RESPIRATORY BURST OXIDASE HOMOLOG 5.1 regulates H3K4me3 deposition and transcription after cold priming in cucumber.

Plants can maintain acquired cold tolerance for a long period after cold priming, even after the resumption of warmer temperatures. However, the transcriptional mechanisms active during the recovery period after cold priming remain unknown. Here, we found that in cucumber (Cucumis sativus), cold priming altered the Histone H3 lysine 4 trimethylation (H3K4me3) signal of sustainably-induced (memory) and non-sustainably-induced (NSI) genes during recovery. In addition, H3K4me3 marks on upregulated memory genes exhibited a specific epigenetic memory during recovery. However, the rank of the H3K4me3 signal on memory and NSI genes in the genome was independent of cold priming, which always contributed to and inhibited the formation of transcription patterns of memory and NIS genes, respectively. Furthermore, the short-lived increase of RESPIRATORY BURST OXIDASE HOMOLOG 5.1 (CsRBOH5.1) expression during recovery after cold priming was essential to maintain high levels of NADPH oxidase activity and apoplastic H2O2, causing cucumber to acquire cold priming and enhancing the maintenance of acquired cold tolerance (MACT). Interestingly, the expression of some key H3K4me3 methyltransferase genes and the accumulation of H3K4me3 on memory genes depended on CsRBOH5.1. Surprisingly, CsRBOH5.1 was essential for almost all genes to form the normal H3K4me3 signaling patterns during recovery, and the necessity was more obvious as recovery progressed. Moreover, transcriptional memory was completely lost in Csrboh5.1 mutants, and the transcriptional patterns of about 80% of NSI genes were disrupted. Overall, our results show that CsRBOH5.1 governs H3K4me3 deposition and cold-induced transcription during recovery after cold priming, affecting the acquisition of cold priming and the intensity of MACT.

SEPPA-mAb: spatial epitope prediction of protein antigens for mAbs.

Identifying the exact epitope positions for a monoclonal antibody (mAb) is of critical importance yet highly challenging to the Ab design of biomedical research. Based on previous versions of SEPPA 3.0, we present SEPPA-mAb for the above purpose with high accuracy and low false positive rate (FPR), suitable for both experimental and modelled structures. In practice, SEPPA-mAb appended a fingerprints-based patch model to SEPPA 3.0, considering the structural and physic-chemical complementarity between a possible epitope patch and the complementarity-determining region of mAb and trained on 860 representative antigen-antibody complexes. On independent testing of 193 antigen-antibody pairs, SEPPA-mAb achieved an accuracy of 0.873 with an FPR of 0.097 in classifying epitope and non-epitope residues under the default threshold, while docking-based methods gave the best AUC of 0.691, and the top epitope prediction tool gave AUC of 0.730 with balanced accuracy of 0.635. A study on 36 independent HIV glycoproteins displayed a high accuracy of 0.918 and a low FPR of 0.058. Further testing illustrated outstanding robustness on new antigens and modelled antibodies. Being the first online tool predicting mAb-specific epitopes, SEPPA-mAb may help to discover new epitopes and design better mAbs for therapeutic and diagnostic purposes. SEPPA-mAb can be accessed at http://www.badd-cao.net/seppa-mab/.

HIT 2.0: an enhanced platform for Herbal Ingredients' Targets.

Literature-described targets of herbal ingredients have been explored to facilitate the mechanistic study of herbs, as well as the new drug discovery. Though several databases provided similar information, the majority of them are limited to literatures before 2010 and need to be updated urgently. HIT 2.0 was here constructed as the latest curated dataset focusing on Herbal Ingredients' Targets covering PubMed literatures 2000-2020. Currently, HIT 2.0 hosts 10 031 compound-target activity pairs with quality indicators between 2208 targets and 1237 ingredients from more than 1250 reputable herbs. The molecular targets cover those genes/proteins being directly/indirectly activated/inhibited, protein binders, and enzymes substrates or products. Also included are those genes regulated under the treatment of individual ingredient. Crosslinks were made to databases of TTD, DrugBank, KEGG, PDB, UniProt, Pfam, NCBI, TCM-ID and others. More importantly, HIT enables automatic Target-mining and My-target curation from daily released PubMed literatures. Thus, users can retrieve and download the latest abstracts containing potential targets for interested compounds, even for those not yet covered in HIT. Further, users can log into 'My-target' system, to curate personal target-profiling on line based on retrieved abstracts. HIT can be accessible at http://hit2.badd-cao.net.

CsBPC2 is essential for cucumber survival under cold stress.

Cold stress affects the growth and development of cucumbers. Whether the BPC2 transcription factor participates in cold tolerance and its regulatory mechanism in plants have not been reported. Here, we used wild-type (WT) cucumber seedlings and two mutant Csbpc2 lines as materials. The underlying mechanisms were studied by determining the phenotype, physiological and biochemical indicators, and transcriptome after cold stress. The results showed that CsBPC2 knockout reduced cucumber cold tolerance by increasing the chilling injury index, relative electrical conductivity and malondialdehyde (MDA) content and decreasing antioxidant enzyme activity. We then conducted RNA sequencing (RNA-seq) to explore transcript-level changes in Csbpc2 mutants. A large number of differentially expressed genes (1032) were identified and found to be unique in Csbpc2 mutants. However, only 489 down-regulated genes related to the synthesis and transport of amino acids and vitamins were found to be enriched through GO analysis. Moreover, both RNA-seq and qPT-PCR techniques revealed that CsBPC2 knockout also decreased the expression of some key cold-responsive genes, such as CsICE1, CsCOR413IM2, CsBZR1 and CsBZR2. These results strongly suggested that CsBPC2 knockout not only affected cold function genes but also decreased the levels of some key metabolites under cold stress. In conclusion, this study reveals for the first time that CsBPC2 is essential for cold tolerance in cucumber and provides a reference for research on the biological function of BPC2 in other plants.

CsBPC2 is a key regulator of root growth and development.

BASIC PENTACYSTEINE (BPCs) transcription factors are important regulators of plant growth and development. However, the regulatory mechanism of BPC2 in roots remains unclear. In our previous study, we created Csbpc2 cucumber mutants by the CRISPR/Cas9 system, and our studies on the phenotype of Csbpc2 mutants showed that the root growth was inhibited compared with wide-type (WT). Moreover, the surface area, volume and number of roots decreased significantly, with root system architecture changing from dichotomous branching to herringbone branching. Compared with WT, the leaf growth of the Csbpc2 mutants was not affected. However, the palisade and spongy tissue were significantly thinner, which was not beneficial for photosynthesis. The metabolome of root exudates showed that compared with WT, amino acids and their derivatives were significantly decreased, and the enriched pathways were mainly regulated by amino acids and their derivatives, indicating that knockout of CsBPC2 mainly affected the amino acid content in root exudates. Importantly, transcriptome analysis showed that knockout of CsBPC2 mainly affected root gene expression. Knockout of CsBPC2 significantly reduced the gene expression of gibberellins synthesis. However, the expression of genes related to amino acid synthesis, nitrogen fixation and PSII-related photosynthesis increased significantly, which may be due to the effect of knocking out CsBPC2 on gibberellins synthesis, resulting in the inhibition of seedling growth, thus forming negative feedback regulation. Generally, we showed for the first time that BPC2 is a key regulator gene of root growth and development, laying the foundation for future mechanisms of BPC2 regulation in roots.

Rank-in: enabling integrative analysis across microarray and RNA-seq for cancer.

Though transcriptomics technologies evolve rapidly in the past decades, integrative analysis of mixed data between microarray and RNA-seq remains challenging due to the inherent variability difference between them. Here, Rank-In was proposed to correct the nonbiological effects across the two technologies, enabling freely blended data for consolidated analysis. Rank-In was rigorously validated via the public cell and tissue samples tested by both technologies. On the two reference samples of the SEQC project, Rank-In not only perfectly classified the 44 profiles but also achieved the best accuracy of 0.9 on predicting TaqMan-validated DEGs. More importantly, on 327 Glioblastoma (GBM) profiles and 248, 523 heterogeneous colon cancer profiles respectively, only Rank-In can successfully discriminate every single cancer profile from normal controls, while the others cannot. Further on different sizes of mixed seq-array GBM profiles, Rank-In can robustly reproduce a median range of DEG overlapping from 0.74 to 0.83 among top genes, whereas the others never exceed 0.72. Being the first effective method enabling mixed data of cross-technology analysis, Rank-In welcomes hybrid of array and seq profiles for integrative study on large/small, paired/unpaired and balanced/imbalanced samples, opening possibility to reduce sampling space of clinical cancer patients. Rank-In can be accessed at http://www.badd-cao.net/rank-in/index.html.

The Evolution Pathway of Ammonia-Oxidizing Archaea Shaped by Major Geological Events.

Primordial nitrification processes have been studied extensively using geochemical approaches, but the biological origination of nitrification remains unclear. Ammonia-oxidizing archaea (AOA) are widely distributed nitrifiers and implement the rate-limiting step in nitrification. They are hypothesized to have been important players in the global nitrogen cycle in Earth's early history. We performed systematic phylogenomic and marker gene analyses to elucidate the diversification timeline of AOA evolution. Our results suggested that the AOA ancestor experienced terrestrial geothermal environments at ∼1,165 Ma (1,928-880 Ma), and gradually evolved into mesophilic soil at ∼652 Ma (767-554 Ma) before diversifying into marine settings at ∼509 Ma (629-412 Ma) and later into shallow and deep oceans, respectively. Corroborated by geochemical evidence and modeling, the timing of key diversification nodes can be linked to the global magmatism and glaciation associated with the assembly and breakup of the supercontinent Rodinia, and the later oxygenation of the deep ocean. Results of this integrated study shed light on the geological forces that may have shaped the evolutionary pathways of the AOA, which played an important role in the ancient global nitrogen cycle.

The Associations Between CYP2D6 Metabolizer Status and Pharmacokinetics and Clinical Outcomes of Venlafaxine: A Systematic Review and Meta-Analysis.

BACKGROUND: The association between CYP2D6 metabolizer status and clinical outcomes of venlafaxine was extensively investigated previously, but no widely accepted conclusion has been reached so far. To obtain a more precise estimation of the association, a systematic review by meta-analysis was conducted in the present study. METHODS: The PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Technology of Chongqing, and Wan Fang Database were searched for eligible studies up to August 2018. RESULTS: Fourteen related studies involving 1035 patients were finally included. Significant associations were found among 3 CYP2D6 phenotypes (NM, IM, and PM) and most pharmacokinetic parameters of venlafaxine. However, CYP2D6 phenotypes were not associated with Hamilton Depression Rating Scale response of venlafaxine. In addition, we also found no significant association between CYP2D6 phenotype and overall rate of adverse events. CONCLUSIONS: CYP2D6 metabolizer status had significant influence on venlafaxine pharmacokinetics, but insufficient evidence demonstrated that CYP2D6 metabolizer status was associated with its therapeutic effects and overall rate of adverse events, which provided further evidence regarding the relationship between CYP2D6 metabolizer status and venlafaxine.

Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis.

PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA. METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA. CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect.

Impact of deep brain stimulation on urogenital function in Parkinson's disease: a systematic review and meta-analysis.

Objectives: Deep Brain Stimulation (DBS) effectively treats Parkinson's motor symptoms, but its effects on the urogenital system are debated. Methods: A research was conducted in PubMed, Embase, Cochrane Library, Web of Science, and Scopus until February 27, 2024. We primarily focused on DBS's impact on Parkinson's patients' Urine storage function, voiding function, sexual function, and quality of life. Results: Our meta-analysis included 14 studies. The main results showed that DBS resulted in fewer instances of urinary urgency (OR = 1.85, 95% CI: 1.26 to 2.70, p = 0.002) and increased maximum bladder capacity (MD = -66.10, 95% CI: -119.37 to -12.82, p = 0.02) in terms of urinary storage function. However, there were no significant differences in first desire to void and strong desire to void. In terms of voiding function, DBS showed significant improvements in maximum flow rate (MD = -0.64, 95% CI: -1.23 to -0.05, p = 0.03), post-void residual (MD = -6.79, 95% CI: 4.54 to 9.05, P < 0.00001) and detrusor pressure during maximum flow (MD = -1.37, 95% CI: -2.73 to -0.02, p = 0.05). Additionally, there was no significant difference in sexual function between the two groups (MD = -1.41, 95% CI: -12.40 to 9.57, p = 0.80). Conclusion: DBS has demonstrated a certain degree of efficacy in ameliorating urinary storage and voiding function in patients with Parkinson's disease. However, certain urodynamic parameters or scores do not demonstrate any statistically significant disparities. Furthermore, DBS has no significant impact on erectile function in male Parkinson's patients. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023476661, identifier CRD42023476661.

The Role of Brassinosteroids in Plant Cold Stress Response.

Temperature affects plant growth and geographical distribution. Cold stress occurs when temperatures fall below the physiologically optimal range for plants, causing permanent and irreversible damage to plant growth, development, and production. Brassinosteroids (BRs) are steroid hormones that play an important role in plant growth and various stress responses. Recent studies have shown that low temperatures affect BR biosynthesis in many plant species and that BR signaling is involved in the regulation of plant tolerance to low temperatures, both in the CBF-dependent and CBF-independent pathways. These two regulatory pathways correspond to transient and acclimation responses of low temperature, respectively. The crosstalk between BRs and other hormones is a significant factor in low-temperature tolerance. We provide an overview of recent developments in our knowledge of BRs' function in plant responses to cold stress and how they interact with other plant hormones in this review.

Effect of Group Cognitive Behavioral Therapy on Patients with Early-Onset Schizophrenia.

Objective: To study the clinical effect of group cognitive behavioral therapy to one-on-one treatment on patients with early-onset schizophrenia. Methods: Totally,133 patients with early-onset schizophrenia admitted to the Department of Psychiatry of our hospital from September 2020 to September 2023 were selected and divided into a control group and an observation group according to whether group behavioral cognitive therapy was performed. The general demographic data of the patients were collected, and the propensity score matching method was used to balance the baseline data of the 2 groups. The Positive and negative syndrome scale, Personal and Social Performance Scale, severity of illness (SI), and efficacy index (EI) were compared between the 2 groups after matching. Results: After matching, 72 patients were included in our study. Compared to the control group, observation group PANSS score were decreased including after intervention (P > .05). Both groups showed a decrease between before and after treatments. Positive and Negative Syndrome Scale reduction rate after treatment and total response rate were increased in the observation group (P <.001). Personal and Social Performance Scale of the Clinical Global Impression (CGI) scores were higher than those of the control group. In the CGI scores, there is a significant difference that SI scores were lower in the observation group (P = .002), while EI scores were higher (P <.001). Conclusion: Group cognitive behavioral therapy is beneficial to the improvement of mental symptoms and disease severity, social function, and curative effect, which is advocated and popularized.

The role of exosomal lncRNAs in acetaminophen-induced induced liver injury in SD rats.

Background: Drug-induced liver injury (DILI) is a leading cause of drug development failures during clinical trials and post-market introduction. Current biomarkers, such as ALT and AST, lack the necessary specificity and sensitivity needed for accurate detection. Exosomes, which protect LncRNAs from RNase degradation, could provide reliable and easily accessible options for biomarkers. Materials and methods: RNA-sequencing was used to identify differentially expressed LncRNAs (DE-LncRNAs), followed by isolation of LncRNAs from plasma exosomes in this study. Exosome characterization was conducted by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). Bioinformatics analysis included functional enrichment and co-expression network analysis. Five rat models were established, and quantitative real-time PCR was used to verify the specificity and sensitivity of two candidate exosomal LncRNAs. Results: The APAP-induced hepatocellular injury model was successfully established for RNA-sequencing, leading to the identification of several differentially expressed exosomal LncRNAs. Eight upregulated exosomal DE-LncRNAs were selected for validation. Among them, NONRATT018001.2 (p < 0.05) and MSTRG.73954.4 (p < 0.05) exhibited a more than 2-fold increase in expression levels. In hepatocellular injury and intrahepatic cholestasis models, both NONRATT018001.2 and MSTRG.73954.4 showed earlier increases compared to serum biomarkers ALT and AST. However, no histological changes were observed until the final time point. In the fatty liver model, NONRATT018001.2 and MSTRG.73954.4 increased earlier than ALT and AST at 21 days. By the 7th day, minor steatosis was evident in liver tissue, while the expression levels of the two candidate exosomal LncRNAs exceeded 2 and 4 times, respectively. In the hepatic fibrosis model, NONRATT018001.2 and MSTRG.73954.4 showed increases at every time point. By the 49th day, hepatocellular necrosis and fibrosis were observed in the liver tissue, with NONRATT018001.2 showing an increase of more than 8 times. The specificity of the identified exosomal DE-LncRNAs was verified using a myocardial injury model and they showed no significant differences between the case and control groups. Conclusion: NONRATT018001.2 and MSTRG.73954.4 hold potential as biomarkers for distinguishing different types of organ injury induced by drugs, particularly enabling early prediction of liver injury. Further experiments, such as siRNA interference or gene knockout, are warranted to explore the underlying mechanisms of these LncRNAs.

Comprehensive Microbiome and Metabolome Analyses Reveal the Medicinal Components of Paeonia lactiflora.

Paeonia lactiflora Pall. is not only a traditional ornamental plant, but also an important medicinal plant. Currently, some P. lactiflora cultivars are used for ornamental purposes, but their potential medicinal value is ignored. To explore the medicinal potential of the ornamental varieties, the medicinal cultivar 'Hangbaishao' (HS) and the ornamental cultivar 'Zifengyu' (ZFY) were selected, and microbiome and metabolome analyses were performed to compare the composition of the endophytes and metabolites in the roots. The diversity and abundance of bacteria were not significantly different between HS and ZFY; however, the diversity and abundance of endophytic fungi in the ornamental cultivar ZFY were much higher than those in the medicinal cultivar HS. The flavonoids and phenolic acid contents of the ornamental cultivar ZFY were significantly higher than those of the medicinal cultivar HS, indicating that ZFY has medicinal value. The differences in root endophytes between HS and ZFY may lead to differences in phenolic acids and flavonoids. To explore the relationship between endophytes and the accumulation of phenolic acids and flavonoids, a joint analyses of the microbiome and metabolome were performed. The key bacterium, Ruminococcaceae bacterium GD7, led to the accumulation of phenolic acids and flavonoids in the ZFY. This study contributes to future research on the potential medicinal value of ornamental P. lactiflora and provides a new approach for realizing the 'dual use of medicine and appreciation' of P. lactiflora.

The Analgesic Effect and Potential Mechanisms of Acupuncture for Migraine Rats: A Systematic Review and Meta-Analysis.

Purpose: To assess the inhibitory effect of acupuncture on pain symptoms in migraine models, and to further summarize the potential mechanisms of acupuncture in regulating hyperalgesia in the treatment of migraine. Materials and Methods: Literature search in databases such as China National Knowledge Infrastructure (CNKI), PubMed, and Web of Science (WOS) etc. The quality was evaluated by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) bias risk assessment tool and Collaborative Approach to Meta-analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. Meta-analyses were performed using Stata 17.0 software. Results: Twenty-one studies involving 489 animals were identified. The qualitative score ranged from 3 to 9 points. Facial mechanical withdrawal threshold (FMWT) and paw mechanical withdrawal threshold (PMWT) measured by Von Frey filaments were selected as major outcomes, and serum calcitonin gene-related peptide (CGRP) levels measured by ELISA were selected as secondary outcome. Meta-analysis results revealed that true acupuncture (TA) group significantly increased FMWT, PMWT and CGRP compared to model group. TA group showed superior effect in FMWT, PMWT relative to sham acupuncture (SA) group. Subgroup analysis results showed that high risk of bias scores may be responsible for the high heterogeneity of FMWT; additionally, CGRP analysis suggests that acupoint selection and blood collection sites may be sources of heterogeneity. In the treatment of migraine pain symptoms, the underlying mechanism of acupuncture treatment is either the regulation of hyperalgesia and neurotransmitters, or the reduction of inflammatory factors. Conclusion: The results indicate that TA treatment effectively increased the pain threshold and reduced hyperalgesia in migraine rats. In summary, our study highlights the potential of TA as an effective treatment for migraine, but further investigation is required to fully comprehend its mechanism of action and optimize its clinical application.

Astrocyte-Microglia Crosstalk: A Novel Target for the Treatment of Migraine.

Migraine is a pervasive neurologic disease closely related to neurogenic inflammation. The astrocytes and microglia in the central nervous system are vital in inducing neurogenic inflammation in migraine. Recently, it has been found that there may be a crosstalk phenomenon between microglia and astrocytes, which plays a crucial part in the pathology and treatment of Alzheimer's disease and other central nervous system diseases closely related to inflammation, thus becoming a novel hotspot in neuroimmune research. However, the role of the crosstalk between microglia and astrocytes in the pathogenesis and treatment of migraine is yet to be discussed. Based on the preliminary literature reports, we have reviewed relevant evidence of the crosstalk between microglia and astrocytes in the pathogenesis of migraine and summarized the crosstalk pathways, thereby hoping to provide novel ideas for future research and treatment.

[Acupuncture relieves pain by inhibiting expression of Cx43 in astrocytes and release of interfe-ron-γ in neurons of trigeminal spinal nucleus in rats with migraine].

OBJECTIVE: To observe the effect of acupuncture on the expression of connexin 43 (Cx43), glial fibrillary acidic protein (GFAP), interferon-γ (IFN-γ) in the trigeminal spinal nucleus (TNC) of rats with migraine, so as to explore its mechanisms underlying amelioration of migraine. METHODS: A total of 44 SD rats were randomly divided into control, model, acu-puncture, and sham acupuncture groups (n=11 in each group). Acupuncture was applied to bilateral "Shuaigu"(GB8) and "Yanglingquan"(GB34) or non-acupoint Ⅰ (the spot about 10 mm superior to the iliac spine and 20 mm lateral to the post-median line) and non-acupoint Ⅱ (behind the iliac spine, the ending-spot of the posterior superior iliac spine at the muscles) on both sides for 20 min, once daily for 9 days. Paw withdrawal latency (mechanical pain threshold,PWMT) and thermal tail flick latency (TFL) were measured using a VonFrey detector and photothermal tail pain meter, respectively. The content of IFN-γ of TNC tissue was detected by ELISA. The expression levels of Cx43 and IFN-γ proteins of TNC tissue were detected by Western blot. The immunofluorescence dual labeling method was used to detect the positive expression of GFAP and Cx43, IFN-γR and NeuN in TNC tissue, for displaying the activity of Cx43 in astrocytes and IFN-γ in neurons, respectively. RESULTS: Compared with the control group, both PWMT and TFL at 3, 5, 7 and 9 days after modeling were significantly decreased (P<0.01), while the expression of Cx43 and IFN-γ proteins, the immunofluorescence intensity of GFAP, Cx43, IFN-γR, and the content of IFN-γ were considerably up-regulated in the model group (P<0.01). In comparison with the model group, both PWMT and TFL at 3, 5, 7 and 9 days after modeling were obviously increased (P<0.01), whereas the expression of Cx43 and IFN-γ proteins, the immunofluorescence intensity of GFAP, Cx43, IFN-γR, and the content of IFN-γ in the acupuncture group, as well as the protein expression of IFN-γR in the sham acupuncture group were also remarkably decreased (P<0.05, P<0.01). The effect of acupuncture was significantly superior to that of sham acupuncture in down-regulating the expression of Cx43 and IFN-γ proteins, and the immunofluorescence intensity of GFAP, Cx43, and IFN-γR (P<0.05, P<0.01). Immunofluorescence dual labeling outcomes showed that in the model group, a large number of GFAP and Cx43 co-expressed astrocytes were found, and the cell body and protrusion of GFAP-labelled astrocytes were evidently increased, and Cx43 was mainly expressed on the surface of astrocyte membrane and the protrusion site, and the proportion of IFN-γR and NeuN co-expressing neurons in the model group was significantly increased, suggesting an activation of astrocytes and neurons after modeling. Whereas in the acupuncture group, the bright green clustered particles on the cell membrane and protrusion of astrocytes, and the proportion of IFN-γR and NeuN co-expressing neurons were significantly reduced, suggesting a suppression of activities of Cx43, astrocytes and neurons and IFN-γ release from TNC after acupuncture intervention. CONCLUSION: Acupuncture can relieve the pain response in rats with migraine, which may be associa-ted with its functions in inhibiting the expression of Cx43 and activation of astrocytes and neurons, and reducing release of pro-inflammatory factor IFN-γ in TNC.

Proteome and phosphoproteome analysis of 2,4-epibrassinolide-mediated cold stress response in cucumber seedlings.

The 2, 4-epibrassinolide (EBR) significantly increased plants cold tolerance. However, mechanisms of EBR in regulating cold tolerance in phosphoproteome and proteome levels have not been reported. The mechanism of EBR regulating cold response in cucumber was studied by multiple omics analysis. In this study, phosphoproteome analysis showed that cucumber responded to cold stress through multi-site serine phosphorylation, while EBR further upregulated single-site phosphorylation for most of cold-responsive phosphoproteins. Association analysis of the proteome and phosphoproteome revealed that EBR reprogrammed proteins in response to cold stress by negatively regulating protein phosphorylation and protein content, and phosphorylation negatively regulated protein content in cucumber. Further functional enrichment analysis of proteome and phosphoproteome showed that cucumber mainly upregulated phosphoproteins related to spliceosome, nucleotide binding and photosynthetic pathways in response to cold stress. However, different from the EBR regulation in omics level, hypergeometric analysis showed that EBR further upregulated 16 cold-up-responsive phosphoproteins participated photosynthetic and nucleotide binding pathways in response to cold stress, suggested their important function in cold tolerance. Analysis of cold-responsive transcription factors (TFs) by correlation between proteome and phosphoproteome showed that cucumber regulated eight class TFs may through protein phosphorylation under cold stress. Further combined with cold-related transcriptome found that cucumber phosphorylated eight class TFs, and mainly through targeting major hormone signal genes by bZIP TFs in response to cold stress, while EBR further increased these bZIP TFs (CsABI5.2 and CsABI5.5) phosphorylation level. In conclusion, the EBR mediated schematic of molecule response mechanisms in cucumber under cold stress was proposed.

Traditional Chinese medicine in treating ischemic stroke by modulating mitochondria: A comprehensive overview of experimental studies.

Ischemic stroke has been a prominent focus of scientific investigation owing to its high prevalence, complex pathogenesis, and difficulties in treatment. Mitochondria play an important role in cellular energy homeostasis and are involved in neuronal death following ischemic stroke. Hence, maintaining mitochondrial function is critical for neuronal survival and neurological improvement in ischemic stroke, and mitochondria are key therapeutic targets in cerebral stroke research. With the benefits of high efficacy, low cost, and high safety, traditional Chinese medicine (TCM) has great advantages in preventing and treating ischemic stroke. Accumulating studies have explored the effect of TCM in preventing and treating ischemic stroke from the perspective of regulating mitochondrial structure and function. In this review, we discuss the molecular mechanisms by which mitochondria are involved in ischemic stroke. Furthermore, we summarized the current advances in TCM in preventing and treating ischemic stroke by modulating mitochondria. We aimed to provide a new perspective and enlightenment for TCM in the prevention and treatment of ischemic stroke by modulating mitochondria.

Bioequivalence Study of Miglitol Orally Disintegrating Tablets in Healthy Chinese Volunteers Under Fasting Condition Based on Pharmacodynamic and Pharmacokinetic Parameters.

To investigate the bioequivalence of miglitol orally disintegrating tablets in healthy Chinese volunteers based on pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Additionally, the safety profile was estimated. Two randomized, open-label, single-dose, crossover trials were conducted under fasting conditions. In the PD trial (CTR20191811), 45 healthy volunteers were randomly divided into 3 groups in a 1:1:1 ratio and administered sucrose alone or coadministered with 50 mg of miglitol orally disintegrating tablet test or reference formulation/sucrose. In the PK trial (CTR20191696), 24 healthy volunteers were randomized (1:1) to receive the test or reference formulation (50 mg). Blood samples were collected at 15 and 17 sampling points per cycle in the PD and PK trials, respectively. Plasma miglitol and serum glucose concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry method. Serum insulin concentrations were measured using electrochemiluminescent immunoassay. Statistical analyses for the PD and PK parameters were subsequently performed. The volunteers' physical indicators were monitored and documented during the entire study to estimate drug safety. The PD and PK parameters of the two formulations were similar. The main PD and PK end points were both within the prespecified range of 80%-125%. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were similar between the test and reference formulation groups, and no serious TEAEs or deaths occurred during the 2 trials. These 2 formulations were demonstrated to be bioequivalent and well tolerated in healthy Chinese volunteers under fasting condition.