (BC2059) is being investigated in a phase 1 open-label trial in patients with a proven primary or recurrent desmoid tumor that is unresectable and symptomatic or progressive.

Regulatory Effect of Adipose-Derived Mesenchymal Stem Cells and/ or Acitretin on Adam10 Gene in Alzheimer's Disease Rat Model.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by progressive cognitive deterioration. All recent therapeutic strategies tend to inhibit the generation of the Aß peptide. These approaches tend to mediate both α - and γ -secretases to undergo the nonamyloidogenic pathway. ADAM10 is the main α-secretase that cleaves APP, and it is regulated by the metabolic product of vitamin A (retinoic acid), which is being widely used recently in AD research as a target for treatment. Mesenchymal stem cells (MSCs) are also used recently as a promising regenerative therapy for AD. OBJECTIVES: The present study aimed to: (1) study the effect of MSCs with/without acitretin on the regulation of Adam10 gene expression in AlCl3-induced AD rat model, and (2) validate the hypothesis that AD is a time-dependent progressive disease that spreads spontaneously even after the stopping of exposure to AlCl3. METHODS: The experimental work has been designed to include three successive phases; AlCl3 induction phase (I), AlCl3 withdrawal phase (W), and therapeutic phase (T). Forty-five male albino Wistar rats were randomly divided into 2 main groups: the control (C) group (15 rats) and AD group (30 rats). The therapeutic potential of MSCs with/without acitretin has been evaluated at behavioral, physiological, molecular, and histopathological levels. RESULTS: Among the three therapeutic groups, combined administration of both MSC and acitretin showed the best compensatory effects on most of the measured parameters. CONCLUSION: The present study approved that AD is a time-dependent progressive disease which spreads spontaneously without more AlCl3 exposure.

Brain-Penetration and Neuron-Targeting DNA Nanoflowers Co-Delivering miR-124 and Rutin for Synergistic Therapy of Alzheimer's Disease.

Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid ß generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.