Neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms.

Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha-synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human-relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF-injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human-relevant pre-clinical measures and suggest that these pre-clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease.

Alternating Dual-Collision Energy Scanning Mass Spectrometry Approach: Discovery of Novel Microbial Bile-Acid Conjugates.

Bile acids (BAs) are a type of gut microbiota-host cometabolites with abundant structural diversity, and they play critical roles in maintaining host-microbiota homeostasis. In this study, we developed a new N-(4-aminomethylphenyl) pyridinium (AMPP) derivatization-assisted alternating dual-collision energy scanning mass spectrometry (AMPP-dual-CE MS) method for the profiling of BAs derived from host-gut microbiota cometabolism in mice. Using the proposed method, we discovered two new types of amino acid conjugations (alanine conjugation and proline conjugation) and acetyl conjugation with host BAs, for the first time, from mouse intestine contents and feces. Additionally, we also determined and identified nine new leucine- and phenylalanine-conjugated BAs. These findings broaden our knowledge of the composition of the BA pool and provide insight into the mechanism of host-gut microbiota cometabolism of BAs.

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo.

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

In situ construction of flower-like nanostructured calcium silicate bioceramics for enhancing bone regeneration mediated via FAK/p38 signaling pathway.

BACKGROUND: The repair of tissue defects has attracted considerable attention and remained a substantial challenge. Calcium silicate (CaSiO3, CS) bioceramics have attracted the interest of researchers due to their excellent biodegradability. Recent studies have demonstrated that nanoscale-modified bioactive materials with favorable biodegradability could promote bone tissue regeneration, providing an alternative approach for the repair of bone defects. However, the direct construction of biodegradable nanostructures in situ on CS bioceramics was still difficult. RESULTS: In this study, flower-like nanostructures were flexibly prepared in situ on biodegradable CS bioceramics via hydrothermal treatment. The flower-like nanostructure surfaces exhibited better hydrophilicity and more significantly stimulated cell adhesion, alkaline phosphatase (ALP) activity, and osteogenic differentiation. Furthermore, the CS bioceramics with flower-like nanostructures effectively promoted bone regeneration and were gradually replaced with newly formed bone due to the favorable biodegradability of these CS bioceramics. Importantly, we revealed an osteogenesis-related mechanism by which the FAK/p38 signaling pathway could be involved in the regulation of bone mesenchymal stem cell (BMSC) osteogenesis by the flower-like nanostructure surfaces. CONCLUSIONS: Flower-like nanostructure surfaces on CS bioceramics exerted a strong effect on promoting bone repair and regeneration, suggesting their excellent potential as bone implant candidates for improving bone regeneration.

Decoupling of Dual-Polarized Antenna Arrays Using Non-Resonant Metasurface.

A non-resonant metasurface (NRMS) concept is reported in this paper to improve the isolation of dual-polarized and wideband large-scale antenna arrays. By properly designing the NRMS, it can perform stable negative permeability and positive permittivity along the tangential direction of the NRMS within a wide band, which can be fully employed to suppress the mutual couplings of large-scale antenna arrays. At the same time, the proposed NRMS can also result in positive permittivity and permeability along the normal direction of the NRMS, which guarantees the free propagation of electromagnetic waves from antenna arrays along the normal direction. For demonstration, a 4×4 dual-polarized antenna array loading with the proposed NRMS is designed to improve the isolations of the antenna array. The simulations demonstrate that the isolations among all ports are over 24 dB from 4.36 to 4.94 GHz, which are experimentally verified by the measured results. Moreover, the radiation patterns of antenna elements are still maintained after leveraging the proposed NRMS. Due to the simple structure of the proposed NRMS, it is very promising to be widely employed for massive MIMO antenna arrays.

A Learning-Based Vehicle-Cloud Collaboration Approach for Joint Estimation of State-of-Energy and State-of-Health.

The state-of-energy (SOE) and state-of-health (SOH) are two crucial quotas in the battery management systems, whose accurate estimation is facing challenges by electric vehicles' (EVs) complexity and changeable external environment. Although the machine learning algorithm can significantly improve the accuracy of battery estimation, it cannot be performed on the vehicle control unit as it requires a large amount of data and computing power. This paper proposes a joint SOE and SOH prediction algorithm, which combines long short-term memory (LSTM), Bi-directional LSTM (Bi-LSTM), and convolutional neural networks (CNNs) for EVs based on vehicle-cloud collaboration. Firstly, the indicator of battery performance degradation is extracted for SOH prediction according to the historical data; the Bayesian optimization approach is applied to the SOH prediction combined with Bi-LSTM. Then, the CNN-LSTM is implemented to provide direct and nonlinear mapping models for SOE. These direct mapping models avoid parameter identification and updating, which are applicable in cases with complex operating conditions. Finally, the SOH correction in SOE estimation achieves the joint estimation with different time scales. With the validation of the National Aeronautics and Space Administration battery data set, as well as the established battery platform, the error of the proposed method is kept within 3%. The proposed vehicle-cloud approach performs high-precision joint estimation of battery SOE and SOH. It can not only use the battery historical data of the cloud platform to predict the SOH but also correct the SOE according to the predicted value of the SOH. The feasibility of vehicle-cloud collaboration is promising in future battery management systems.

Environmental application of emerging zero-valent iron-based materials on removal of radionuclides from the wastewater: A review.

Owing to high surface energy, strong chemical reactivity and large surface area, nanoscale zero-valent iron (nZVI) as a novel emerging material has been extensively utilized in environmental cleanup. Although a lot of reviews regarding the removal of organic contaminants and heavy metals on nZVI are summarized in recent years, the advanced progress concerning the removal of radionuclides on nZVI is still scarce. In this review, we summarized the removal of technetium (Tc), uranium (U), selenium (Se) and other radionuclides on nZVI and nZVI-based composites, then their interaction mechanisms were reviewed in details. This review is crucial for the environmental chemist and material engineer to exploit the actual application of nZVI-based composites as the emerging materials of permeable reactive barrier on the removal of radionuclides from aqueous solutions.

A robust prediction of U(VI) sorption on Fe3O4/activated carbon composites with surface complexation model.

A robust prediction of U(VI) on Fe3O4/activated carbon (Fe3O4/AC, fabricated by co-precipitation method under N2 conditions) under different pH was developed via diffuse layer model, in accordance with FI-IR, XRD and XPS analysis. No influence of ionic strength onto U(VI) adsorption by Fe3O4/AC under ambient conditions suggested the inner-sphere surface adsorption, which was attributed to abundant surficial functional groups according to FT-IR and XPS analysis. The batch experiments indicated Fe3O4/AC with fast adsorption rate (equilibrium within 60 min), high adsorption capacity (56 mg/g at pH 4.0) towards U(VI). The adsorbed U(VI) was partly reduced by Fe2+ of Fe3O4/AC by XPS analysis. Surface complexation modeling showed that a single set of monodentate and mononuclear species (SOUO2+) cannot predict U(VI) adsorption at high pH, whereas the robust prediction of U(VI) adsorption over wide pH range was observed by adding the other binuclear and tridentate species ((SO)2UO2(CO3)6-). These findings revealed that magnetic AC as a candidate for immobilization and/or preconcentration of radioactive wastewater in environment management.

The enhanced photodegradation of bisphenol A by TiO2/C3N4 composites.

A new photocatalyst of TiO2/C3N4 composite (TiO2/g-C3N4) was synthesized by the hydrothermal method. The characterization showed that TiO2/g-C3N4 extended absorption light range and enhanced generation efficiency of photo-induced electron. Under the simulated solar irradiation, the photodegradation rate of bisphenol A (BPA) by TiO2/g-C3N4 was twice as fast as that of g-C3N4. Furthermore, TiO2/g-C3N4 presented the good stability and excellent selectivity for BPA degradation. The high degradation rate of BPA by TiO2/g-C3N4 was demonstrated to be superoxide radical (·O2-) and singlet oxygen (1O2) by radical quenching experiment, which was further evidenced by EPR, XPS, DRS and PL analysis. These findings revealed that TiO2/g-C3N4 can be used as a potential photocatalyst for removing organic pollutants in actual environmental remediation.

Mouth breathing impairs the development of temporomandibular joint at a very early stage.

OBJECTIVES: The study aimed to explore the effects of mouth breathing and hypoxia on the condyle of temporomandibular joint (TMJ) via two animal models. METHODS: 24 four-week-old rats were randomly separated into three groups, consisting of eight control rats, eight intermittent hypoxia (IH) rats, and eight intermittent nasal obstruction (INO) rats. We use the IH model and the INO model to simulate children suffering from hypoxia and mouth breathing. After 16 days, the condyle of TMJ and surrounding white adipose tissue (WAT) and skeletal muscle tissue were obtained for further staining and qRT-PCR. Finally, RNA-seq was used to verify the results. RESULTS: The intermittent hypoxia cannot significantly change the overall structure in the cause of short-term hypoxia stimulation, but the intermittent nasal obstruction can alter the condyle, WAT, and muscle, while also introducing noticeable structural changes in tissue hypoxia and macrophage infiltration. Sequencing data verified these findings and also suggested that this process might involve the Hif-1α/Vegf axis. CONCLUSIONS: Our findings reveal the very early structural impact of mouth breathing on condyle reconstruction in rat models, and hypoxia does not induce evident alteration on condyle. However, since these results are mainly focused on rats, further studies are needed to understand its effects on humans.

[Fingerprint analysis and Q-marker prediction of processed liquorice products].

Licorice has long been regarded as one of the most popular herbs, with a very wide clinical application range. Whether being used alone or as an ingredient in prescription, it has an important role which cannot be ignored. However, the efficacy and chemical constituents of licorice will change after honey-processing. Therefore, it is necessary to find quality markers before and after honey-processing to lay the foundation for a comprehensive evaluation of the differences between raw and processed licorice pieces. HPLC-DAD was employed to establish fingerprints of raw and processed licorice. Multivariate statistical analysis methods including principal component analysis(PCA) and orthogonal partial least squares discrimination analysis(OPLS-DA) were applied to screen out the differential components before and after processing of licorice. Based on network pharmacology, the targets and pathways corresponding to the differential components were analyzed with databases such as Swiss Target Prediction and Metascape, and the "component-target-pathway" diagram was constructed with Cytoscape 3.6.0 software to predict the potential quality markers. A total of 17 common peaks were successfully identified in the established fingerprint, and seven differential components were selected as potential quality markers(licoricesaponin G2, glycyrrhizic acid, liquiritigenin, liquiritin, isoliquiritin, liquiritin apioside and isoliquiritigenin). The HPLC fingerprint method proposed in this study was efficient and feasible. The above seven differential chemical components screened out as potential quality markers of licorice can help to improve and promote the overall quality. These researches offer more sufficient theoretical basis for scientific application of licorice and its corresponding products.

Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma.

Recently, XRCC1 polymorphisms were reported to be associated with glioma in Chinese population. However, only a few studies reported on the XRCC1 expression, and cancer progression. In this study, we investigated whether XRCC1 plays a role in glioma pathogenesis. Using the tissue microarray technology, we found that XRCC1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P < 0.01, χ2 test) and reduced XRCC1 staining was associated with WHO stages (P < 0.05, χ2 test). The mRNA and protein levels of XRCC1 were significantly downregulated in human primary glioma tissues (P < 0.001, χ2 test). We also found that XRCC1 was significantly decreased in glioma cell lines compared to normal human astrocytes (P < 0.01, χ2 test). Overexpression of XRCC1 dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 is diminished whereas p16 is upregulated. We further demonstrated that XRCC1 overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of XRCC1 sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that XRCC1 may be a tumor suppressor involved in the progression of glioma.

BARCOSEL: a tool for selecting an optimal barcode set for high-throughput sequencing.

BACKGROUND: Current high-throughput sequencing platforms provide capacity to sequence multiple samples in parallel. Different samples are labeled by attaching a short sample specific nucleotide sequence, barcode, to each DNA molecule prior pooling them into a mix containing a number of libraries to be sequenced simultaneously. After sequencing, the samples are binned by identifying the barcode sequence within each sequence read. In order to tolerate sequencing errors, barcodes should be sufficiently apart from each other in sequence space. An additional constraint due to both nucleotide usage and basecalling accuracy is that the proportion of different nucleotides should be in balance in each barcode position. The number of samples to be mixed in each sequencing run may vary and this introduces a problem how to select the best subset of available barcodes at sequencing core facility for each sequencing run. There are plenty of tools available for de novo barcode design, but they are not suitable for subset selection. RESULTS: We have developed a tool which can be used for three different tasks: 1) selecting an optimal barcode set from a larger set of candidates, 2) checking the compatibility of user-defined set of barcodes, e.g. whether two or more libraries with existing barcodes can be combined in a single sequencing pool, and 3) augmenting an existing set of barcodes. In our approach the selection process is formulated as a minimization problem. We define the cost function and a set of constraints and use integer programming to solve the resulting combinatorial problem. Based on the desired number of barcodes to be selected and the set of candidate sequences given by user, the necessary constraints are automatically generated and the optimal solution can be found. The method is implemented in C programming language and web interface is available at http://ekhidna2.biocenter.helsinki.fi/barcosel . CONCLUSIONS: Increasing capacity of sequencing platforms raises the challenge of mixing barcodes. Our method allows the user to select a given number of barcodes among the larger existing barcode set so that both sequencing errors are tolerated and the nucleotide balance is optimized. The tool is easy to access via web browser.

H1/pHGFK1 nanoparticles exert anti-tumoural and radiosensitising effects by inhibition of MET in glioblastoma.

BACKGROUND: The therapeutic resistance to ionising radiation (IR) and anti-angiogenesis mainly impair the prognosis of patients with glioblastoma. The primary and secondary MET aberrant activation is one crucial factor for these resistances. The kringle 1 domain of hepatocyte growth factor (HGFK1), an angiogenic inhibitor, contains a high-affinity binding domain of MET; however, its effects on glioblastoma remain elusive. METHODS: We formed the nanoparticles consisting of a folate receptor-targeted nanoparticle-mediated HGFK1 gene (H1/pHGFK1) and studied its anti-tumoural and radiosensitive activities in both subcutaneous and orthotopic human glioma cell-xenografted mouse models. We then elucidated its molecular mechanisms in human glioblastoma cell lines in vitro. RESULTS: We demonstrated for the first time that peritumoural injection of H1/pHGFK1 nanoparticles significantly inhibited tumour growth and prolonged survival in tumour-bearing mice, as well as enhanced the anti-tumoural efficacies of IR in vivo by reducing Ki-67 expression, enhancing TUNEL staining-indicated apoptotic indexes, reducing microvascular intensity and reversing IR-induced MET overexpression in tumour tissues. Furthermore, we showed that HGFK1 suppressed the proliferation and induced cell apoptosis and enhanced sensitivity to IR in glioblastoma cell lines, mainly by suppressing the activities of MET receptor, down-regulating ATM-Chk2 axis but up-regulating Chk1. CONCLUSIONS: H1/pHGFK1 exerts anti-tumoural and radiosensitive activities mainly through the inhibition and reversal of IR-induced MET and ATM-Chk2 axis activities in glioblastoma. H1/pHGFK1 nanoparticles are a potential radiosensitiser and angiogenic inhibitor for glioblastoma treatment.

Highly Ordered Mesostructured Vanadium Phosphonate toward Electrode Materials for Lithium-Ion Batteries.

Highly ordered mesostructured vanadium phosphonates (VP) have been synthesized in the presence of cetyltrimethylammonium bromide (CTAB) as a structure-directing agent. Nitrilotris(methylene)triphosphonic acid (NMPA) and (ammonium/sodium) metavanadate (NH4 VO3 /NaVO3 ) have been used for the construction of pore walls. The CTAB templates are removed from the materials by an extraction process without destroying the parent mesostructure. The formation mechanism for the ordered mesoporous structure and its impact on electrochemical application in lithium ion batteries (LIBs) are explained by considering the structural and electrochemical stability of the framework. The results demonstrate that the counter cations (NH4+ /Na+ ) of the metavanadate precursors have a crucial role in stabilizing the mesoporous structure of the mesoporous VP materials. Mesoporous VP materials with highly ordered structure have great applicability as high-performance electrode materials in LIBs due to the advantages of their large contact area with electrolyte and short transport paths for lithium ions. Mesoporous VP electrodes exhibit high reversible specific capacity with superb cycling stability (100 cycles) and excellent retention of capacity (92 %).

Facile synthesis of nanoporous Li1+xV1-xO2@C composites as promising anode materials for lithium-ion batteries.

Recently, a layered material with composition Li1+xV1-xO2 has been discovered as a promising alternative anode material to graphite due to its high volumetric capacity and low operation potential. Herein, we demonstrate a mild and cost-effective synthetic methodology to construct a novel nanoporous anode material (P-LVO@C), comprising Li1+xV1-xO2 nanocrystals embedded in a porous carbon matrix. The thermal decomposition of organic materials, including a triblock copolymer (P123) and citric acid, in a N2 atmosphere is the source of the nanoporous carbon in the porous composite material, while citric acid also plays a crucial role in maintaining the reductive environment of the synthetic medium. Due to the novel composition of Li1+xV1-xO2 (x ≥ 0.03), as well as its porous structure and well-integrated conductive framework, our P-LVO@C has great applicability as a high performance anode material for lithium-ion batteries. Our P-LVO@C composite electrode shows high reversible capacity with an excellent cycling performance (100 cycles) and good capacity retention (82%) at a higher rate (0.48C).

Dynamic network link prediction with node representation learning from graph convolutional networks.

Dynamic network link prediction is extensively applicable in various scenarios, and it has progressively emerged as a focal point in data mining research. The comprehensive and accurate extraction of node information, as well as a deeper understanding of the temporal evolution pattern, are particularly crucial in the investigation of link prediction in dynamic networks. To address this issue, this paper introduces a node representation learning framework based on Graph Convolutional Networks (GCN), referred to as GCN_MA. This framework effectively combines GCN, Recurrent Neural Networks (RNN), and multi-head attention to achieve comprehensive and accurate representations of node embedding vectors. It aggregates network structural features and node features through GCN and incorporates an RNN with multi-head attention mechanisms to capture the temporal evolution patterns of dynamic networks from both global and local perspectives. Additionally, a node representation algorithm based on the node aggregation effect (NRNAE) is proposed, which synthesizes information including node aggregation and temporal evolution to comprehensively represent the structural characteristics of the network. The effectiveness of the proposed method for link prediction is validated through experiments conducted on six distinct datasets. The experimental outcomes demonstrate that the proposed approach yields satisfactory results in comparison to state-of-the-art baseline methods.

Downregulation of Serum PTEN Expression in Mercury-Exposed Population and PI3K/AKT Pathway-Induced Inflammation.

Objective: This study investigated the impact of occupational mercury (Hg) exposure on human gene transcription and expression, and its potential biological mechanisms. Methods: Differentially expressed genes related to Hg exposure were identified and validated using gene expression microarray analysis and extended validation. Hg-exposed cell models and PTEN low-expression models were established in vitro using 293T cells. PTEN gene expression was assessed using qRT-PCR, and Western blotting was used to measure PTEN, AKT, and PI3K protein levels. IL-6 expression was determined by ELISA. Results: Combined findings from gene expression microarray analysis, bioinformatics, and population expansion validation indicated significant downregulation of the PTEN gene in the high-concentration Hg exposure group. In the Hg-exposed cell model (25 and 10 µmol/L), a significant decrease in PTEN expression was observed, accompanied by a significant increase in PI3K, AKT, and IL-6 expression. Similarly, a low-expression cell model demonstrated that PTEN gene knockdown led to a significant decrease in PTEN protein expression and a substantial increase in PI3K, AKT, and IL-6 levels. Conclusion: This is the first study to report that Hg exposure downregulates the PTEN gene, activates the PI3K/AKT regulatory pathway, and increases the expression of inflammatory factors, ultimately resulting in kidney inflammation.

Deciphering the Performance Enhancement, Cell Failure Mechanism, and Amelioration Strategy of Sodium Storage in Metal Chalcogenides-Based Andes.

Transition metal chalcogenides (TMCs) emerge as promising anode materials for sodium-ion batteries (SIBs), heralding a new era of energy storage solutions. Despite their potential, the mechanisms underlying their performance enhancement and susceptibility to failure in ether-based electrolytes remain elusive. This study delves into these aspects, employing CoS2 electrodes as a case in point to elucidate the phenomena. The investigation reveals that CoS2 undergoes a unique irreversible and progressive solid-liquid-solid phase transition from its native state to sodium polysulfides (NaPSs), and ultimately to a Cu1.8S/Co composite, accompanied by a gradual morphological transformation from microspheres to a stable 3D porous architecture. This reconstructed 3D porous structure is pivotal for its exceptional Na+ diffusion kinetics and resilience to cycling-induced stress, being the main reason for ultrastable cycling and ultrahigh rate capability. Nonetheless, the CoS2 electrode suffers from an inevitable cycle life termination due to the microshort-circuit induced by Na metal corrosion and separator degradation. Through a comparative analysis of various TMCs, a predictive framework linking electrode longevity is established to electrode potential and Gibbs free energy. Finally, the cell failure issue is significantly mitigated at a material level (graphene encapsulation) and cell level (polypropylene membrane incorporation) by alleviating the NaPSs shuttling and microshort-circuit.

An alkaloid from Menispermum dauricum, dauricine mediates Ca2+ influx and inhibits NF-κB pathway to protect chondrocytes from IL-1ß-induced inflammation and catabolism.

ETHNOPHARMACOLOGICAL RELEVANCE: Dauricine (DA) is a natural plant-derived alkaloid extracted from Menispermum dauricum. Menispermum dauricum has been used in traditional Chinese medicine as a classic remedy for rheumatoid arthropathy and is believed to be effective in alleviating swelling and pain in the limbs. AIM OF THE STUDY: Osteoarthritis (OA) is a classic degenerative disease involving chondrocyte death, and there is still a lack of effective therapeutic agents that can reverse the progression of the disease. Here we explored the therapeutic effects of DA against OA and further explored the mechanism. MATERIALS AND METHODS: The effect of DA on cell viability was assessed by CCK-8. IL-1ß-treated mouse chondrocytes were used as an in vitro model of OA, and apoptosis was detected by flow cytometry. QRT-PCR, western blotting, cell staining, and immunofluorescence were used to detect relevant inflammatory factors and cartilage-specific expression. RNA sequencing was used to identify pertinent signaling pathways. The therapeutic effect of DA was verified by micro-CT, histological analysis and immunohistochemical analysis in a mouse OA model. RESULTS: DA demonstrated a high safety profile on chondrocytes, significantly reversing the inflammatory response induced by IL-1ß, and promoting factors associated with cartilage regeneration. Moreover, DA exhibited a significant protective effect on the knee joints of mice undergoing ACLT-DMM, effectively preventing cartilage degeneration and subchondral bone tissue destruction. These positive therapeutic effects were achieved through the modulation of the NF-κB pathway and the Ca2+ signaling pathway by DA. CONCLUSION: Being derived from a traditional herb, DA exhibits remarkable therapeutic potential and safety in OA treatment, presenting a promising option for patients dealing with osteoarthritis.