Guanxinning Tablet Alleviates Post-Ischemic Stroke Injury Via Regulating Complement and Coagulation Cascades Pathway and Inflammatory Network Mobilization.

Background: Currently, ischemic stroke (IS) continues to significantly contribute to functional deterioration and reduced life quality. Regrettably, the choice of neuro-rehabilitation interventions to enhance post-IS outcomes is limited. Guanxinning tablet (GXNT), a multi-component medicine composed of Danshen and Chuanxiong, has demonstrated neuroprotective potential against ischemic brain injury and diabetic encephalopathy. However, the therapeutic impact of GXNT on post-IS functional outcomes and pathological injury, as well as the underlying molecular mechanisms and anti-IS active substances, remain unclear. Methods: To answer the above questions, neurological and behavioral assessment, cerebral lesions, and blood-brain barrier (BBB) integrity were combined to comprehensively investigate GXNT's pharmacodynamic effects against post-IS injury. The possible molecular mechanisms were revealed through transcriptome sequencing coupled with experimental verification. Furthermore, the brain tissue distribution of main components in GXNT, behavioral changes of IS zebrafish, and molecular docking were integrated to identify the anti-IS active compounds. Results: Treatment with GXNT significantly mitigated the functional deficits, cerebral cortex lesions, and BBB disruption following IS. Transcriptome sequencing and bioinformatics analysis suggested that complement and coagulation cascades as well as inflammation might play crucial roles in the GXNT's therapeutic effects. Molecular biology experiments indicated that GXNT administration effectively normalized the abnormal expression of mRNA and protein levels of key targets related to complement and coagulation cascades (eg C3 and F7) and inflammation (eg MMP3 and MMP9) in the impaired cortical samples of IS mice. The locomotor promotion in IS zebrafish as well as favorable affinity with key proteins (C3, F7, and MMP9) highlighted anti-IS activities of brain-permeating constituents (senkyunolide I and protocatechuic acid) of GXNT. Conclusion: Taken together, these intriguing findings indicate that GXNT intervention exerts a beneficial effect against post-IS injury via regulating the complement and coagulation cascades pathway and mobilizing inflammatory network. Senkyunolide I and protocatechuic acid show promise as anti-IS active compounds.

The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB.

Hepatic gluconeogenesis plays a crucial role in maintaining glucose homeostasis and serves as a potential therapeutic target for type 2 diabetes, while its underlying mechanisms are not fully understood. This study elucidates the role of the deubiquitinase OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) in gluconeogenesis. We found that hepatic OTUB1 expression is reduced in both db/db mice and patients with type 2 diabetes. Deletion of hepatic OTUB1 significantly elevates fasting blood glucose levels and increases the expression of key gluconeogenic genes. Conversely, overexpression of OTUB1 in hepatocytes mitigates diabetic hyperglycemia and enhances insulin sensitivity. It is known that the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein ß (YWHAB) functions as an inhibitor of hepatic gluconeogenesis by interacting with forkhead box protein O (FOXO1) and glucagon receptor (GPCR), but its own modification mechanism remains unclear. Our findings indicate that OTUB1 interacts with YWHAB and deubiquitinates it through a catalytic process, which in turn suppresses gluconeogenesis. Therefore, OTUB1 plays a pivotal role in inhibiting hepatic gluconeogenesis, highlighting its potential as a therapeutic target for type 2 diabetes.

On-Surface Synthesis of Five-Membered Copper Metallacycles Using Terminal Alkynes.

We present our studies on the adsorption, deprotonation, and reactions of 4,4″-diethynyl-1,1':4',1″-terphenyl on Cu(111) under ultrahigh-vacuum conditions using scanning tunneling microscopy combined with density functional theory calculations. Sequential annealing treatments induce deprotonation of pristine molecules followed by chemical reactions, resulting in branched nanostructures. Within the nanostructures, a previously unreported, double-spot linkage is observed. Our density functional theory calculations unravel that this linkage corresponds to a five-membered copper metallacycle.

Multi-Region Markovian Gaussian Process: An Efficient Method to Discover Directional Communications Across Multiple Brain Regions.

Studying the complex interactions between different brain regions is crucial in neuroscience. Various statistical methods have explored the latent communication across multiple brain regions. Two main categories are the Gaussian Process (GP) and Linear Dynamical System (LDS), each with unique strengths. The GP-based approach effectively discovers latent variables with frequency bands and communication directions. Conversely, the LDS-based approach is computationally efficient but lacks powerful expressiveness in latent representation. In this study, we merge both methodologies by creating an LDS mirroring a multi-output GP, termed Multi-Region Markovian Gaussian Process (MRM-GP). Our work establishes a connection between an LDS and a multi-output GP that explicitly models frequencies and phase delays within the latent space of neural recordings. Consequently, the model achieves a linear inference cost over time points and provides an interpretable low-dimensional representation, revealing communication directions across brain regions and separating oscillatory communications into different frequency bands.

A multifunctional evanescent wave biosensor for the universal assay of SARS-CoV-2 variants and affinity analysis of coronavirus spike protein-hACE2 interactions.

The conventional detection model of passive adaptation to pathogen mutations, i.e., developing assays using corresponding antibodies or nucleic acid probes, is difficult to address frequent outbreaks of emerging infectious diseases. In particular, adaptive mutations observed in coronaviruses, which increase the affinity of the spike protein with the human cellular receptor hACE2, play pivotal roles in the transmission and immune evasion of coronaviruses. Herein, we developed a multifunctional optical fiber evanescent wave biosensor for the universal assay of coronavirus and affinity analysis of the spike protein interacting with hACE2, namely, My-SPACE. By competitively binding with Cy5.5-hACE2 between coronavirus spike proteins in mobile buffer and that modified on optical fibers from the SARS-CoV-2 wild type, My-SPACE could automatically detect SARS-CoV-2 and its variants within 10 min. My-SPACE demonstrated greater sensitivity and faster results than ELISA for SARS-CoV-2 variants, achieving 100% specificity and 94.10% sensitivity in detecting the Omicron variant in 18 clinical samples. Moreover, the interaction between hACE2 and the coronavirus spike protein was accurately characterized across SARS-CoV-2 mutants, SARS-CoV and hCoV-NL63. The accuracy of the affinity determined by My-SPACE was verified by SPR. This approach enables preliminary assessment of the transmissibility and hazards of emerging coronaviruses. The sensor fibers of My-SPACE can be reused more than 40 times, and the device is compact and easy to use; moreover, it is available as a rapid and cost-effective on-site detection tool adapted to coronavirus variability and as an effective assessment platform for early warning of coronavirus transmission risk.

Identification of two key genes involved in flavonoid catabolism and their different roles in apple resistance to biotic stresses.

Biosynthesis of flavonoid aglycones and glycosides is well established. However, key genes involved in their catabolism are poorly understood, even though the products of hydrolysis and oxidation play important roles in plant resistance to biotic stress. Here, we report on catabolism of dihydrochalcones (DHCs), the most abundant flavonoids in domesticated apple and wild Malus. Two key genes, BGLU13.1 and PPO05, were identified by activity-directed protein purification. BGLU13.1-A hydrolyzed phlorizin, (the most abundant DHC in domesticated apple) to produce phloretin which was then oxidized by PPO05. The process differed in some wild Malus, where trilobatin (a positional isomer of phlorizin) was mainly oxidized by PPO05. The effects of DHC catabolism on apple resistance to biotic stresses was investigated using transgenic plants. Either directly or indirectly, phlorizin hydrolysis affected resistance to the phytophagous pest two-spotted spider mite, while oxidation of trilobatin was involved in resistance to the biotrophic fungus Podosphaera leucotricha. DHC catabolism did not affect apple resistance to necrotrophic pathogens Valsa mali and Erwinia amylovara. These results suggest that different DHC catabolism pathways play different roles in apple resistance to biotic stresses. The role of DHC catabolism on apple resistance appeared closely related to the mode of invasion/damage used by pathogen/pest.

Dihydrochalcone glycoside biosynthesis in Malus is regulated by two MYB-like transcription factors and is required for seed development.

Dihydrochalcones (DHCs) including phlorizin (phloretin 2'-O-glucoside) and its positional isomer trilobatin (phloretin 4'-O-glucoside) are the most abundant phenylpropanoids in apple (Malus spp.). Transcriptional regulation of DHC production is poorly understood despite their importance in insect- and pathogen-plant interactions in human physiology research and in pharmaceuticals. In this study, segregation in hybrid populations and bulked segregant analysis showed that the synthesis of phlorizin and trilobatin in Malus leaves are both single-gene-controlled traits. Promoter sequences of PGT1 and PGT2, two glycosyltransferase genes involved in DHC glycoside synthesis, were shown to discriminate Malus with different DHC glycoside patterns. Differential PGT1 and PGT2 promoter activities determined DHC glycoside accumulation patterns between genotypes. Two transcription factors containing MYB-like DNA-binding domains were then shown to control DHC glycoside patterns in different tissues, with PRR2L mainly expressed in leaf, fruit, flower, stem, and seed while MYB8L mainly expressed in stem and root. Further hybridizations between specific genotypes demonstrated an absolute requirement for DHC glycoside production in Malus during seed development which explains why no Malus spp. with a null DHC chemotype have been reported.

Huperzine A injection ameliorates motor and cognitive abnormalities via regulating multiple pathways in a murine model of Parkinson's disease.

As a common progressive neurodegenerative disorder, the satisfied therapies for Parkinson's disease (PD) are still unavailable. As a natural acetylcholinesterase inhibitor, the neuroprotective characteristic of Huperzine A (HupA) was supported by previous studies. However, questions remain on whether HupA injection (HAI, a main preparation of HupA) intervention conduces to PD treatment and if so, the potential molecular mechanisms. In this study, the efficacies of HAI treatment on PD-like pathological phenotypes were evaluated in a MPTP-induced PD murine model. The network pharmacology, transcriptome sequencing and experimental verification were integrated to comprehensively reveal the primary molecular mechanisms. Therapeutically, HAI intervention significantly improved the impaired locomotor behaviors as well as learning and memory abilities, and prevented the degeneration of dopaminergic neurons of PD mice. The network pharmacology analysis combined with experimental results showed that HAI treatment could effectively restore the disordered transcriptional levels of inflammatory factors and apoptosis related genes in the SNpc and striatum tissues of PD mice. Transcriptome sequencing results found that inflammation and oxidative phosphorylation served as significant functional mechanisms involved in HAI administration. The experimental verification indicated that HAI treatment effectively regulated the abnormal transcription levels of inflammation and oxidative phosphorylation related hub genes in the hippocampal samples of PD mice. In addition, molecular docking suggested strong affinity between HupA and the above core targets. Overall, this work displayed the reliable therapeutic effects of HAI on ameliorating the pathological symptoms of PD mice via modulating multiple pathways. The current findings were expected to provide a potential anti-PD agent.

Discovery of novel polysubstituted N-alkyl acridone analogues as histone deacetylase isoform-selective inhibitors for cancer therapy.

Pan-histone deacetylase (HDAC) inhibitors often have some toxic side effects. In this study, three series of novel polysubstituted N-alkyl acridone analogous were designed and synthesised as HDAC isoform-selective inhibitors. Among them, 11b and 11c exhibited selective inhibition of HDAC1, HDAC3, and HDAC10, with IC50 values ranging from 87 nM to 418 nM. However, these compounds showed no inhibitory effect against HDAC6 and HDAC8. Moreover, 11b and 11c displayed potent antiproliferative activity against leukaemia HL-60 cells and colon cancer HCT-116 cells, with IC50 values ranging from 0.56 µM to 4.21 µM. Molecular docking and energy scoring functions further analysed the differences in the binding modes of 11c with HDAC1/6. In vitro anticancer studies revealed that the hit compounds 11b and 11c effectively induced histone H3 acetylation, S-phase cell cycle arrest, and apoptosis in HL-60 cells in a concentration-dependent manner.

Selective Oxidation of Cyclohexane to Cyclohexanol/Cyclohexanone by Surface Peroxo Species on Cu-Mesoporous TiO2.

Selective oxidation of cyclohexane to cyclohexanol/cyclohexanone (KA-oil) is an important chemical process, which is still constrained by low conversion and selectivity and high energy consumption. In this study, Cu-doped mesoporous TiO2 (Cu-MT) has been successfully synthesized via calcinating MIL-125(Ti) doped with copper acetylacetonate, which shows high reactivity in selective oxidation of cyclohexane to KA-oil by persulfate (PS) with the desirable cyclohexane conversion of 16.8% and a selectivity of 98.0% under mild conditions and the low ratio of PS/cyclohexane of 1:1. A series of characterizations and density functional theory calculations reveal that the doped Cu(I,II) on Cu-MT is the reactive site for non-radical activation of PS with the moderate elongation of the O-O bond in PS, which then abstracts 1H (1H+ + 1e-) from cyclohexane to form Cy• and eventually KA-oil. This study gives new insight on the importance of moderately activated PS in selective oxidation of C-H.

1,2,4,5-Tetrazine-tethered probes for fluorogenically imaging superoxide in live cells with ultrahigh specificity.

Superoxide (O2·-) is the primary reactive oxygen species in mammal cells. Detecting superoxide is crucial for understanding redox signaling but remains challenging. Herein, we introduce a class of activity-based sensing probes. The probes utilize 1,2,4,5-tetrazine as a superoxide-responsive trigger, which can be modularly tethered to various fluorophores to tune probe sensitivity and emission color. These probes afford ultra-specific and ultra-fluorogenic responses towards superoxide, and enable multiplexed imaging of various cellular superoxide levels in an organelle-resolved way. Notably, the probes reveal the aberrant superoxide generation in the pathology of myocardial ischemia/reperfusion injury, and facilitate the establishment of a high-content screening pipeline for mediators of superoxide homeostasis. One such identified mediator, coprostanone, is shown to effectively ameliorating oxidative stress-induced injury in mice with myocardial ischemia/reperfusion injury. Collectively, these results showcase the potential of 1,2,4,5-tetrazine-tethered probes as versatile tools to monitor superoxide in a range of pathophysiological settings.

Effect of Repetitive Transcranial Magnetic Stimulation on Post-stroke Dysphagia in Acute Stage.

Repetitive transcranial magnetic stimulation (rTMS) play a important role for rehabilitation in stroke. But therapeutic schedule of rTMS in dysphagia after acute stroke is still controversial. The purpose of this study was to investigate the therapeutic effect of rTMS with different frequencies on dysphagia after acute stroke. From August 2019 to December 2020, 45 patients with post-stroke dysphagia were selected as research subjects, and randomly divided into 3 groups: the high frequency stimulation on bilateral hemisphere group (High group), bilateral high frequency stimulation on the affected hemisphere and low frequency stimulation on the unaffected hemisphere group (High-low group), and sham stimulation group (Sham group). On the basis of routine swallowing training (30 min) for all patients, the high group received 5 Hz rTMS in both hemispheres, the high- low group received 5 Hz rTMS in the unaffected hemisphere, 1 Hz rTMS in the affected hemisphere, and the sham stimulation group received sham stimulation in bilateral hemisphere. All participants were assessed with dysphagia handicap index (DHI), functional oral intake scale (FOIS) and videofluoroscopic swallowing study (VFSS) before the intervention (T1), immediately after intervention (T2) and 1 month after the intervention (T3). Meanwhile, according to the results of VFSS, Rosenbek penetration aspiration scale (PAS), the moving distance of hyoid bone towards the superior side (H), and pharyngeal response time (T) were analyzed and evaluated. After intervention, all three groups showed significant improvement in post-treatment scores from baseline (P = 0.000). The results of DHI, PAS and H showed that the improvement in high group and high-low group was significantly greater than sham group (P = 0.000). The results of FOIS and T showed that the improvement of bilateral high-frequency group was significantly greater than that of high-low group and sham group (P = 0.000), and the difference lasted until 1 month after the end of treatment. Therefore, bilateral pharyngeal cortex high frequency rTMS and affected side high frequency/unaffected side low frequency rTMS can effectively improve swallowing disorder after acute stroke. However, the effect of bilateral high frequency rTMS is significantly higher than high-low in improving oral feeding function and pharyngeal response time.

Angong Niuhuang Pill ameliorates cerebral ischemia/reperfusion injury in mice partly by restoring gut microbiota dysbiosis.

Angong Niuhuang Pill (ANP) is a famous traditional Chinese patent medicine and is used for treating ischemic or hemorrhagic stroke for centuries. However, the mechanism of action of ANP in stroke treatment has rarely been reported. With increasing evidence for a mechanistic link between acute ischemic stroke and gut microbiota alterations, this study aimed to determine the mechanism of action of ANP in treating acute ischemic stroke from the perspective of the gut microbiota. A mouse model of acute ischemic stroke by middle cerebral artery occlusion (MCAO) was established, and 16S ribosomal RNA (rRNA) gene sequencing and metabolomic analysis were performed on the cecal content samples collected from the sham, model, and ANP-treated MCAO mice. The results showed that ANP significantly ameliorated cerebral infarct volume, improved neurological deficits, and reduced histopathological injuries in the ipsilateral ischemic cortex, hippocampus, and striatum. The latter effects included inhibition of neuronal death, increased Nissl bodies, and decreased cell apoptosis. Moreover, ANP reversed gut microbiota dysbiosis by modulating the abundance of bacteria whose effects may mitigate MCAO damage, such as the phyla Bacteroidetes and Firmicutes, the families Lachnospiraceae and Prevotellaceae, and the genera Alloprevotella and Roseburia. Microbial metabolites related to inflammation and neuroprotection, such as prostaglandin I2 and uridine, were also regulated by ANP treatment. Uridine, guanosine, and inosine might be potential neuromodulators produced by the gut microbiota in the ANP-treated group. Spearman correlation analysis revealed that these metabolites were intimately related to certain genera, including Alloprevotella, Lachnoclostridium, Enterorhabdus, Roseburia, Lachnospiraceae_UCG-006, and Colidextribacter. Our results demonstrated that alleviating gut microbiota dysbiosis is one of the mechanisms by which ANP protects against ischemic stroke and suggest that targeting Alloprevotella, Lachnoclostridium, Enterorhabdus, Roseburia, Lachnospiraceae_UCG-006, and Colidextribacter might be a potential anti-stroke therapy.

Discovery of anti-stroke active substances in Guhong injection based on multi-phenotypic screening of zebrafish.

Ischemic stroke is a leading cause of death worldwide, and it remains an urgent task to develop novel and alternative therapeutic strategies for the disease. We previously reported the positive effects of Guhong injection (GHI), composed of safflower extract and aceglutamide, in promoting functional recovery in ischemic stroke mice. However, the active substances and pharmacological mechanism of GHI is still elusive. Aiming to identify the active anti-stroke components in GHI, here we conducted a multi-phenotypic screening in zebrafish models of phenylhydrazine-induced thrombosis and ponatinib-induced cerebral ischemia. Peripheral and cerebral blood flow was quantified endogenously in erythrocytes fluorescence-labeled thrombosis fish, and baicalein and rutin were identified as major anti-thrombotic substances in GHI. Moreover, using a high-throughput video-tracking system, the effects of locomotion promotion of GHI and its main compounds were analyzed in cerebral ischemia model. Chlorogenic acid and gallic acid showed significant effects in preventing locomotor dyfunctions. Finally, GHI treatment greatly decreased the expression levels of coagulation factors F7 and F2, NF-κB and its mediated proinflammatory cytokines in the fish models. Molecular docking suggested strong affinities between baicalein and F7, and between active substances (baicalein, chlorogenic acid, gallic acid, and rutin) and NF-κB p65. In summary, our findings established a novel drug discovery method based on multi-phenotypic screening of zebrafish, provided endogenous evidences of GHI in preventing thrombus formation and promoting behavioral recovery after cerebral ischemia, and identified baicalein, rutin, chlorogenic acid, and gallic acid as active compounds in the management of ischemic stroke.

DiHuangYin decoction protects dopaminergic neurons in a Parkinson's disease model by alleviating peripheral inflammation.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease, which brings increasing threaten for human health and is still lacking of satisfied treatment. Recently, numerous studies have also demonstrated the effect of particular subsets of CD4+ T cells on PD pathology. Th17 cells played an important role in the pathogenesis of PD. Traditional Chinese medicine has been widely used to treat PD clinically, and has a tremendous potential in clinical drug development. PURPOSE: The aim of this study was to verify the therapeutic effects of DHY on PD mice model, and investigate the underlying molecular mechanisms. METHODS: Herein, we verified the effects of a traditional Chinese medicine formula, named DiHuangYin (DHY), on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD through behavioral and histopathological tests. High-resolution mass spectrometry combined with molecular networking was applied for substance profiling of DHY. Based on the chemical compositions of DHY, network pharmacology was performed. Immunofluorescence and ELISA were used to evaluate the expressions of cytokines in peripheral immune system. qPCR and immunofluorescence were used to detect the inflammation infiltration of central nervous system. RESULTS: DHY improves the motor function and prevents the loss of dopaminergic neurons in the MPTP induced mouse model of PD. 118 components of DHY were identified or tentatively characterized based on the MS/MS data and molecular networking. Network pharmacology suggested IL-17 signaling pathway and neuroactive ligand-receptor interaction as the important targets. Compared to the MPTP-intoxicated mice, the DHY group showed a decreased number of Th17 cells from splenocytes and a decreased level of IL-17A in the serum. On the other hand, less inflammatory infiltration was found in the midbrain of DHY treatment mice which might be associated with the attenuated peripheral inflammation. CONCLUSIONS: Though the underlying pharmacological mechanism of DHY is still lacking, we provided evidence that DHY decoction could protect dopaminergic neurons by mitigating peripheral inflammation.

An Optimization on the Neuronal Networks Based on the ADEX Biological Model in Terms of LUT-State Behaviors: Digital Design and Realization on FPGA Platforms.

Design and implementation of biological neural networks is a vital research field in the neuromorphic engineering. This paper presents LUT-based modeling of the Adaptive Exponential integrate-and-fire (ADEX) model using Nyquist frequency method. In this approach, a continuous term is converted to a discrete term by sampling factor. This new modeling is called N-LUT-ADEX (Nyquist-Look Up Table-ADEX) and is based on accurate sampling of the original ADEX model. Since in this modeling, the high-accuracy matching is achieved, it can exactly reproduce the spiking patterns, which have the same behaviors of the original neuron model. To confirm the N-LUT-ADEX neuron, the proposed model is realized on Virtex-II Field-Programmable Gate Array (FPGA) board for validating the final hardware. Hardware implementation results show the high degree of similarity between the proposed and original models. Furthermore, low-cost and high-speed attributes of our proposed neuron model will be validated. Indeed, the proposed model is capable of reproducing the spiking patterns in terms of low overhead costs and higher frequencies in comparison with the original one. The properties of the proposed model cause can make it a suitable choice for neuromorphic network implementations with reduced-cost attributes.

Effects of Electromyography Bridge on Upper Limb Motor Functions in Stroke Participants: An Exploratory Randomized Controlled Trial.

The electromyography bridge (EMGB) plays an important role in promoting the recovery of wrist joint function in stroke patients. We investigated the effects of the EMGB on promoting the recovery of upper limb function in hemiplegia. Twenty-four stroke patients with wrist dorsal extension dysfunction were recruited. Participants were randomized to undergo EMGB treatment or neuromuscular electrical stimulation (NMES). Treatments to wrist extensors were conducted for 25 min, twice a day, 5 days per week, for 1 month. Outcome measures: active range of motion (AROM) of wrist dorsal extension; Fugl-Meyer assessment for upper extremity (FMA-UE); Barthel index (BI); and muscle strength of wrist extensors. After interventions, patients in the NMES group had significantly greater improvement in the AROM of wrist dorsal extension at the 4th week and 1st month follow-up (p < 0.05). However, patients in the EMGB group had a statistically significant increase in AROM only at the follow-up assessment. No significant differences were observed in the AROM between the EMGB group and the NMES group (p > 0.05). For secondary outcomes in the EMGB group, compared to baseline measurements, FMA-UE, BI, extensor carpi radialis and extensor carpi ulnaris muscle strength were significantly different as early as the 4th week (p < 0.05). The muscle strength of the extensor digitorum communis muscle showed significant differences at the follow-up (p < 0.05). There were no statistically significant differences between patients in the two groups in any of the parameters evaluated (p > 0.05). The combination of EMGB or NMES with conventional treatment had similar effects on the improvement of the hemiplegic upper limb as assessed by wrist dorsal extension, FMA-UE, and activities of daily living. The improvement in both groups was maintained until 1 month after the intervention.

Rapid and universal detection of SARS-CoV-2 and influenza A virus using a reusable dual-channel optic fiber immunosensor.

Establishment of rapid on-site detection technology capable of concurrently detecting SARS-Cov-2 and influenza A virus is urgent to effectively control the epidemic from these two types of important viruses. Accordingly, we developed a reusable dual-channel optical fiber immunosensor (DOFIS), which utilized the evanescent wave-sensing properties and tandem detection mode of the mobile phase, effectively accelerating the detection process such that it can be completed within 10 min. It could detect the nucleoprotein of multiple influenza A viruses (H1N1, H3N2, and H7N9), as well as the spike proteins of the SARS-CoV-2 Omicron and Delta variants, and could respond to 20 TCID50 /ml SARS-CoV-2 pseudovirus and 100 TCID50 /ml influenza A (A/PR/8/H1N1), presenting lower limit of detection and wider linear range than enzyme-linked immunosorbent assay. The detection results on 26 clinical samples for SARS-CoV-2 demonstrated its specificity (100%) and sensitivity (94%), much higher than the sensitivity of commercial colloidal gold test strip (35%). Particularly, DOFIS might be reused more than 80 times, showing not only cost-saving but also potential in real-time monitoring of the pathogenic viruses. Therefore, this newly-developed DOFIS platform is low cost, simple to operate, and has broad spectrum detection capabilities for SARS-CoV-2 mutations and multiple influenza A strains. It may prove suitable for deployment as a rapid on-site screening and surveillance technique for infectious disease.

A novel inhalable quercetin-alginate nanogel as a promising therapy for acute lung injury.

BACKGROUND: Acute lung injury (ALI), a severe health-threatening disease, has a risk of causing chronic pulmonary fibrosis. Informative and powerful evidence suggests that inflammation and oxidative stress play a central role in the pathogenesis of ALI. Quercetin is well recognized for its excellent antioxidant and anti-inflammatory properties, which showed great potential for ALI treatment. However, the application of quercetin is often hindered by its low solubility and bioavailability. Therefore, to overcome these challenges, an inhalable quercetin-alginate nanogel (QU-Nanogel) was fabricated, and by this special "material-drug" structure, the solubility and bioavailability of quercetin were significantly enhanced, which could further increase the activity of quercetin and provide a promising therapy for ALI. RESULTS: QU-Nanogel is a novel alginate and quercetin based "material-drug" structural inhalable nanogel, in which quercetin was stabilized by hydrogen bonding to obtain a "co-construct" water-soluble nanogel system, showing antioxidant and anti-inflammatory properties. QU-Nanogel has an even distribution in size of less than 100 nm and good biocompatibility, which shows a stronger protective and antioxidant effect in vitro. Tissue distribution results provided evidence that the QU-Nanogel by ultrasonic aerosol inhalation is a feasible approach to targeted pulmonary drug delivery. Moreover, QU-Nanogel was remarkably reversed ALI rats by relieving oxidative stress damage and acting the down-regulation effects of mRNA and protein expression of inflammation cytokines via ultrasonic aerosol inhalation administration. CONCLUSIONS: In the ALI rat model, this novel nanogel showed an excellent therapeutic effect by ultrasonic aerosol inhalation administration by protecting and reducing pulmonary inflammation, thereby preventing subsequent pulmonary fibrosis. This work demonstrates that this inhalable QU-Nanogel may function as a promising drug delivery strategy in treating ALI.

Qishen Yiqi Dropping Pill facilitates post-stroke recovery of motion and memory loss by modulating ICAM-1-mediated neuroinflammation.

BACKGROUND: Promotion of functional recovery in patients is the primary goal of stroke management. However, its achievement is low due to the lack of full understanding of the complex pathological process of stroke and therefore limited therapeutic strategies. Qishen Yiqi Dropping Pill (QSYQ) is a component-based Chinese medicine that has been widely used in clinical treatment of ischemic cardiovascular diseases. Our previous studies indicated that QSYQ were protective for acute ischemic stroke in animal models and this study aimed to investigate the effect of QSYQ on brain function during stroke recovery. METHODS: The therapeutic effects of QSYQ were evaluated by neurological deficit score, dark avoidance test, gait analysis, Morris water maze and brain tissue atrophy volume in a rat model of middle cerebral artery occlusion (MCAO) with ischemia for 60 min. The underlying mechanisms of QSYQ accelerating the functional recovery of MCAO rats was then revealed using proteomic sequencing and validated by immunohistochemistry, qRT-PCR and ELISA assays. The active components in QSYQ were elucidated by molecular docking and verified biochemically in vitro. RESULTS: QSYQ treatment for 28 days significantly improved the neurological function, gait, spontaneous activity, spatial memory, and reduced brain atrophy in MCAO rats. Proteomic analysis of ischemic brain region and the following bioinformatics studies showed that QSYQ intervention markedly modulated neuroinflammatory responses post stroke, in which ICAM-1 played a dominant role. In particular, QSYQ reversed high cerebral expression of ICAM-1 in MCAO rats and decreased the content of TNF-α, IL-6 and IL1ß in brain tissue and serum. In vitro, it was found that the active component rosmarinic acid in QSYQ evidently inhibit the expression of ICAM-1 caused by oxygen glucose deprivation/reoxygenation injury via using immunofluorescence staining. CONCLUSION: QSYQ effectively accelerates the recovery of motor impairment and memory loss in rats after stroke via downregulation of ICAM-1-mediated neuroinflammation, and rosmarinic acid is one of its main active components.