Heparin-Modified Superparamagnetic Iron Oxide Nanoparticles Suppress Lithium Chloride/Pilocarpine-Induced Temporal Lobe Epilepsy in Rats through Attenuation of Inflammation and Oxidative Stress.

The development of antiepileptic drugs is still a long process. In this study, heparin-modified superparamagnetic iron oxide nanoparticles (UFH-SPIONs) were prepared, and their antiepileptic effect and underlying mechanism were investigated. UFH-SPIONs are stable, homogeneous nanosystems with antioxidant enzyme activity that are able to cross the blood-brain barrier (BBB) and enriched in hippocampal epileptogenic foci. The pretreatment with UFH-SPIONs effectively prolonged the onset of seizures and reduced seizure severity after lithium/pilocarpine (LP)-induced seizures in rats. The pretreatment with UFH-SPIONs significantly decreased the expression of inflammatory factors in hippocampal tissues, including IL-6, IL-1ß, and TNF-α. LP-induced oxidative stress in hippocampal tissues was in turn reduced upon pretreatment with UFH-SPIONs, as evidenced by an increase in the levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and a decrease in the level of lipid peroxidation (MDA). Moreover, the LP-induced upregulation of apoptotic cells was decreased upon pretreatment with UFH-SPIONs. Together, these observations suggest that the pretreatment with UFH-SPIONs ameliorates LP-induced seizures and downregulates the inflammatory response and oxidative stress, which exerts neuronal protection during epilepsy.

Biomimetic Bone-Like Composite Hydrogel Scaffolds Composed of Collagen Fibrils and Natural Hydroxyapatite for Promoting Bone Repair.

Bone is a complex organic-inorganic composite tissue composed of ∼30% organics and ∼70% hydroxyapatite (HAp). Inspired by this, we used 30% collagen and 70% HAp extracted from natural bone using the calcination method to generate a biomimetic bone composite hydrogel scaffold (BBCHS). In one respect, BBCHS, with a fixed proportion of inorganic and organic components similar to natural bone, exhibits good physical properties. In another respect, the highly biologically active and biocompatible HAp from natural bone effectively promotes osteogenic differentiation, and type I collagen facilitates cell adhesion and spreading. Additionally, the well-structured porosity of the BBCHS provides sufficient growth space for bone marrow mesenchymal stem cells (BMSCs) while promoting substance exchange. Compared to the control group, the new bone surface of the defective location in the B-HA70+Col group is increased by 3.4-fold after 8 weeks of in vivo experiments. This strategy enables the BBCHS to closely imitate the chemical makeup and physical structure of natural bone. With its robust biocompatibility and osteogenic activity, the BBCHS can be easily adapted for a wide range of bone repair applications and offers promising potential for future research and development.

Development and Validation of a Risk Score for Mild Cognitive Impairment in Individuals with Type 2 Diabetes in China: A Practical Cognitive Prescreening Tool.

Aim: Numerous evidence suggests that diabetes increases the risk of cognitive impairment. This study aimed to develop and validate a multivariable risk score model to identify mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM). Methods: This cross-sectional study included 1256 inpatients (age: 57.5 ± 11.2 years) with T2DM in a tertiary care hospital in China. MCI was diagnosed according to the criteria recommended by the National Institute on Aging-Alzheimer's Association Workgroup, and a MoCA score of 19-25 indicated MCI. Participants were randomly allocated into the derivation and validation sets at 7:3 ratio. Logistic regression models were used to identify predictors for MCI in the derivation set. A scoring system based on the predictors' beta coefficient was developed. Predictive ability of the risk score was tested by discrimination and calibration methods. Results: Totally 880 (285 with MCI, 32.4%) and 376 (167 with MCI, 33.8%) patients were allocated in the derivation and validation set, respectively. Age, education, HbA1c, self-reported history of severe hypoglycemia, and microvascular disease were identified as predictors for MCI and constituted the risk score. The AUCs (95% CI) of the risk score were 0.751 (0.717, 0.784) in derivation set and 0.776 (0.727, 0.824) in validation set. The risk score showed good apparent calibration of observed and predicted MCI probabilities and was capable of stratifying individuals into 3 risk categories by two cut-off points (low risk: ≤ 3, medium risk: 4-13, and high risk ≥ 14). Conclusion: The risk score based on age, education, HbA1c, self-reported history of severe hypoglycemia, and microvascular disease can effectively assess MCI risk in adults with T2DM at different age. It can serve as a practical prescreening tool for early detection of MCI in daily diabetes care.

Altered Dynamics of Brain Spontaneous Activity and Functional Networks Associated With Cognitive Impairment in Patients With Type 2 Diabetes.

BACKGROUND: Cognitive impairment is increasingly recognized as an important comorbidity and complication of type 2 diabetes (T2D), affecting patients' quality of life and diabetes management. Dynamic brain activity indicators can reflect changes in key neural activity patterns of cognition and behavior. PURPOSE: To investigate dynamic functional connectivity (DFC) changes and spontaneous brain activity based on resting-state functional magnetic resonance imaging (rs-fMRI) in patients with T2D, exploring their correlations with clinical features. STUDY TYPE: Retrospective. SUBJECTS: Forty-five healthy controls (HCs) (22 males and 23 females) and 102 patients with T2D (57 males and 45 females). FIELD STRENGTH/SEQUENCE: 3.0 T/T1-weighted imaging and rs-fMRI with gradient-echo planar imaging sequence. ASSESSMENT: Functional networks were created using independent component analysis. DFC states were determined using sliding window approach and k-means clustering. Spontaneous brain activity was assessed using dynamic regional homogeneity (dReHo) variability. STATISTICAL TESTS: One-way analysis of variance and post hoc analysis were used to compare the essential information including demographics, clinical data, and features of DFC and dReHo among groups. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve. P-values <0.05 were taken to indicate statistical significance. RESULTS: T2D group had significantly decreased mean dwell time and fractional windows in state 4 compared to HC. T2D with mild cognitive impairment showed significantly increased dReHo variability in left superior occipital gyrus compared to T2D with normal cognition. Mean dwell time and number of fractional windows of state 4 both showed significant positive correlations with the Montreal cognitive assessment scores (r = 0.309; r = 0.308, respectively) and the coefficient of variation of dReHo was significantly positively correlated with high-density lipoprotein cholesterol (r = 0.266). The integrated index had an area under the curve of 0.693 (95% confidence interval = 0.592-0.794). DATA CONCLUSION: Differences in DFC and dynamic characteristic of spontaneous brain activity associated with T2D-related functional impairment may serve as indicators for predicting symptom progression and assessing cognitive dysfunction. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Development of Pure Certified Reference Material of Cannabidiol.

Cannabidiol (CBD) is the major functional component in hemp and has a broad range of pharmacological applications, such as analgesic, anti-epileptic, anti-anxiety, etc. Currently, CBD is widely used in pharmaceuticals, cosmetics, and food. To ensure the quality and safety of the products containing CBD, more and more related sample testing is being conducted, and the demand for CBD-certified reference material (CRM) has also sharply increased. However, there is currently a lack of relevant reference materials. In this paper, a simple method for preparing CBD CRM was established based on preparative liquid chromatography using crude hemp extract as a raw material. A qualitative analysis of CBD was performed using techniques such as ultraviolet absorption spectroscopy (UV), infrared spectroscopy (IR), mass spectrometry (MS), nuclear magnetic resonance spectroscopy (NMR), and differential scanning calorimetry (DSC). High-performance liquid chromatography (HPLC) was used for the homogeneity and stability tests, and the data were analyzed using an F-test and a T-test, respectively. Then, eight qualified laboratories were chosen for the determination of a certified value using HPLC. The results show that the CBD CRM had excellent homogeneity and good stability for 18 months. The certified value was 99.57%, with an expanded uncertainty of 0.24% (p = 0.95, k = 2). The developed CBD CRM can be used for the detection and quality control of cannabidiol products.

Multifunctional nanomaterials via cell cuproptosis and oxidative stress for treating osteosarcoma and OS-induced bone destruction.

Reactive Oxygen Species (ROS) refers to a highly reactive class of oxidizing species that have the potential to induce cellular apoptosis and necrosis. Cuproptosis, a type of cell death, is primarily associated with the effects of copper ions. However, the specific relationship between ROS, cuproptosis, and osteosarcoma (OS) remains relatively unexplored. Additionally, there is limited research on the use of cuproptosis in conjunction with oxidative stress for treating OS and inhibiting tumor-induced bone destruction. To address these gaps, a novel treatment approach has been developed for OS and neoplastic bone destruction. This approach involves the utilization of glutathione (GSH) and pH-responsive organic-inorganic mesoporous silica nanoparticles@Cu2S@oxidized Dextran (short for MCD). The MCD material demonstrates excellent cytocompatibility, osteogenesis, tumor suppression, and the ability to inhibit osteoclast formation. The specific mechanism of action involves the mitochondria of the MCD material inhibiting key proteins in the tricarboxylic acid (TCA) cycle. Simultaneously, the generation of ROS promotes this inhibition and leads to alterations in cellular energy metabolism. Moreover, the MCD biomaterial exhibits promising mild-temperature photothermal therapy in the second near-infrared (NIR-II) range, effectively mitigating tumor growth and OS-induced bone destruction in vivo.

The transformation of multifunctional bio-patch to hydrogel on skin wounds for efficient scarless wound healing.

Hydrogels have been widely used in various biomedical applications, including skin regeneration and tissue repair. However, the capability of certain hydrogels to absorb exudate or blood from surrounding wounds, coupled with the challenge in their long-term storage to prevent bacterial growth, can pose limitations to their efficacy in biological applications. To address these challenges, the development of a multifunctional aloin-arginine-alginate (short for 3A) bio-patch capable of transforming into a hydrogel upon absorbing exudate or blood from neighboring wounds for cutaneous regeneration is proposed. The 3A bio-patch exhibits outstanding features, including an excellent porous structure, swelling properties, and biodegradability. These characteristics allow for the rapid absorption of wound exudates and subsequent transformation into a hydrogel that is suitable for treating skin wounds. Furthermore, the 3A bio-patch exhibits remarkable antibacterial and anti-inflammatory properties, leading to accelerated wound healing and scarless repair in vivo. This study presents a novel approach to the development of cutaneous wound dressing materials.

International consensus on clinical use of presynaptic dopaminergic positron emission tomography imaging in parkinsonism.

PURPOSE: Presynaptic dopaminergic positron emission tomography (PET) imaging serves as an essential tool in diagnosing and differentiating patients with suspected parkinsonism, including idiopathic Parkinson's disease (PD) and other neurodegenerative and non-neurodegenerative diseases. The PET tracers most commonly used at the present time mainly target dopamine transporters (DAT), aromatic amino acid decarboxylase (AADC), and vesicular monoamine type 2 (VMAT2). However, established standards for the imaging procedure and interpretation of presynaptic dopaminergic PET imaging are still lacking. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform presynaptic dopaminergic PET imaging. METHOD: A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for presynaptic dopaminergic PET imaging in parkinsonism, focusing on standardized recommendations, procedures, interpretation, and reporting. CONCLUSION: This international consensus and practice guideline will help to promote the standardized use of presynaptic dopaminergic PET imaging in parkinsonism. It will become an international standard for this purpose in clinical practice.

In vivo cerebral metabolic and dopaminergic characteristics in multiple system atrophy with orthostatic hypotension.

PURPOSE: Multiple system atrophy (MSA) is a rare neurodegenerative disease, often presented with orthostatic hypotension (OH), which is a disabling symptom but has not been very explored. Here, we investigated MSA patients with OH by using positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) and 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) for in vivo evaluation of the glucose metabolism and dopaminergic function of the brain. METHODS: Totally, 51 patients with MSA and 20 healthy controls (HC) who underwent 18F-FDG PET/CT were retrospectively enrolled, among which 24 patients also underwent 11C-CFT PET/CT. All patients were divided into MSA-OH(+) and MSA-OH(-) groups. Then, statistical parametric mapping (SPM) method was used to reveal the regional metabolic and dopaminergic characteristics of MSA-OH(+) compared with MSA-OH(-). Moreover, the metabolic networks of MSA-OH(+), MSA-OH(-) and HC groups were also constructed and analyzed based on graph theory to find possible network-level changes in MSA patients with OH. RESULTS: The SPM results showed significant hypometabolism in the pons and right cerebellar tonsil, as well as hypermetabolism in the left parahippocampal gyrus and left superior temporal gyrus in MSA-OH(+) compared with MSA-OH(-). A reduced 11C-CFT uptake in the left caudate was also shown in MSA-OH(+) compared with MSA-OH(-). In the network analysis, significantly reduced local efficiency and clustering coefficient were shown in MSA-OH(+) compared with HC, and decreased nodal centrality in the frontal gyrus was found in MSA-OH(+) compared with MSA-OH(-). CONCLUSION: In this study, the changes in glucose metabolism in the pons, right cerebellar tonsil, left parahippocampal gyrus and left superior temporal gyrus were found closely related to OH in MSA patients. And the decreased presynaptic dopaminergic function in the left caudate may contribute to OH in MSA. Taken together, this study provided in vivo pathophysiologic information on MSA with OH from neuroimaging approach, which is essential for a better understanding of MSA with OH.

Associations between complexity of glucose time series and cognitive function in adults with type 2 diabetes.

AIMS: To characterize the comparative contributions of different glycaemic indicators to cognitive dysfunction, and further investigate the associations between the most significant indicator and cognitive function, along with related cerebral alterations. MATERIALS AND METHODS: We performed a cross-sectional study in 449 subjects with type 2 diabetes who completed continuous glucose monitoring and cognitive assessments. Of these, 139 underwent functional magnetic resonance imaging to evaluate cerebral structure and olfactory neural circuit alterations. Relative weight and Sobol's sensitivity analyses were employed to characterize the comparative contributions of different glycaemic indicators to cognitive dysfunction. RESULTS: Complexity of glucose time series index (CGI) was found to have a more pronounced association with mild cognitive impairment (MCI) compared to glycated haemoglobin, time in range, and standard deviation. The proportion and multivariable-adjusted odds ratios (ORs) for MCI increased with descending CGI tertile (Tertile 1: reference group [≥4.0]; Tertile 2 [3.6-4.0] OR 1.23, 95% confidence interval [CI] 0.68-2.24; Tertile 3 [<3.6] OR 2.27, 95% CI 1.29-4.00). Decreased CGI was associated with cognitive decline in executive function and attention. Furthermore, individuals with decreased CGI displayed reduced olfactory activation in the left orbitofrontal cortex (OFC) and disrupted functional connectivity between the left OFC and right posterior cingulate gyrus. Mediation analysis demonstrated that the left OFC activation partially mediated the associations between CGI and executive function. CONCLUSION: Decreased glucose complexity closely relates to cognitive dysfunction and olfactory brain activation abnormalities in diabetes.

A nano-conductive osteogenic hydrogel to locally promote calcium influx for electro-inspired bone defect regeneration.

Conductive nano-materials and electrical stimulation (ES) have been recognized as a synergetic therapy for ordinary excitable tissue repair. It is worth noting that hard tissues, such as bone tissue, possess bioelectrical properties as well. However, insufficient attention is paid to the synergetic therapy for bone defect regeneration via conductive biomaterials with ES. Here, a novel nano-conductive hydrogel comprising calcium phosphate-PEDOT:PSS-magnesium titanate-methacrylated alginate (CPM@MA) was synthesized for electro-inspired bone tissue regeneration. The nano-conductive CPM@MA hydrogel has demonstrated excellent electroactivity, biocompatibility, and osteoinductivity. Additionally, it has the potential to enhance cellular functionality by increasing endogenous transforming growth factor-beta1 (TGF-ß1) and activating TGF-ß/Smad2 signaling pathway. The synergetic therapy could facilitate intracellular calcium enrichment, resulting in a 5.8-fold increase in calcium concentration compared to the control group in the CPM@MA ES + group. The nano-conductive CPM@MA hydrogel with ES could significantly promote electro-inspired bone defect regeneration in vivo, uniquely allowing a full repair of rat femoral defect within 4 weeks histologically and mechanically. These results demonstrate that our synergistic strategy effectively promotes bone restoration, thereby offering potential advancements in the field of electro-inspired hard tissue regeneration using novel nano-materials with ES.

The Presence and Severity of NAFLD are Associated With Cognitive Impairment and Hippocampal Damage.

CONTEXT: Although cognitive impairment in nonalcoholic fatty liver disease (NAFLD) has received attention in recent years, little is known about detailed cognitive functions in histologically diagnosed individuals. OBJECTIVE: This study aimed to investigate the association of liver pathological changes with cognitive features and further explore the underlying brain manifestations. METHODS AND PATIENTS: We performed a cross-sectional study in 320 subjects who underwent liver biopsy. Among the enrolled participants, 225 underwent assessments of global cognition and cognitive subdomains. Furthermore, 70 individuals received functional magnetic resonance imaging scans for neuroimaging evaluations. The associations among liver histological features, brain alterations, and cognitive functions were evaluated using structural equation model. RESULTS: Compared with controls, patients with NAFLD had poorer immediate memory and delayed memory. Severe liver steatosis (odds ratio, 2.189; 95% CI, 1.020-4.699) and ballooning (OR, 3.655; 95% CI, 1.419-9.414) were related to a higher proportion of memory impairment. Structural magnetic resonance imaging showed that patients with nonalcoholic steatohepatitis exhibited volume loss in left hippocampus and its subregions of subiculum and presubiculum. Task-based magnetic resonance imaging showed that patients with nonalcoholic steatohepatitis had decreased left hippocampal activation. Path analysis demonstrated that higher NAFLD activity scores were associated with lower subiculum volume and reduced hippocampal activation, and such hippocampal damage contributed to lower delayed memory scores. CONCLUSIONS: We are the first to report the presence and severity of NAFLD to be associated with an increased risk of memory impairment and hippocampal structural and functional abnormalities. These findings stress the significance of early cognitive evaluation in patients with NAFLD.

Research progress of applications for nano-materials in improved QuEChERS method.

The quick, easy, cheap, effective, rugged, and safe (QuEChERS) approach is widely used in sample pretreatment in agricultural products, food, environment, etc. And nano-materials are widely used in QuEChERS method due to its small size and large specific surface area. In this review, we examine the typical applications of several commonly used nano-materials in improved QuEChERS method. These materials include multi-walled carbon nanotubes (MWCNTs) and their derivatives, magnetic nanoparticles (MNPs), metal organic frameworks (MOFs), covalent organic frameworks (COFs), graphene oxide (GO), lipid and protein adsorbent (LPAS), cucurbituril (CBs), and carbon nano-cages (CNCs), and so on. The strengths and weaknesses of each nano-material are presented, as well as the challenging aspects that need to be addressed in future research. By comparing the applications and the current technology development, this review suggests utilizing artificial intelligence (AI) to screen suitable combinations of purification agents and performing virtual simulation experiments to verify the reliability of this methodology. By doing so, we aim to accelerate the development of new products and decrease the cost of innovation. It also recommends designing smarter pretreatment instruments to enhance the convenience and automation of the sample pretreatment process and reduce the margin for human error.

Synergistic Effect of Magneto-Mechanical Bioengineered Stem Cells and Magnetic Field to Alleviate Osteoporosis.

Therapeutic bioengineering based on stem cell therapy holds great promise in biomedical applications. However, the application of this treatment is limited in orthopedics because of their poor survival, weak localization, and low cell retention. In this work, magneto-mechanical bioengineered cells consisting of magnetic silica nanoparticles (MSNPs) and mesenchymal stem cells (MSCs) are prepared to alleviate osteoporosis. The magneto-mechanical bioengineered MSCs with spatial localization, cell retention, and directional tracking capabilities could be mediated by a guided magnetic field (MF) in vitro and in vivo. Furthermore, high uptake rates of the MSNPs ensure the efficient construction of magnetically controlled MSCs within 2 h. In conjunction with external MF, the magneto-mechanical bioengineered MSCs have the potential for the activation of the YAP/ß-catenin signaling pathway, which could further promote osteogenesis, mineralization, and angiogenesis. The synergistic effects of MSNPs and guided MF could also decline bone resorption to rebalance bone metabolism in bone loss diseases. In vivo experiments confirm that the functional MSCs and guided MF could effectively alleviate postmenopausal osteoporosis, and the bone mass of the treated osteoporotic bones by using the bioengineered cells for 6 weeks is nearly identical to that of the healthy ones. Our results provide a new avenue for osteoporosis management and treatment, which contribute to the future advancement of magneto-mechanical bioengineering and treatment.

Effects of fruits and vegetables on gut microbiota in a mouse model of metabolic syndrome induced by high-fat diet.

The aim of this study was to evaluate the effect of fruit and vegetable intake on gut microbiota using a mouse model of metabolic syndrome (MS) induced by a high-fat diet. Forty-eight male mice were randomly divided into four groups, control group (C), high-fat diet-fed model group (H), high fat plus low intake of fruits and vegetables diet-fed group (H.LFV), high fat plus high intake of fruits and vegetables diet-fed group (H.HFV), and each group were fed for 60 days. During the experiment, mouse body weights were recorded and fecal samples were collected. Cetyltrimethyl ammonium bromide (CTAB) method was used to extract fecal bacterial DNA, and the purity and concentration of the DNA were detected by electrophoresis. DNA samples underwent PCR amplification (primers in 16 S V4 (515F and 806R)). Raw sequencing data were processed, and sample complexity and multiple-sample comparisons were investigated. Mouse organ coefficient, serum lipid levels, fecal TC (total cholesterol) and TBA (total bile acid) levels, and hepatic glutathione and malondialdehyde levels were determined. Compared to the H group, the fecal TC and TBA levels decreased significantly in the H.HFV group (p < .05), and hepatic glutathione and malondialdehyde levels decreased significantly in both H.LFV and H.HFV groups (p < .05). Decreased abundance of Firmicutes, Burkholderiales, Syntrophomonas, and Pseudomonadales in gut microbiota was observed in H.LFV and H.HFV groups compared to the H group. The Anosim results showed significant differences in pairwise comparison between groups. The linear discriminant analysis effect size (LEfSe) results showed that k_bacteria not only exhibited statistically differences between H and C groups but also among H.LFV, H.LFV, and H groups, and hence, could be used as a biomarker between groups. To sum up, fruit and vegetable powder could increase the fecal excretion of TC and TBA, and the antioxidant capacity in C57BL/6N mice. Meanwhile, the mechanism that fruit and vegetable powder could prevent MS in C57BL/6N mice was related to the decreased abundance of gut microbiota, including Firmicutes, Syntrophomonadales, and Pseudomonadales. Hence, fruit and vegetable powder could be used as a recommended food to regulate gut microbiota and prevent the occurrence of MS-related diseases.

Altered brain spontaneous and synchronization activity in latent autoimmune diabetes in adults: A resting-state functional MRI study.

AIMS: This study aimed to explore the clinical features and spontaneous brain activity among patients with latent autoimmune diabetes in adults (LADA) and to investigate the relationship among these characteristics. METHODS: We conducted a cross-sectional study using cognitive assessments and resting-state functional magnetic resonance imaging (rs-fMRI) to evaluate the cognitive function and brain activities of healthy controls (HCs) and patients with LADA. Functional connectivity (FC) analysis was performed on the brain regions that showed significantly different activation in regional homogeneity (ReHo) analysis between the two groups. Furthermore, a linear regression model was conducted for the association between metabolism and cognition. RESULTS: This study enrolled patients with LADA (and age-, sex-, and education-matched HCs). Patients with LADA had worse cognitive status at the general level and poorer memory than controls. Rs-fMRI analysis among patients with LADA showed decreased ReHo values in the right occipital lobe and temporal lobe and decreased seed-based FC in the right parietal lobe compared to those of controls. The seed-based FC values in the right parietal lobe were positively associated with word fluency and processing speed in patients with LADA. Furthermore, low-density lipoprotein cholesterol was negatively correlated with Montreal Cognitive Assessment scores in patients with LADA. CONCLUSIONS: Patients with LADA had worse cognitive function and decreased spontaneous brain activity in the temporal lobe and occipital lobe compared to controls. Moreover, glycolipid metabolism was closely related to brain structure and function in patients with LADA.

Theacrine alleviates sepsis-induced acute kidney injury by repressing the activation of NLRP3/Caspase-1 inflammasome.

Acute kidney injury (AKI) is a frequent and serious complication of sepsis, which results in a rapid decline of kidney function. Currently, there are no curative therapies for AKI. Theacrine is a purine alkaloid and exerts significant role in regulating inflammation, oxidative stress, and mood elevation. The study aims to evaluate the biological role and potential mechanism of theacrine in septic AKI. The murine and cellular models of septic AKI were established in lipopolysaccharide (LPS)-treated C57BL/6 mice and HK-2 cells, respectively. The effect of theacrine on alleviating septic AKI was assessed after pretreatment with theacrine in vivo and in vitro. We found that theacrine treatment significantly alleviated LPS-induced kidney injury, as evidenced by decreased levels of kidney injury markers (blood urea nitrogen and creatinine), inflammatory factors (IL-1ß and IL-18), and cell apoptosis in vivo and in vitro. Mechanistically, theacrine markedly repressed the activation of NOD-like receptor (NLR) pyrin domain-containing protein 3 (NLRP3)inflammasome. As expected, MCC950 (a specific inhibitor of NLRP3) treatment also decreased LPS-induced production of IL-18 and IL-1ß and cell apoptosis in HK-2 cells. More important, Nigericin sodiumsalt (a NLRP3 agonist) damaged the effect of theacrine on repressing kidney injury markers (blood urea nitrogen and creatinine), pro-inflammatory cytokines (IL-18 and IL-1ß), and cell apoptosis. Taken together, these results demonstrate that theacrine alleviates septic AKI, at least in part by repressing the activation of NLRP3 inflammasome.

Dual-dynamic-bond cross-linked injectable hydrogel of multifunction for intervertebral disc degeneration therapy.

Developing smart hydrogels with integrated and suitable properties to treat intervertebral disc degeneration (IVDD) by minimally invasive injection is of high desire in clinical application and still an ongoing challenge. In this work, an extraordinary injectable hydrogel PBNPs@OBG (Prussian blue nanoparticles@oxidized hyaluronic acid/borax/gelatin) with promising antibacterial, antioxidation, rapid gelation, and self-healing characteristics was designed via dual-dynamic-bond cross-linking among the oxidized hyaluronic acid (OHA), borax, and gelatin. The mechanical performance of the hydrogel was studied by dynamic mechanical analysis. Meanwhile, the swelling ratio and degradation level of the hydrogel was explored. Benefiting from its remarkable mechanical properties, sufficient tissue adhesiveness, and ideal shape-adaptability, the injectable PBNPs containing hydrogel was explored for IVDD therapy. Astoundingly, the as-fabricated hydrogel was able to alleviate H2O2-induced excessive ROS against oxidative stress trauma of nucleus pulposus, which was further revealed by theoretical calculations. Rat IVDD model was next established to estimate therapeutic effect of this PBNPs@OBG hydrogel for IVDD treatment in vivo. On the whole, combination of the smart multifunctional hydrogel and nanotechnology-mediated antioxidant therapy can serve as a fire-new general type of therapeutic strategy for IVDD and other oxidative stress-related diseases.