Paeonol ameliorates hippocampal neuronal damage by inhibiting GRM5/GABBR2/ß-arrestin2 and activating the cAMP-PKA signaling pathway in premenstrual irritability rats.

Premenstrual dysphoric disorder (PMDD) is a periodic psychiatric disorder with high prevalence in women of childbearing age, seriously affecting patients' work and life. Currently, the international first-line drugs for PMDD have low efficiency and increased side effects. Paeonol, a major component of the traditional Chinese medicine Cortex Moutan, has been applied in treating PMDD in China with satisfactory results, but the therapeutic mechanism is not fully understood. This study aims to evaluate the therapeutic effects and pharmacological mechanisms of paeonol on the main psychiatric symptoms and hippocampal damage in PMDD. We established a premenstrual irritability rat model by the resident-intruder paradigm and performed elevated plus maze and social interactions. And we employed the HE and Nissl staining techniques to observe the therapeutic effect of paeonol on hippocampal damage in PMDD rats. Subsequently, Elisa, qRT-PCR Array, Western Blotting, and cell models were utilized to elucidate the underlying molecular mechanisms through which paeonol intervenes in treating PMDD. In this study, we demonstrated the therapeutic effects of paeonol on irritability, anxiety, and social withdrawal behaviors in rats. In addition, we found that paeonol significantly reduced the serum corticosterone (CORT) level, improved hippocampal morphological structure and neuron number, and reduced hippocampal neuron apoptosis in PMDD rats. Paeonol reduced GRM5, GABBR2, ß-arrestin2, and GRK3 expression levels in hippocampal brain regions of PMDD rats and activated the cAMP/PKA signaling pathway. Inhibitor cell experiments showed that paeonol specifically ameliorated hippocampal injury by modulating the ß-arrestin2/PDE4-cAMP/PKA signaling pathway. The present study demonstrates, for the first time, that paeonol exerts a therapeutic effect on periodic psychotic symptoms and hippocampal injury in PMDD through inhibiting GRM5/GABBR2/ß-arrestin2 and activating cAMP-PKA signaling pathway. These findings enhance our understanding of the pharmacological mechanism underlying paeonol and provide a solid scientific foundation for its future clinical application.

Genomic epidemiology and heterogeneity of Providencia and their blaNDM-1-carrying plasmids.

Providencia as an opportunistic pathogen can cause serious infection, and moreover the emergence of multi-drug-resistant Providencia strains poses a potentially life-threatening risk to public health. However, a comprehensive genomic study to reveal the population structure and dissemination of Providencia is still lacking. In this study, we conducted a genomic epidemiology analysis on the 580 global sequenced Providencia isolates, including 257 ones sequenced in this study (42 ones were fully sequenced). We established a genome sequence-based species classification scheme for Providencia, redefining the conventional 11 Providencia species into seven genocomplexes that were further divided into 18 genospecies, providing an extensively updated reference for Providencia species discrimination based on the largest Providencia genome dataset to date. We then dissected the profile of antimicrobial resistance genes and the prevalence of multi-drug-resistant Providencia strains among these genocomplexes/genospecies, disclosing the presence of diverse and abundant antimicrobial resistance genes and high resistance ratios against multiple classes of drugs in Providencia. We further dissected the genetic basis for the spread of blaNDM-1 in Providencia. blaNDM-1 genes were mainly carried by five incompatible (Inc) groups of plasmids: IncC, IncW, IncpPROV114-NR, IncpCHS4.1-3, and IncpPrY2001, and the last three were newly designated in this study. By tracking the spread of blaNDM-1-carrying plasmids, IncC, IncpPROV114-NR, IncpCHS4.1-3, and IncpPrY2001 plasmids were found to be highly involved in parallel horizontal transfer or vertical clonal expansion of blaNDM-1 among Providencia. Overall, our study provided a comprehensive genomic view of species differentiation, antimicrobial resistance prevalence, and plasmid-mediated blaNDM-1 dissemination in Providencia.

Abundant diversity of accessory genetic elements and associated antimicrobial resistance genes in pseudomonas aeruginosa isolates from a single Chinese hospital.

OBJECTIVES: Pseudomonas aeruginosa has intrinsic antibiotic resistance and the strong ability to acquire additional resistance genes. However, a limited number of investigations provide detailed modular structure dissection and evolutionary analysis of accessory genetic elements (AGEs) and associated resistance genes (ARGs) in P. aeruginosa isolates. The objective of this study is to reveal the prevalence and transmission characteristics of ARGs by epidemiological investigation and bioinformatics analysis of AGEs of P. aeruginosa isolates taken from a Chinese hospital. METHODS: Draft-genome sequencing was conducted for P. aeruginosa clinical isolates (n = 48) collected from a single Chinese hospital between 2019 and 2021. The clones of P. aeruginosa isolates, type 3 secretion system (T3SS)-related virulotypes, and the resistance spectrum were identified using multilocus sequence typing (MLST), polymerase chain reaction (PCR), and antimicrobial susceptibility tests. In addition, 17 of the 48 isolates were fully sequenced. An extensive modular structure dissection and genetic comparison was applied to AGEs of the 17 sequenced P. aeruginosa isolates. RESULTS: From the draft-genome sequencing, 13 STs were identified, showing high genetic diversity. BLAST search and PCR detection of T3SS genes (exoT, exoY, exoS, and exoU) revealed that the exoS+/exoU- virulotype dominated. At least 69 kinds of acquired ARGs, involved in resistance to 10 different categories of antimicrobials, were identified in the 48 P. aeruginosa isolates. Detailed genetic dissection and sequence comparisons were applied to 25 AGEs from the 17 isolates, together with five additional prototype AGEs from GenBank. These 30 AGEs were classified into five groups -- integrative and conjugative elements (ICEs), unit transposons, IncpPBL16 plasmids, Incp60512-IMP plasmids, and IncpPA7790 plasmids. CONCLUSION: This study provides a broad-scale and deeper genomics understanding of P. aeruginosa isolates taken from a single Chinese hospital. The isolates collected are characterized by high genetic diversity, high virulence, and multiple drug resistance. The AGEs in P. aeruginosa chromosomes and plasmids, as important genetic platforms for the spread of ARGs, contribute to enhancing the adaptability of P. aeruginosa in hospital settings.

Characterization of Three Novel IMP Metallo-ß-Lactamases, IMP-89, IMP-91, and IMP-96, and Diverse blaIMP-Carrying Accessory Genetic Elements from Chinese Clinical Isolates.

Three novel imipenemase (IMP)-type metallo-ß-lactamases (MBLs), referred to as IMP-89, IMP-91, and IMP-96, were detected in three clinical isolates from China. Antimicrobial susceptibility tests indicated these novel enzymes were resistant to most ß-lactams, and IMP-96 with a Ser262Gly mutation had higher activity against meropenem than its point mutant. We then collected sequence data on all 91 available IMP variants for phylogenetic analysis. To further analyze the genetic environment of blaIMP, an extensive comparison was applied to nine accessory genetic elements (AGEs), including six sequenced blaIMP-carrying AGEs in this study and three others from GenBank. These nine AGEs were divided into three groups: three IncpJBCL41 plasmids, Tn6417 and its two derivatives, and three Tn6879-related integrative and conjugative elements (ICEs). All blaIMP genes in this study were captured by class 1 integrons. In the integrons, blaIMP genes usually coexisted with other resistance genes, which further impeded clinical antibacterial treatment. The emergence of new IMP variants and the diversity and complexity of their genetic environment make the prevention and control of drug-resistant strains critical, requiring serious attention from clinical and public health management departments. IMPORTANCE The spread of IMP-type MBLs has increased dramatically in recent years. We discovered three novel IMP variants from three clinical isolates in China. We summarized the classification and evolutionary relationship of all available IMP variants. Moreover, we detailed the genetic characteristics of blaIMP-carrying accessory genetic elements in five clinical isolates. Given the risk of rapid and extensive spread of blaIMP genes, we suggest that continuous surveillance is crucial to combat the acquisition and transmission of blaIMP genes by bacteria, which can impede clinical therapy effectiveness.

Genetic Characterization of Four Groups of Chromosome-Borne Accessory Genetic Elements Carrying Drug Resistance Genes in Providencia.

Purpose: The aim of this study was to gain a deeper genomics and bioinformatics understanding of diversification of accessory genetic elements (AGEs) in Providencia. Methods: Herein, the complete genome sequences of five Providencia isolates from China were determined, and seven AGEs were identified from the chromosomes. Detailed genetic dissection and sequence comparison were applied to these seven AGEs, together with additional 10 chromosomal ones from GenBank (nine of them came from Providencia). Results: These 17 AGEs were divided into four groups: Tn6512 and its six derivatives, Tn6872 and its two derivatives, Tn6875 and its one derivative, and Tn7 and its four derivatives. These AGEs display high-level diversification in modular structures that had complex mosaic natures, and particularly different multidrug resistance (MDR) regions were presented in these AGEs. At least 52 drug resistance genes, involved in resistance to 15 different categories of antimicrobials and heavy metal, were found in 15 of these 17 AGEs. Conclusion: Integration of these AGEs into the Providencia chromosomes would contribute to the accumulation and distribution of drug resistance genes and enhance the ability of Providencia isolates to survive under drug selection pressure.

A Genomic and Bioinformatics View of the Classification and Evolution of Morganella Species and Their Chromosomal Accessory Genetic Elements Harboring Antimicrobial Resistance Genes.

In this study, draft-genome sequencing was conducted for 60 Chinese Morganella isolates, and furthermore, 12 of them were fully sequenced. Then, a total of 166 global sequenced Morganella isolates, including the above 60, were collected to perform average nucleotide identity-based genomic classification and core single nucleotide polymorphism-based phylogenomic analysis. A genome sequence-based species classification scheme for Morganella was established, and accordingly, the two conventional Morganella species were redefined as two complexes and further divided into four and two genospecies, respectively. At least 88 acquired antimicrobial resistance genes (ARGs) were disseminated in these 166 isolates and were prevalent mostly in the isolates from hospital settings. IS26/IS15DI, IS10 and IS1R, and Tn3-, Tn21-, and Tn7-subfamily unit transposons were frequently presented in these 166 isolates. Furthermore, a detailed sequence comparison was applied to 18 Morganella chromosomal accessory genetic elements (AGEs) from the fully sequenced 12 isolates, together with 5 prototype AGEs from GenBank. These 23 AGEs were divided into eight different groups belonging to composite/unit transposons, transposable prophages, integrative and mobilizable elements, and integrative and conjugative elements, and they harbored at least 52 ARGs involved in resistance to 15 categories of antimicrobials. Eleven of these 23 AGEs acquired large accessory modules, which exhibited complex mosaic structures and contained many antimicrobial resistance loci and associated ARGs. Integration of ARG-containing AGEs into Morganella chromosomes would contribute to the accumulation and dissemination of ARGs in Morganella and enhance the adaption and survival of Morganella under complex and diverse antimicrobial selection pressures. IMPORTANCE This study presents a comprehensive genomic epidemiology analysis on global sequenced Morganella isolates. First, a genome sequence-based species classification scheme for Morganella is established with a higher resolution and accuracy than those of the conventional scheme. Second, the prevalence of accessory genetic elements (AGEs) and associated antimicrobial resistance genes (ARGs) among Morganella isolates is disclosed based on genome sequences. Finally, a detailed sequence comparison of eight groups of 23 AGEs (including 19 Morganella chromosomal AGEs) reveals that Morganella chromosomes have evolved to acquire diverse AGEs harboring different profiles of ARGs and that some of these AGEs harbor large accessory modules that exhibit complex mosaic structures and contain a large number of ARGs. Data presented here provide a deeper understanding of the classification and evolution of Morganella species and also those of ARG-containing AGEs in Morganella at the genomic scale.

Therapies of varicose veins: Protocol for the reporting and methodological quality of pairwise meta-analyses.

BACKGROUND: Many pairwise meta-analyses (MAs) related to therapies of varicose veins have been published, but their reporting and methodological quality remain unclear. The present study was designed to assess the overall quality of pairwise MAs related to therapies of varicose veins. METHODS: We will systematically search 4 electronic databases, including PubMed, EMBASE, Cochrane Library, Chinese Biomedical Database, to identify pairwise MAs related to therapies of varicose veins. The search time-span was set from inception to March 2019. The pairwise MAs related to therapies of varicose veins will be included in our overview. The reporting and methodological quality of included MAs will be assessed using preferred reporting items for systematic review and meta-analysis and a measurement tool to assess systematic reviews 2, respectively. Meanwhile, we will extract some general characteristics of included MAs, including first author; published year, journal, sample size, number of studies, number of randomized controlled trials and intervention details, and so on. All literatures screening, quality assessment, and data extraction will be independently completed by 2 of all reviewers, and any disagreement will be resolved by discussion. Besides, an increasingly popular method - evidence mapping, will be used to present the whole evidence landscape related to therapies of varicose veins. The assessment results will be presented as percentage and event/total. The Excel 2016 will be used to manage and analyze data. RESULTS: The results of the overview will be submitted to a peer-reviewed journal for publication. CONCLUSION: This overview will summarize the overall reporting and methodological quality related to therapies of varicose veins. PROSPERO REGISTRATION NUMBER: CRD42019126722.

Treatment with Shuyu capsule increases 5-HT1AR level and activation of cAMP-PKA-CREB pathway in hippocampal neurons treated with serum from a rat model of depression.

Depressive disorder (DD) is one of the typical affective disorders with a high morbidity, high suicide rate and high recurrence rate. Dysfunction of the 5­hydroxytryptamine 1A receptor (5­HT1AR) in the brain may serve an important role in the pathogenesis of DD. Currently, selective serotonin reuptake inhibitors are the first line antidepressants with 60­70% efficacy and severe adverse effects. Previous studies have demonstrated that Chinese herbal medicines, including the Shuyu capsule (SYC), are effective antidepressants with few side effects. However, the mechanism remains unclear. In the present study, the effects of the SYC on the 5­HT1AR level and the activation of adenylyl cyclase­cyclic adenosine monophosphate (cAMP)­protein kinase A (PKA)­cAMP response element­binding (CREB) signaling pathway that 5­HT1AR mediates in the cells of hippocampal neurons were investigated in vitro. The SYC demonstrated an antidepressant effect similar to that of fluoxetine in a rat depression model. Treatment of hippocampal neurons with the serum of depressive rats resulted in a decrease in the 5­HT1AR protein level and the activation of the cAMP­PKA­CREB signaling pathway in hippocampal neurons. Exposure to the serum of rats that received chronic mild stress plus SYC treatment led to no alterations in the 5­HT1AR level or the activation of the cAMP­PKA­CREB signaling pathway compared with those of cells exposed to normal rat serum. This effect is similar to the effects of 5­HT1AR antagonist WAY­100635. In addition, the 5­HT1A agonist 8­hydroxy­(dipropylamino) tetralin did not antagonize the effects of the SYC. Furthermore, the SYC exhibited an increased effect compared with fluoxetine on 5­HT1AR levels and CREB activation. The present study suggested that the SYC functions by increasing 5­HT1AR protein levels and the activation of the 5­HT1AR­mediated cAMP­PKA­CREB signaling pathway in hippocampal neurons.

Enlarged geniculate ganglion fossa: CT sign of facial nerve canal fracture.

RATIONALE AND OBJECTIVES: The aim of this study was to preliminarily investigate whether an enlarged geniculate ganglion fossa (GGF) on temporal bone computed tomography can diagnose GGF fracture in patients with traumatic facial paralysis by evaluating the diameter of the GGF. MATERIALS AND METHODS: Thirty-six patients who underwent computed tomography before confirmation of GGF fracture on otologic surgery were recruited into a study group. Additionally, a cohort of 107 patients with no histories of head trauma, no structural abnormalities of inner ear, and no clinical symptoms of facial nerve disability who underwent computed tomography for other reasons were selected as a control group. The diameters of the GGFs of the study group were evaluated by two observers and compared retrospectively with those of the control group. Wilcoxon's test was used to compare discrepancies of both sides, and intraclass correlation coefficients were used to evaluate intraobserver and interobserver reliability. RESULTS: The measurement of diameters showed good interobserver and intraobserver consistency. The discrepancy in the measurement of transdiameter between both sides of the GGF on reformatted transverse images of the study group was significantly different from that of the control group (Wilcoxon's test, P < .001). Discrepancy in the GGF on transverse images of the study group was larger than that of the control group. A significant difference existed in the discrepancy in vertical diameter between the study and control groups (Wilcoxon's test, P < .001) as well. CONCLUSIONS: An enlarged GGF on temporal bone computed tomography offers an additional sign for the diagnosis of GGF fracture in patients with traumatic facial paralysis.