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.

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.

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.

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.

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.

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.

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.

The effect of corticosteroid injection in the treatment of greater trochanter pain syndrome: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: corticosteroid injection (CSI) has been used to treat greater trochanter pain syndrome (GTPS) for many years. However, so far, the efficacy of CSI in the treatment of GTPS is still controversial. Therefore, the aim of this review is to evaluate the effectiveness of CSI in comparison with sham intervention, nature history, usual care, platelet-rich plasma (PRP), physiotherapy/exercise therapy, dry needling, or other nonsurgical treatment for improvements in pain and function in GTPS. METHODS: PubMed (Medline), Embase, Cochrane Library were searched from their inception until April 2021. Randomized controlled trails (RCTs) comparing CSI to nonsurgical treatment were included. Data on the effect of CSI on pain and function were extracted and checked by two review authors independently. The treatment effect was analyzed in the short term, medium term, and long term. RESULTS: Eight RCTs (764 patients) were included. This review suggests CSI may be superior to usual care and 'wait and see,' ESWT, but may not be superior to exercise, PRP, dry needling, and sham intervention in short-term pain or function improvement. In terms of medium-term pain or function improvement, CSI may be superior to usual care and 'wait and see,' but may not be superior to PRP. In terms of long-term pain or function improvement, CSI may be inferior to PRP and ESWT, but it may be superior to usual care and 'wait and see' at 12 months. CONCLUSIONS: Due to the small sample size and lack of sufficient clinical studies, current evidence is equivocal regarding the efficacy of CSI in the treatment of GTPS. Considering the limitations, more large-sample and high-quality RCTs are needed to prove the therapeutic effect of CSI on GTPS. TRIAL REGISTRATION: PROSPERO registration number: CRD42021247991. Registered 09 May 2021.

Synergy of "Yiqi" and "Huoxue" components of QishenYiqi formula in ischemic stroke protection via lysosomal/inflammatory mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Ischemic stroke is one of the leading causes of mortality and long-term disability worldwide. Currently, approved therapies of intravenous thrombolysis and mechanical thrombectomy are limited only to selected patients with rescuable brain tissue. Chinese medicine that benefits Qi (Yiqi, YQ) and activates blood (Huoxue, HX) is widely used in the clinic for treating stroke, but their mechanisms are not well understood yet. We have previously reported that QishenYiqi (QSYQ) formula exerts cerebral protective effect and promotes post-stroke recovery. AIM OF THE STUDY: This study aimed to explore the chemical basis and molecular mechanism of anti-stroke therapy of QSYQ and its YQ and HX components further. MATERIALS AND METHODS: Serum pharmacochemistry was performed to identify the bioactive constituents in QSYQ for cerebral protection. The survival rate, mNSS test, open field test, gait analysis, cerebral infarction volume, and blood-brain barrier (BBB) integrity were determined to uncover the synergistic and differential contributions of YQ and HX components in a cerebral ischemia/reperfusion injury (CI/RI) model. Bioinformatic mining of QSYQ proteomics data and experimental validation were executed to access the functional mechanism of YQ and HX components. RESULTS: Eleven prototype ingredients and six metabolites were successfully identified or tentatively characterized in rat plasma. Therapeutically, YQ and HX components of QSYQ synergistically boosted the survival rate, improved neurological and motor functions, alleviated cerebral infarction as well as protected BBB integrity in CI/RI model in rats. Individually, YQ component contributed more to ameliorating locomotive ability than that of HX component. Mechanistically, HX component played a more prominent role in the modulation of galectin-3 mediated inflammation whereas YQ component regulated lysosomal-autophagy signaling. CONCLUSIONS: This study identifies major prototype ingredients and metabolites of QSYQ in plasma which may contribute to its cerebral protection. YQ and HX components of QSYQ differentially and synergistically protect the brain from CI/RI by regulating galectin-3-mediated inflammation and lysosomal-autophagy signaling. These findings demonstrate that a maximal stroke protection by a component-based Chinese medicine could be attributed to the combination of its individual components via different mechanisms. It may shed new light on our understanding of the TCM principle of tonifying Qi and activating blood, particularly in a setting of ischemic stroke.

Guhong injection promotes post-stroke functional recovery via attenuating cortical inflammation and apoptosis in subacute stage of ischemic stroke.

BACKGROUND: As a leading cause of death and disability, alternative therapies for stroke are still limited by its complicated pathophysiological manifestations. Guhong injection (GHI), consisting of safflower aqueous extract and aceglutamide, has been widely applied for the clinical treatment of cerebrovascular diseases, especially ischemic stroke and post-stroke recovery, in China. Recently, a series of studies have reported the positive effect of GHI against cerebral ischemia/reperfusion injury via targeting various molecular mechanisms. However, questions remain on whether treatment with GHI contributes to better functional recovery after stroke and if so, the potential mechanisms and active substances. PURPOSE: The aim of this work was to explore the potential therapeutic possibilities of GHI for the neurological and behavioral recovery after stroke and to investigate the underlying molecular mechanisms as well as active substances. METHODS: The neural and motor deficits as well as cortical lesions after GHI treatment were investigated in a mouse model of transient ischemic stroke. Based on the substance identification of GHI, network pharmacology combined with an experimental verification method was used to systematically decipher the biological processes and signaling pathways closely related to GHI intervention in response to post-stroke functional outcomes. Subsequently, ingenuity pathway analysis (IPA) analysis was performed to determine the anti-stroke active substances targeting to the hub targets involved in the significant molecular pathways regulated by GHI treatment. RESULTS: Therapeutically, administration of GHI observably ameliorated the post-stroke recovery of neural and locomotor function as well as reduced infarct volume and histopathological damage to the cerebral cortex in subacute stroke mice. According to 26 identified or tentatively characterized substances in GHI, the compound-target-pathway network was built. Bioinformatics analysis suggested that inflammatory and apoptotic pathways were tightly associated with the anti-stroke effect of GHI. Based on protein-protein interaction network analysis, the hub targets (such as NF-κB p65, TNF-α, IL-6, IL-1ß, Bax, Bcl-2, and Caspase-3) involved in inflammation and apoptosis were selected. On the one hand, immunofluorescence and ELISA results showed that GHI (10 ml/kg) treatment obviously reduced NF-κB p65 nuclear translocation as well as decreased the abnormally elevated concentrations of proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) in damaged cortex tissues. On the other hand, GHI (10 ml/kg) treatment significantly downregulated the number of TUNEL-positive apoptotic cells in ischemic cortex and effectively restored the abnormal expression of Bax, Bcl-2, and Caspase-3. Based on the results of IPA, hydroxysafflor yellow A, baicalin, scutellarin, gallic acid, syringin, chlorogenic acid, kaempferol, kaempferol-3-O-ß-rutinoside, and rutin acted synergistically on core targets, which could be considered as the active substances of GHI. CONCLUSION: Overall, the current findings showed that the beneficial action of GHI on improving post-stroke functional recovery of subacute stroke mice partly via the modulation of cortical inflammation and apoptosis. These findings not only provide a reliable reference for the clinical application of GHI, but also shed light on a promising alternative therapeutic strategy for ischemic stroke patients.

The fast redox cycle of Cu(II)-Cu(I)-Cu(II) in the reduction of Cr(VI) by the Cu(II)-thiosulfate system.

Thiosulfate (S2O32-) is an important ligand to complex metal cations, however, the reactivity of metal-thiosulfate complexes has barely been mentioned. In this study, the reactivity of the Cu(II)-S2O32- system in the reduction of Cr(VI) was investigated. Kinetic results show that the reduction rates of Cr(VI) decrease with increasing pH values from 3.0 to 5.0, and 94.3% and 97.5% of 10 mg L-1 Cr(VI) was rapidly reduced within 1 min at pH 3.0 and within 30 min at pH 5.0, respectively at the molar ratio of Cu(II):S2O32- of 0.05. We rule out the contributions of S species of tetrathionate (S4O62-) and sulfite (SO32-) to Cr(VI) reduction and point out that the produced Cu(I) in the Cu(II)-S2O32- system is the key reductant that mediates the reduction of Cr(VI). We suggest that complexation between Cu(II) and S2O32- with the formation of CuII(S2O3)22- is the pre-requisite for the formation of CuI(S2O3)n1-2n, which plays an important role in Cr(VI) reduction, accompanied by the re-oxidation of Cu(I) to Cu(II) by Cr(VI), achieving the rapid redox cycling of Cu(II)-Cu(I)-Cu(II). Such a redox cycle also mediates the denitrification process of NO2- to NH3/NH4+ under weakly acidic conditions. This study enriches our understanding on the reducing reactivity of the Cu(II)-S2O32- system and the importance of the Cu(II)-Cu(I)-Cu(II) redox cycle towards environmental oxidizing contaminants.

Correction: Wang et al. 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. Biology 2022, 11, 1125.

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