In Situ Self-Assembled Phytopolyphenol-Coordinated Intelligent Nanotherapeutics for Multipronged Management of Ferroptosis-Driven Alzheimer's Disease.

Ferroptosis is a vital driver of pathophysiological consequences of Alzheimer's disease (AD). High-efficiency pharmacological inhibition of ferroptosis requires comprehensive coordination of diverse abnormal intracellular events, which is an urgent problem and great challenge for its application in AD treatment. Herein, a triphenylphosphonium-modified quercetin-derived smart nanomedicine (TQCN) is developed for multipronged anti-ferroptosis therapy in AD. Taking advantage of the favorable brain-targeting and mitochondria-locating properties, TQCN can efficiently chelate iron through phytopolyphenol-mediated spontaneous coordination and self-assemble into metal-phenolic nanocomplexes in situ, exerting escalating exogenous offensive effects to attenuate iron overload and its induced free radical burst. Meanwhile, the Nrf2 signaling-mediated endogenous defensive system is reconstituted to restore iron metabolism homeostasis represented by iron export and storage and enhance cytoprotective antioxidant cascades represented by lipid peroxidation detoxification. Benefiting from the multifaceted regulation of pathogenic processes triggering ferroptosis, TQCN treatment can ameliorate various neurodegenerative manifestations associated with brain iron deposition and rescue severe cognitive decline in AD mice. This work displays great promise of in situ self-assembled phytopolyphenol-coordinated intelligent nanotherapeutics as advanced candidates against ferroptosis-driven AD progression.

mTOR-Mediated Immunometabolic Reprogramming Nanomodulators Enable Sensitive Switching of Energy Deprivation-Induced Microglial Polarization for Alzheimer's Disease Management.

Metabolic reprogramming that senses brain homeostasis imbalances is necessary to drive detrimental microglial polarization, and specific targeting of this process contributes to the flexible control of pathological inflammatory responses in Alzheimer's disease (AD), displaying distinctive therapeutic benefits. Herein, glutathione-functionalized gold nanocages loaded with the immunosuppressant fingolimod hydrochloride are developed as brain-targeted and microglia-located immunometabolic reprogramming nanomodulators (GAF NPs) for AD management. By virtue of glutathione-mediated transport properties, this nanomodulator can cross the blood-brain barrier and localize to microglia in AD lesions. Through blocking Akt/mTOR/HIF-1α signaling pathways, GAF NPs not only promote the dominated metabolic shift from glycolysis to oxidative phosphorylation under immune activation but also inhibit transporter-mediated glucose overconsumption by microglia. Correlation analysis based on real-time bioenergetic assessment and 18F-labeled fluorodeoxyglucose (FDG) PET reveals that brain glucose utilization and metabolism restored by GAF NP treatment can serve as a sensitive and effective indicator for microglial M1 to M2 polarization switching, ultimately alleviating neuroinflammation and its derived neurodegeneration as well as ameliorating cognitive decline in AD mice. This work highlights a potential nanomedicine aimed at modifying mTOR-mediated immunometabolic reprogramming to halt energy deprivation-induced AD progression.

Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer's disease by neurotoxin neutralization and immune recognition suppression.

Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote (OT-Lipo@M) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow OT-Lipo@M with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, OT-Lipo@M exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.

Targeting Emerging Pathogenic Mechanisms by Natural Molecules as Potential Therapeutics for Neurodegenerative Diseases.

Natural molecules with favorable safety profile and broad pharmacological activities have shown great promise in the treatment of various neurodegenerative diseases (NDDs). Current studies applying natural molecules against NDDs mainly focus on well-recognized conventional pathogenesis, such as toxic protein aggregation, oxidative stress, and neuroinflammation. However, accumulating evidence reveals that some underlying pathogenic mechanisms are involved earlier and more deeply in the occurrence and development of NDDs, such as ferroptosis, energy metabolism disorders, autophagy-lysosomal dysfunction, endoplasmic reticulum stress, and gut dysbiosis. Therefore, determining whether natural molecules can play therapeutic roles in these emerging pathogenic mechanisms will help clarify the actual targets of natural molecules and their future clinical translation. Furthermore, how to overcome the inability of most poorly water-soluble natural molecules to cross the blood-brain barrier is also critical for effective NDD treatment. This review summarizes emerging pathogenic mechanisms targeted by natural molecules for NDD treatment, proposes nanocarrier-based drug delivery and intranasal administration to enhance the intracerebral bioavailability of natural molecules, and summarizes the current state of clinical research on natural product-based therapeutics.

A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer's disease (AD). Here, we design a dual-targeted Prussian blue nanoformulation (PTCN) that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects. An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages. The results show that PTCN could effectively ameliorate AD-related pathological processes, improve the cognitive decline, and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials. Altogether, PTCN provided here is a successful combination of three traditional biomaterials with good biosafety, which has broad prospects for the early prevention, mild remission, and late treatment of AD, and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.

Natural Phyto-Antioxidant Albumin Nanoagents to Treat Advanced Alzheimer's Disease.

Phytotherapeutic approaches are of immense value in the treatment of advanced Alzheimer's disease (AD) because of their diverse biological components and potential multitarget mechanisms. In this study, quercetin, a natural neuroprotective flavonoid, was encapsulated in human serum albumin to obtain HSA@QC nanoparticles (HQ NPs) as a natural phyto-antioxidant albumin nanoagent for the treatment of advanced AD. HQ NPs showed excellent antioxidant effects and protected PC12 cells from H2O2-induced oxidative damage. The intranasal administration of HQ NPs in 11-month-old APP/PS1 mice, which represented advanced AD, effectively prevented the loss of body weight, increased survival rates, and significantly reduced oxidative stress, Aß aggregation, neuronal apoptosis, and synaptic damage in the brain. It also ultimately reversed severely impaired cognitive function. In addition to their favorable anti-AD effects, HQ NPs exhibited excellent biosafety and biocompatibility owing to their natural composition and are expected to become an ideal choice for future drug development and clinical applications.

Effects of resistance exercise on complications, cancer-related fatigue and quality of life in nasopharyngeal carcinoma patients undergoing chemoradiotherapy: A randomised controlled trial.

BACKGROUND: Chemotherapy of nasopharyngeal carcinoma (NPC) can lead to significant side effects and complications. Exercises during chemoradiotherapy have potential to reduce complications and fatigue and improve quality of life. The aim of the randomised clinical study was to investigate the benefits of resistance exercise during chemoradiotherapy in NPC patients. METHODS: A total of 146 patients were randomised to perform resistance or relaxation exercises during chemoradiotherapy. Resistance exercise consisted of eight machine-based progressive resistance exercises, and relaxation control consisted of progressive muscle relaxation. Side effects and complications were analysed, and fatigue was assessed by Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) scores. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ30) scale was used to evaluate the effects of resistance exercise or relaxation control on quality of life. Per-protocol analysis was performed on the collected data. RESULTS: Resistance exercise has stronger effects than relaxation in reducing complications, including oral mucositis, mouth-opening difficulties, xerostomia, hearing loss and nasal congestion, and alleviating both physical fatigue and mental fatigue. The improvement in quality of life was also more prominent among patients performing resistance exercise. CONCLUSIONS: For NPC patients undergoing chemoradiotherapy, resistance exercise has a better efficacy in reducing complications, alleviating fatigue and improving quality of life.

Long noncoding RNA SBF2-AS1 act as a ceRNA to modulate cell proliferation via binding with miR-188-5p in acute myeloid leukemia.

LncRNA SBF2-AS1 has been reported to be implicated in the deterioration of multiple human cancers. However, the roles and underlying mechanisms of SBF2-AS1 in acute myeloid leukemia (AML) are still unclear. In the present study, the online GEPIA database showed that SBF2-AS1 expression was significantly increased in AML samples. QRT-PCR results showed that SBF2-AS1 expression was upregulated in AML cells. CCK-8 assay revealed that SBF2-AS1 inhibition decreased AML cells proliferation ability in vitro. Flow cytometry assays showed that SBF2-AS1 inhibition induced AML cells apoptosis and arrested AML cells in G0/G1 phase. Mechanistically, miR-188-5p was identified as a direct target of SBF2-AS1. SBF2-AS1 upregulated the expression level of ZFP91 by sponging miR-188-5p. And the effects of SBF2-AS1 suppression on AML cells progression could be abolished by miR-188-5p inhibitors. Moreover, we found that SBF2-AS1 inhibition reduced tumor growth in vivo. Taken together, our findings elucidated that SBF2-AS1 could act as a miRNA sponge in AML progression, and provided a potential therapeutic strategy for AML treatment.

MicroRNA-203 inhibits the malignant progression of neuroblastoma by targeting Sam68.

Neuroblastoma (NB) is the most common solid extracranial tumor in children. However, the molecular mechanism of NB remains to be elucidated. In the present study, reverse transcription quantitative polymerase chain reaction data demonstrated that the expression of Sam68 was significantly upregulated in NB tissues compared with their matched adjacent normal tissues. Furthermore, it was revealed that reduced expression of miR­203 and increased expression of Sam68 co­existed in NB tissues. Knockdown of Sam68 reduced the proliferation, migration and invasion of human SK­N­SH and SH­SY5Y NB cells. Similarly, overexpression of miR­203 also inhibited the proliferation, migration and invasion of these two cell lines. It was further demonstrated that the protein expression level of Sam68 was negatively mediated by miR­203 in the SK­N­SH and SH­SY5Y NB cells. Additionally, data from a dual luciferase reporter assay confirmed that miR­203 directly targeted Sam68 by binding to its 3'­untranslated region. In conclusion, the present study suggested for the first time, to the best of our knowledge, that the aberrant downregulation of miR­203 may contribute to the aberrant upregulation of Sam68 in NB and that miR­203 has an inhibitory role in malignant progression of NB by targeting Sam68. The present study provided evidence to support miR-203/Sam68 as a novel diagnostic or therapeutic targets for NB.

[Serum levels of insulin-like growth factor-1 and growth factor binding protein-3 in children with acute lymphocytic leukemia].

OBJECTIVE: To study serum levels and clinical significance of insulin-like growth factor-1 (IGF-1) and growth factor binding protein 3 (IGFBP-3) in children with acute lymphocytic leukemia (ALL). METHODS: Serum samples were obtained from 36 children with ALL before treatment and 6 months after complete remission. Thirty children with surgical diseases severed as the control group. Serum IGF-1 levels were measured using radioimmunoassay (RIA). Serum IGFBP-3 levels were measured using immunoradioassays (IRMA). RESULTS: Serum levels of IGF-1 and IGFBP-3 in the ALL group were 19±4 ng/mL and 1216±132 ng/mL, respectively before treatment, which were lower than those in the control group (32±3 ng/mL and 2104±191 ng/mL respectively) (P<0.01). Serum levels of IGF-1 and IGFBP-3 in the ALL group increased to 30±3 ng/mL and 1941±164 ng/mL respectively 6 months after complete remission, which were significantly higher than those before treatment (P<0.01) and were similar to the levels of the control group. CONCLUSIONS: Serum levels of IGF-1 and IGFBP-3 are reduced in children with ALL, but increase significantly after complete remission, suggesting that IGF-1 and IGFBP-3 might serve as useful markers for the diagnosis and evaluation of therapeutic effects of childhood ALL.