Negative regulation of type I interferon signaling by integrin-linked kinase permits dengue virus replication.

Dengue virus (DENV) infection can induce life-threatening dengue hemorrhagic fever/dengue shock syndrome in infected patients. DENV is a threat to global health due to its growing numbers and incidence of infection in the last 50 years. During infection, DENV expresses ten structural and nonstructural proteins modulating cell responses to benefit viral replication. However, the lack of knowledge regarding the cellular proteins and their functions in enhancing DENV pathogenesis impedes the development of antiviral drugs and therapies against fatal DENV infection. Here, we identified that integrin-linked kinase (ILK) is a novel enhancing factor for DENV infection by suppressing type I interferon (IFN) responses. Mechanistically, ILK binds DENV NS1 and NS3, activates Akt and Erk, and induces NF-κB-driven suppressor of cytokine signaling 3 (SOCS3) expression. Elevated SOCS3 in DENV-infected cells inhibits phosphorylation of STAT1/2 and expression of interferon-stimulated genes (ISGs). Inhibiting ILK, Akt, or Erk activation abrogates SOCS3 expression. In DENV-infected mice, the treatment of an ILK inhibitor significantly reduces viral loads in the brains, disease severity, and mortality rate. Collectively, our results show that ILK is a potential therapeutic target against DENV infection.

Simvastatin induces pyroptosis via ROS/caspase-1/GSDMD pathway in colon cancer.

BACKGROUND: The outcome of patients with colon cancer is still unsatisfied nowadays. Simvastatin is a type of statins with anti-cancer activity, but its effect on colon cancer cells remains unclear. The present study is intended to determine the underlying mechanism of simvastatin in treatment of colon cancer. METHODS: The viability and pyroptosis rate of cells treated and untreated with simvastatin were analysed by CCK-8 and flow cytometry assays, respectively. We used DCFH-DA and flow cytometry to detect reactive oxygen species (ROS) production. Levels of pyroptosis markers were detected by western blotting analysis or immunofluorescence staining. Besides, the anticancer properties of simvastatin on colon cancer were further demonstrated using a cell line based xenograft tumor model. RESULTS: Simvastatin treatment in HCT116 and SW620 induced pyroptosis and suppressed cell proliferation, with changes in the expression level of NLPR3, ASC, cleaved-caspase-1, mature IL-1ß, IL-18 and GSDMD-N. Moreover, inhibition of caspase-1 and ROS attenuated the effects of simvastatin on cancer cell viability. In addition, it was identified that simvastatin has an anti-tumor effect by down-regulating ROS production and inducing downstream caspase-1 dependent pyroptosis in the subcutaneous transplantation tumors of HCT116 cells in BALB/c nude mice. CONCLUSIONS: Our in vitro and in vivo results indicated that simvastatin induced pyroptosis through ROS/caspase-1/GSDMD pathway, thereby serving as a potential agent for colon cancer treatment. Video Abstract.

Dynamic analysis of circulating tumor DNA to predict prognosis and monitor therapeutic response in metastatic relapsed cervical cancer.

Limited and inefficient treatment options exist for metastatic relapsed cervical cancer (MRCC), and there are currently no reliable indicators to guide therapeutic selection. We performed deep sequencing analyses targeting 322 cancer-related genes in plasma cell-free DNA and matched white blood cells in 173 serial blood samples from 82 locally advanced CC (LACC) or MRCC patients and when possible during treatment. We identified five notable nonsynonymous mutant genes (PIK3CA, BRAF, GNA11, FBXW7 and CDH1) in the MRCC samples as the metastatic relapse significantly mutated (MSG) genes and found that MRCC patients with any detectable MSG mutations had significantly shorter progression-free survival (PFS) (P = .005) and overall survival (OS) (P = .007) times than those without detectable MSG mutations. Additionally, analyses of matched prechemotherapy and postchemotherapy plasma revealed that a reduction in the number of MSG mutations after chemotherapy was significantly associated with partial remission (PR) and stable disease (SD) (P = .007). Among the patients included in the longitudinal tracking ctDNA analysis, an increase in MSG mutations was observed earlier in response to disease progression than radiological imaging. Our results outline the mutation profiles of MRCC. We show how longitudinal monitoring with ctDNA in liquid biopsy samples provides both predictive and prognostic information during treatment.

Weakening Investigation of Reservoir Rock by Coupled Uniaxial Compression, Computed Tomography and Digital Image Correlation Methods: A Case Study.

Cyclic wetting and drying treatment is commonly used to accelerate the weakening process of reservoir rock. The weakening is reflected in strength variation and structure variation, while the latter receives less attention. Based on a series of cyclic wetting and drying tests, this study tentatively applied the uniaxial compressive test, computed tomography (CT) test and digital image correlation (DIC) test to investigate the weakening of slate in a reservoir area. Test results show that the weakening is mainly reflected in the reduction of compressive strength, followed by the decrease of ability to resist cracking and elastic deformation. The weakening seems more likely to be caused by structure variation rather than composition change. Two failure modes, e.g., splitting and splitting-tension, are concluded based on the crack paths: the splitting failure mode occurs in the highly weathered samples and the splitting-tension failure mode appears in the low-weathered samples. The transition zones of deformation are inside samples. The nephogram maps quantify the continuous deformation and correspond to the aforementioned structure variation process. This study offers comprehensive methods to the weakening investigation of slate in reservoir area and may provide qualitative reference in the stability evaluation of related slate rock slope.

Experimental Investigation of the Physical Properties and Microstructure of Slate under Wetting and Drying Cycles Using Micro-CT and Ultrasonic Wave Velocity Tests.

Cyclic wetting and drying processes have been considered as important factors that accelerate the weathering process and have deteriorative effects on rock properties. In the present study, a fully nondestructive and noninvasive testing approach utilizing micro-CT and ultrasonic wave velocity tests was employed to investigate the microstructure of slate under wetting and drying cycles. We studied variations in the physical properties, including the dry weight and the velocities of P- and S-waves versus the number of wetting and drying cycles. The internal microstructural distributions were visualized and quantified by the 3D reconstruction and hybrid image segmentation of CT images. The degree of deterioration caused by wetting and drying cycles was reflected by exponential decreases of physical properties, including dry weight and velocities of the P- and S-waves. Parameters relating to the microfracture diameter, volume, etc. were quantified. The nondestructive and noninvasive testing approach utilizing micro-CT and ultrasonic wave velocity tests has potential for the detection and visualization of the internal microstructure of rock under wetting and drying cycles.

Size Distribution of Nanoparticles in Solution Characterized by Combining Resonance Light Scattering Correlation Spectroscopy with the Maximum Entropy Method.

A single-nanoparticle detection method is reported for characterizing the size distribution of noble metal nanoparticles in solution by combining resonance light scattering correlation spectroscopy (RLSCS) with the maximum entropy method (MEM). The principle of RLSCS is based on the autocorrelation analysis of the resonance light scattering (RLS) fluctuations due to Brownian motion of a single nanoparticle in a highly focused detection volume (less than 1.0 fL), which resembles fluorescence correlation spectroscopy (FCS). However, RLS intensity of nanoparticles such as gold nanoparticles (GNPs) is proportional to the sixth power of sizes according to the Mie theory, which is different from the optical properties of fluorescent molecules. Herein the present FCS theoretical model cannot be directly applied in RLSCS to characterize GNPs. In this study, we used GNPs as model samples and first established an RLSCS theoretical model for the size distribution of GNPs by using the maximum entropy method (MEM), which is called MEM-RLSCS. This model covers the contribution of single-particle brightness of GNPs to the MEM fitting process based on the Mie theory. Then we preformed computer simulations of this model. The simulated results documented that the model proposed was able to well describe the diffusion behaviors and size distribution of nanoparticles. We investigated the effects of certain factors such as size difference, the relative concentration, and single-particle brightness on the size distribution. Finally, we used the MEM-RLSCS for characterization of GNPs in solution, and the results obtained were in agreement with the size distribution of GNPs from transmission electron microscopy (TEM). This method is also suitable for characterization of other metal nanoparticles (such as silver nanoparticles) in solution and in situ study diffusion dynamics of nanoparticles in living cells.

Relative efficacy and safety of mesenchymal stem cells for osteoarthritis: a systematic review and meta-analysis of randomized controlled trials.

Introduction: The aim of this meta-analysis was to evaluate the efficacy and safety of mesenchymal stem cells (MSCs) for the treatment of knee osteoarthritis (OA). Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases were searched from inception to May 6, 2024 to identify randomized controlled trials that compared MSCs and placebo or other nonsurgical approaches for treating OA. Two investigators independently searched the literature and extracted data, and conventional meta-analyses were conducted with Review Manager 5.3. The outcomes included pain relief, functional improvement, and risk of adverse events (AEs). Results: A total of 18 articles were included. Overall, MSCs were superior to placebo in terms of relieving pain and improving function at the 12-month follow-up. However, the differences in treatment-related AEs were not significant. Conclusion: MSCs may relieving pain and improving function of OA. The limitations of this study include the high heterogeneity of the included studies. Additionally, the follow-up time in the included studies was relatively short, so more clinical trials are needed to predict the long-term efficacy and safety of MSCs. Systematic review registration: https://doi.org/10.17605/OSF.IO/5BT6E, identifier CRD42022354824.

let-7g sensitized liver cancer cells to 5-fluorouracil by downregulating ABCC10 expression.

Patients with advanced liver cancer may benefit from 5-fluorouracil (5-FU) therapy. However, most of them eventually faced drug resistance, resulting in a poor prognosis. The present study aims to explore the potential mechanism of let-7g/ABCC10 axis in the regulation of 5-FU resistance in liver cancer cells. Huh-7 cells were used to construct 5-FU resistant Huh-7/4X cells. CCK8, flow cytometry, and TUNEL staining were used to detect the characterization of Huh-7 cells and Huh-7/4X cells. Double luciferase report, PCR, and western blot analyses were used to detect the regulatory effects between let-7g and ABCC10. The levels of biomarkers related to cell cycle progression and apoptosis were detected by western blot assays. The role of let-7g in 5-FU sensitivity of liver cancer cells was evaluated in nude mice. Compared with LX-2 cells, the expression of let-7g was decreased in Hep3B, HepG2, Huh-7, and SK-Hep1 cells, with the lowest expression in Huh-7 cells. The sensitivity of Huh-7 cell to 5-FU was positively correlated with let-7g expression. Transfection of let-7g mimics inhibited the viability of Huh-7/4X cells by prolonging the G1 phase, with the downregulation of ABCC10, PCNA, Cyclin D1, and CDK4. Meanwhile, let-7g promoted apoptosis to increase 5-FU sensitivity of Huh-7/4X by downregulating ABCC10, Bcl-XL as well as upregulating Bax, C-caspase 3, and C-PARP. Dual-luciferase assay further confirmed that let-7g inhibited ABCC10 expression by binding to the ABCC10 3'-UTR region. Furthermore, let-7g increased the sensitivity of Huh-7/4X to 5-FU in vitro and in vivo, which can be reversed by ABCC10 overexpression. In conclusion, let-7g sensitized liver cancer cells to 5-FU by downregulating ABCC10 expression.

Defect-induced triple synergistic modulation in copper for superior electrochemical ammonia production across broad nitrate concentrations.

Nitrate can be electrochemically degraded to produce ammonia while treating sewage while it remains grand challenge to simultaneously realize high Faradaic efficiency and production rate over wide-range concentrations in real wastewater. Herein, we report the defect-rich Cu nanowire array electrode generated by in-situ electrochemical reduction, exhibiting superior performance in the electrochemical nitrate reduction reaction benefitting from the triple synergistic modulation. Notably, the defect-rich Cu nanowire array electrode delivers current density ranging from 50 to 1100 mA cm-2 across wide nitrate concentrations (1-100 mM) with Faradaic efficiency over 90%. Operando Synchrotron radiation Fourier Transform Infrared Spectroscopy and theoretical calculations revealed that the defective Cu sites can simultaneously enhance nitrate adsorption, promote water dissociation and suppress hydrogen evolution. A two-electrode system integrating nitrate reduction reaction in industrial wastewater with glycerol oxidation reaction achieves current density of 550 mA cm-2 at -1.4 V with 99.9% ammonia selectivity and 99.9% nitrate conversion with 100 h stability, demonstrating outstanding practicability.

Sensitive single particle method for characterizing rapid rotational and translational diffusion and aspect ratio of anisotropic nanoparticles and its application in immunoassays.

In this article, we reported a new and sensitive method for characterizing rapid rotational and translational diffusion of gold nanoparticles (GNPs) and gold nanorods (GNRs) by resonance light scattering correlation spectroscopy (RLSCS). The RLSCS is a new single nanoparticle method, and its principle is based on measuring the resonance light scattering fluctuations in a highly focused volume due to Brownian motion of single particles, which resembles fluorescence correlation spectroscopy (FCS). On the basis of the theory of FCS, we first developed a model for rotational and translational diffusion and aspect ratio of nanoparticles in the RLSCS system. Then, we investigated the effects of certain factors such as the wavelength of illumination light and viscosity of solution using GNPs and GNRs as model samples and discovered that the polarization anisotropy and the scattering light intensity of GNPs and GNRs were significantly dependent on the wavelengths of illumination light. Using the 632.8 nm He-Ne laser as a light source, which was close to the resonance scattering band, we successfully obtained the translational and rotational diffusion coefficients and aspect ratios of anisotropic nanoparticles by the RLSCS method. The results obtained by this new method were in good agreement with transmission electron microscopy and theoretical calculation. Furthermore, the homogeneous sandwich immunoreaction was investigated using the antibody-modified GNPs as the probes. The changes in translational diffusion behaviors and aspect ratios of GNPs in immunoreaction were observed by the RLSCS method. By these changes, we can develop a new homogeneous immunoassay. Our preliminary results illustrated that the RLSCS method was a powerful tool for characterizing rapid rotational and translational diffusion behaviors of anisotropic nanoparticles in solution. We believe that the RLSCS method exhibits the wide applications in biological science especially in vivo study on the interaction of nanoparticles and biomolecules.

An Automatic Method Framework for Personalized Knee Prosthetic Modeling Based on Kinematic Geometry.

The shape of a knee prosthesis has an important impact on the effect of total knee arthroplasty. Comparing to a standard common prosthesis, the personalized prosthesis has inherent advantages. However, how to construct a personalized knee prosthesis has not been studied deeply. In this paper, we present an automatic method framework of modeling personalized knee prostheses based on shape statistics and kinematic geometry. Firstly, the average healthy knee model is established through an unsupervised process. Secondly, the sTEA (Surgical Transecpicondylar Axis) is calculated, and the average healthy knee model is resized according to it. Thirdly, the resized model is used to simulate the knee's motion in a healthy state. Fourthly, according to the target patient's condition, an excising operation is simulated on both patient's knee model and the resized model to generate an initial knee prosthesis model. Finally, the initial prosthesis model is adjusted according to the simulated motion results. The average maximum error between the resized healthy knee model and the patient's own knee model is less than 2 mm, and the average maximum error between the motion simulation results and actual motion results is less than 3 mm. This framework can generate personalized knee prosthesis models according to the patient's different conditions, which makes up for the deficiencies of standard common prostheses.

Cancer susceptibility 18 positively regulates NUAK Family Kinase 1 expression to promote migration and invasion via sponging of miR-5586-5p in cervical cancer cells.

INTRODUCTION: Cervical squamous cell carcinoma (CESC) is the most common gynecological malignancy worldwide. Although the cancer susceptibility 18 (CASC18) gene was involved in the regulation of cancer biology, its specific role in CESC is not well characterized. METHODS: CASC18-related axis was predicted by bioinformatic analyses, and the competing endogenous RNA (ceRNA) interaction was further validated using quantitative real-time PCR, western blotting, RNA pulldown, and luciferase reporter assays. Transwell and wound healing assays were performed to verify the effect of CASC18 on SiHa and HeLa cell motility. RESULTS: We found that CASC18 was upregulated in CESC tissues. Moreover, interference with CASC18 attenuated NUAK1-mediated epithelial-mesenchymal transition (EMT) and thus suppressed cancer cell motility. Furthermore, the effects of CASC18 knockdown on CESC cells were partly rescued by transfection with the miR-5586-5p inhibitor. Additionally, our findings indicated that CASC18 acts as a ceRNA to enhance NUAK1 expression by sponging miR-5586-5p. CONCLUSION: Our study showed a novel CASC18/miR-5586-5p/NUAK1 ceRNA axis that could regulate cell invasion and migration by modulating EMT in CESC. These findings suggest that CASC18 may potentially serve as a novel therapeutic target in CESC treatment.

Hepatic inflammatory myofibroblastic tumor: A case report.

BACKGROUND: Hepatic inflammatory myofibroblastic tumor (HIMT) is a rare type of hepatic tumor. It is always misdiagnosed and mistreated because it is primarily found with no obvious specific manifestation, and its imaging findings are diverse. CASE SUMMARY: Here, we report a case of HIMT that was initially diagnosed as liver malignancy but was confirmed as HIMT by histopathology after hepatectomy. Mostly, HIMTs are infiltrated with plasma cells and stain positively for anaplastic lymphoma kinase on immunohistochemistry as well as for some other kinases. CONCLUSION: HIMT can be treated with single nonsteroidal anti-inflammatory drugs and without surgery when it is diagnosed accurately. Because the etiology of HIMT is unknown and the diagnosis is difficult, the pathogenesis and clinical process need to be further studied.

Overexpression of the lncRNA HOTAIRM1 promotes lenvatinib resistance by downregulating miR-34a and activating autophagy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. Despite pharmacological advances such as sorafenib and lenvatinib approval, responses are seen only in a limited fraction of HCCs, and the majority of HCC patients do not benefit from this treatment. In recent years, researchers have verified that the long noncoding RNAs (lncRNAs) impact the efficiency of lenvatinib and the prognosis of patients with HCC. MATERIALS AND METHODS: This work obtained gene expression profile from an Arraystar lncRNA microarray. Expression of HOTAIRM1, Beclin-1, and p62 in HCC was characterized in clinical HCC tissues of 24 patients with HCC. Overexpression and knockdown experiments were performed in HCC cells to examine the effects of the HOTAIRM1 on lenvatinib sensitivity. The interactions between HOTAIRM1, miR-34a and Beclin-1 were predicted according to GSEA and CNC network. The effects of HOTAIRM1, autophagy and lenvatinib on tumor inhibit were validated in orthotopic tumor-bearing nude mouse model. RESULTS: Lenvatinib-resistant HCC cell lines were established using the concentration gradient method. Data from an Arraystar lncRNA microarray indicated that HOTAIRM1, a specific lncRNA located in an evolutionarily highly conserved HOX gene cluster, was differentially expressed between lenvatinib-resistant HCC cells and their parental cells. Expression of HOTAIRM1 and Beclin-1 in HCC was characterized in clinical HCC tissues of 24 patients who have different sensitivity to lenvatinib. Knocking down of HOTAIRM1 decreased the autophagy level in lenvatinib-resistant HCC cells and increased their sensitivity to lenvatinib, especially when combined with autophagy inhibitors both in vitro and in vivo. Further study indicated that knocking down HOTAIRM1 in lenvatinib-resistant cell lines increased the level of miR-34a and inhibited the expression of Beclin-1 in Huh7-R and HepG2-R cells. Investigation according to GSEA and CNC network, lncRNA and nearby coding gene and lncRNA-miRNA analyses demonstrated that the resistance of HCC to lenvatinib was affected by the HOTAIRM1-miR-34a-Beclin-1 regulatory axis. CONCLUSION: HOTAIRM1 is an independent drug resistance factor which significantly associated with the efficacy of lenvatinib in HCC. HOTAIRM1 may downregulation of miR-34a and upregulation of Beclin-1, leading to activation of autophagy, thereby inducing lenvatinib resistance in HCC.

Methylprednisolone alleviates cognitive functions through the regulation of neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and linked to abnormal deposition of amyloid-ß (Aß), neurofibrillary tangles (NFTs), synaptic dysfunction, and neuroinflammation. Despite significant progress in unravelling the pathogenesis of AD, currently main therapeutic interventions is limited to symptomatic alleviation. Methylprednisolone (MP), a synthetic glucocorticoid, is recognized for its extensive anti-inflammatory properties. Our study assessed the neuroprotective effect of MP (25 mg/kg) administration to an Aß1-42-induced AD mouse model. Our findings demonstrate that MP treatment can ameliorate cognitive impairment in Aß1-42-induced AD mice and suppress microglial activation in the cortex and hippocampus. RNA-Sequencing analysis reveals that MP ultimately rescues cognitive dysfunction through improving the synapse function and inhibiting the immune and inflammatory processes. Our study suggests that MP could be a promising drug alternative for the treatment of AD, either alone or in combination with other existing drugs.

Gold nanoparticle-enzyme conjugates based FRET for highly sensitive determination of hydrogen peroxide, glucose and uric acid using tyramide reaction.

In this paper, we report a new strategy for highly sensitive determination of hydrogen peroxide, glucose and uric acid based on fluorescence resonance energy transfer (FRET) using gold nanoparticles (AuNPs) as energy acceptors. The principle is based on highly sensitive reaction of tetramethyl rhodamine (TMR) labeled tyramide and hydrogen peroxide catalysed by horseradish peroxidase (HRP), and the fluorescence spectrum of TMR (EX(max) 575 nm) partially overlaps with the visible absorption bands of AuNPs. We demonstrated an efficient FRET between tyramide labeled TMR (as energy donors) and HRP (BSA) conjugated AuNPs (as energy acceptors) due to the formation of TMR-labeled HRP-AuNPs or TMR-labeled BSA-AuNPs in the presence of H(2)O(2). We observed that the quenching of the fluorescence signal depended linearly on the H(2)O(2) concentration within a range of concentrations from 25 to 400 nM and the detection limit of this assay was 10 nM. Based on the principle for determination of H(2)O(2), we developed a new strategy for assay of glucose and uric acid by coupling with glucose oxidase (GOx)-mediated and uricase-mediated reaction. The established methods were successfully used for determination of glucose and uric acid levels in human sera, and the results obtained are in good agreement with commercially available methods. Our methods are at least 1 order of magnitude more sensitive than the commercially available methods. More importantly, our method described here can be extended to other assay designs using different oxidase enzymes, energy donors and energy acceptors, such as fluorescent quantum dots, near-infrared (NIR)-to-visible upconversion nanoparticles and even other metallic nanoparticles.

Hypoxia-Preconditioned Extracellular Vesicles from Mesenchymal Stem Cells Improve Cartilage Repair in Osteoarthritis.

In the past decade, mesenchymal stem cells (MSCs) have been widely used for the treatment of osteoarthritis (OA), and extracellular vesicles (EVs) may play a major role in the efficacy of this treatment. Hypoxia can change the cargo and biological functions of MSC-derived EVs (MSC-EVs). The aim of the present study was to determine whether the effects of hypoxia-preconditioned MSC-EVs on OA cartilage repair are superior to normoxia-preconditioned MSC-EVs. By using in vitro and in vivo OA models, we verified that hypoxia-preconditioned MSC-EVs improved chondrocyte proliferation and migration and suppressed chondrocyte apoptosis to a greater extent than normoxia-preconditioned MSC-EVs. Furthermore, we found that hypoxia altered the microRNA expression in MSC-EVs and identified four differentially expressed microRNAs: hsa-miR-181c-5p, hsa-miR-18a-3p, hsa-miR-376a-5p, and hsa-miR-337-5p. Bioinformatics analysis revealed that hypoxic pretreatment may promote cartilage repair by stimulating chondrocyte proliferation and migration and suppressing chondrocyte apoptosis through the miRNA-18-3P/JAK/STAT or miRNA-181c-5p/MAPK signaling pathway. Therefore, hypoxia-preconditioned EVs may be a novel treatment for OA.

New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer's Disease and Its Potential for Therapeutic Intervention.

Alzheimer's disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored.

Discovery of novel hybrids containing clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease.

Based on the multitarget strategy, a series of novel clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation in vitro revealed that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE). The optimal compound, 19n, exhibited excellent AChE inhibitory potency (IC50 = 0.11 µM), appropriate metal chelating functions, modulation of AChE- and metal-induced Aß aggregation, neuroprotection against okadaic acid-induced mitochondrial dysfunction and ROS damage, and interesting properties that reduced p-Tau levels in addition to no toxicity on SH-SY5Y cells observed at a concentration up to 50 µM. Most importantly, compound 19n was more well tolerated (>1200 mg/kg) than donepezil (LD50 = 28.124 mg/kg) in vivo. Moreover, compound 19n demonstrated marked improvements in cognitive and spatial memory in two AD mice models (scopolamine-induced and Aß1-42-induced) and suppressed inflammation induced by Aß1-42 in the cortex. The multifunctional profiles of compound 19n demonstrate that it deserves further investigation as a promising lead in the development of innovatively multifunctional drugs for Alzheimer's disease.

Design, Synthesis, and Biological Evaluation of Novel Chromanone Derivatives as Multifunctional Agents for the Treatment of Alzheimer's Disease.

Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC50 = 0.58 ± 0.05 µM; MAO-B: IC50 = 0.41 ± 0.04 µM). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.