Lipoprotein-Inspired Nanoscavenger for the Three-Pronged Modulation of Microglia-Derived Neuroinflammation in Alzheimer's Disease Therapy.

The inflammatory dysfunction of microglia from excess amyloid-ß peptide (Aß) disposal is an overlooked but pathogenic event in Alzheimer's disease (AD). Here, we exploit a native high-density lipoprotein (HDL)-inspired nanoscavenger (pHDL/Cur-siBACE1) that combines the trinity of phosphatidic acid-functionalized HDL (pHDL), curcumin (Cur), and ß-site APP cleavage enzyme 1 targeted siRNA (siBACE1) to modulate microglial dysfunction. By mimicking the natural lipoprotein transport route, pHDL can penetrate the blood-brain barrier and sequentially target Aß plaque, where Aß catabolism is accelerated without microglial dysfunction. The benefit results are from a three-pronged modulation strategy, including promoted Aß clearance with an antibody-like Aß binding affinity, normalized microglial dysfunction by blocking the NF-κB pathway, and reduced Aß production by gene silence (44%). After treatment, the memory deficit and neuroinflammation of APPswe/PSEN 1dE9 mice are reversed. Collectively, this study highlights the double-edged sword role of microglia and provides a promising tactic for modulating microglial dysfunction in AD treatment.

Efficacy and safety of probiotics in irritable bowel syndrome: A systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disease characterized by abdominal pain, distension, and altered bowel habits. Probiotics may alleviate IBS symptoms, but clinical trials remain conflicting. AIMS: To conduct a systematic review and meta-analysis of clinical trials to evaluate the efficacy and safety of probiotics for IBS patients. METHODS: We searched relevant trials in PubMed, Web of Science, Embase, Cochrane Library, and Google Scholar from 2000 to June 2023. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated for continuous outcomes. A risk ratio (RR) and a 95% CI were calculated for dichotomous outcomes. RESULTS: A total of 20 studies involving 3011 patients were obtained. The results demonstrated that probiotics are more effective than placebo in reducing global IBS symptoms improvement rate (RR = 1.401, 95% CI 1.182-1.662, P < 0.001) and quality of life scores (SMD = 0.286, 95% CI = 0.154-0.418, P < 0.001). Subgroup analyses showed that a shorter treatment time (less than eight weeks) could reduce distension scores (SMD = 0.197, 95% CI = 0.038-0.356, P = 0.015). High doses (daily dose of probiotics ≥ 10ˆ10) or multiple strains of probiotics exhibit beneficial effects on abdominal pain (SMD = 0.412, 95% CI = 0.112-0.711, P = 0.007; SMD = 0.590, 95% CI = 0.050-1.129, P = 0.032; respectively). However, there was no significant benefit on global symptom scores (SMD = 0.387, 95% CI 0.122 to 0.653, P = 0.004) with statistically high inter-study heterogeneity (I2 = 91.9%, P < 0.001). Furthermore, there was no significant inter-group difference in terms of adverse events frequency (RR = 0.997, 95% CI 0.845-1.177, P = 0.973). CONCLUSION: Probiotics are effective and safe for IBS patients. High doses or multiple probiotic strains seem preferable, but definite conclusions are challenging due to the high heterogeneity. Large-scale, well-designed, and rigorous trials are needed to confirm their effectiveness.

Tumor-oriented mathematical models in hydrogel regulation for precise topical administration regimens.

Increasing knowledge of drug delivery properties, tumor profiles and their relationship promotes precise administration regimens, representing a promising pattern to personalized tumor treatment. Herein, we propose a regulatory hydrogel depot toward metastatic cancer by establishing mathematical models between tumor characteristics and administration regimens. Specifically, a thermo-sensitive PLGA-PEG-PLGA polymer is introduced as injectable hydrogel matrix, of which the administration volume and frequency are manipulated elaborately according to tumor size and gel-degradation kinetics. Structurally, doxorubicin (Dox) and arginine-terminated nanoparticles containing KIAA1199 specific shRNA (shKIAARPDNs) are incorporated into hydrogels, thereby formulating a topical and sustained drug depot to achieve synergy treatment. For dual-targeting therapy, Dox interdicts DNA replication/transcription, and shKIAA persistently silences KIAA1199 protein to modulate aggressive phenotypes. After individual peritumoral injection, Gel/shKIAARPDNs/Dox demonstrates desirable distribution patterns and gel degradation kinetics with enhanced tumor penetration. Moreover, a preferable inhibition of tumor proliferation and metastasis is confirmed after twice treatment in 12 days, indicating better therapeutic efficacy with less dosage and frequency. Consequently, the controllable administration regimen inspired mathematical models of thermosensitive hydrogel provides an intelligent platform for personalized treatment to metastatic cancer.

A machine learning methodology for reliability evaluation of complex chemical production systems.

System reliability evaluation is very important for safe operation and sustainable development of complex chemical production systems. This paper proposes a hybrid model for the reliability evaluation of chemical production systems. First, the influential factors in system reliability are categorized into five aspects: Man, Machine, Material, Management and Environment (4M1E), each of which represents a component subsystem of a complex chemical production process. Second, the Support Vector Machine (SVM) algorithm is used to develop machine learning models for the reliability evaluation of each subsystem, during which Particle Swarm Optimization (PSO) is applied for model parameter optimization. Third, the Random Forest (RF) algorithm is employed to correlate the reliability of the five subsystems with the reliability of the corresponding whole chemical production system. Then, Markov Chain Residual error Correction (MCRC) is adopted to improve the predictive accuracy of the machine learning model. The efficacy of the proposed hybrid model is tested on a case study, and the results indicate that the proposed model is capable of delivering satisfactory prediction results.

Reassembly of native components with donepezil to execute dual-missions in Alzheimer's disease therapy.

Alzheimer's disease (AD) is a multifaceted and progressive neurodegenerative disease characterized by accumulation of amyloid-beta (Aß) and deficits of acetylcholine. Accordingly, the intra-/extra-cerebral level of high density lipoprotein (HDL) is crucial on the pathogenesis of AD; and most of all, various HDL-protein subtypes play a double-edged role in AD pathology, of which apolipoprotein A-I (apoA-I) gives protective outcomes. Inspired from "HDL bionics", we proposed biologically reassembled nanodrugs, donepezil-loaded apolipoprotein A-I-reconstituted HDL (rHDL/Do) that concurrently executed dual-missions of Aß-targeting clearance and acetylcholinesterase (AChE) inhibition in AD therapy. Once prepared, rHDL/Do nanodrug achieved high drug encapsulation efficiency of 90.47%, and mimicked the configurations and properties of natural lipoproteins aiming to significantly enhance BBB penetration and modulate Aß-induced neuronal damage both in vitro and in vivo. Surface plasmon resonance (SPR) analysis confirmed that rHDL/Do facilitated microglial-mediated Aß intake and degradation, demonstrating low KD value with Aß affinity (2.45 × 10-8 of Aß monomer and 2.78 × 10-8 of Aß oligomer). In AD animal models, daily treatment of rHDL/Do efficiently inhibited AChE activity, ameliorated neurologic variation, promoted Aß clearance, and rescued memory loss at a safe level. The collective findings indicated that the biological nanodrug was provided with the capacities of BBB penetration, Aß capture and degradation via microglial cells, and cholinergic dysfunction amelioration after controlled donepezil release. In summary, rHDL/Do nanodrugs could offer a promising strategy to synergize both symptom control and disease modification in AD therapy.

Immune lipoprotein nanostructures inspired relay drug delivery for amplifying antitumor efficiency.

Chemo-immunotherapy represents an appealing approach to improving cancer treatment. Simultaneously administrating chemotherapeutics with immunoadjuvants can elicit potent tumor death and immune responses. Herein, high density lipoprotein (HDL) inspired immune lipoprotein was proposed for relay drug delivery and amplifying antitumor therapy. Lipophilic AS1411 aptamer-immunoadjuvant CpG fused sequences (Apt-CpG-DSPE) were conjugated to facilitate decoration onto HDLs; and doxorubicin (Dox) was successively intercalated into the consecutive base pairs of Apt-CpG to complete immune HDL nanodrug imHDL/Apt-CpG-Dox. For relay drug delivery, imHDL/Apt-CpG-Dox underwent site-specific structure collapse in tumor intercellular substances inspired from HDL biofunctions (sequential module I); subsequently, dissociated Apt-CpG-Dox was endocytosed into tumor cells mediated by the recognition of AS1411 and nucleolin (sequential module II), translocating Dox to nucleus and enabling tumor ablation and antigens release. The liberated CpG motif further evoked antigen recognition, induced vast secretion of pro-inflammatory cytokines and potentiated host antitumor immunity. Our studies demonstrated that HDL biomimetic platform based relay drug delivery strategy outperformed the monotherapy counterparts in malignant tumor models, eventually generating an augmented antitumor efficacy.