Changes in the Antimicrobial Resistance and Bacterial Epidemiology of Moraxella catarrhalis from Pediatric Community-Acquired Pneumonia Patients During the COVID-19 Pandemic: A 5-Year Study at a Tertiary Hospital of Southwest China.

This study aimed to assess the impact of the COVID-19 pandemic on Moraxella catarrhalis infections in pediatric patients hospitalized with community-acquired pneumonia (CAP). The epidemiological features and antimicrobial resistance (AMR) patterns of M. catarrhalis were compared between the pre-pandemic period (2018-2019) and during the pandemic (2020-2022). The results revealed a marked increase in the positivity rate of M. catarrhalis in 2020 and 2021 compared with the pre-pandemic years. The median age of the patients increased significantly in 2021 and 2022, while the proportion of male patients decreased substantially from 2019 to 2021. In addition, there were notable changes in the co-infections of Haemophilus influenzae, parainfluenza virus, and respiratory syncytial virus during the COVID-19 pandemic. The AMR profile of M. catarrhalis also changed significantly, showing increased resistance to ampicillin, but decreased resistance to trimethoprim-sulfamethoxazole and ofloxacin, and a lower proportion of multidrug-resistant isolates. Notably, ampicillin resistance increased among ß-lactamase-producing isolates. Before the pandemic, the number and detection rate of isolates, along with resistance to ampicillin and trimethoprim-sulfamethoxazole, were seasonally distributed, peaking in autumn and winter. However, coinciding with local COVID-19 outbreaks, these indices sharply fell in February 2020, and the number of isolates did not recover during the autumn and winter of 2022. These findings indicate that the COVID-19 pandemic has significantly altered the infection landscape of M. catarrhalis in pediatric CAP patients, as evidenced by shifts in the detection rate, demographic characteristics, respiratory co-infections, AMR profiles, and seasonal patterns.

Developing a nomogram for forecasting the 28-day mortality rate of individuals with bleeding esophageal varices using MELD scores.

BACKGROUND: The goal is to create a nomogram using the model for end-stage liver disease (MELD) that can better predict the risk of 28-day mortality in patients with bleeding esophageal varices. METHODS: Data on patients with bleeding esophageal varices were gathered retrospectively from the marketplace for medical information in intensive care (MIMIC) database. Variables were selected using least absolute shrinkage and selection operator (LASSO)-Logistic regression, then used to construct a prognostic nomogram. The nomogram was evaluated against the MELD model through various methods including receiver operating characteristic (ROC) analysis, calibration plotting, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision-curve analysis (DCA). RESULTS: A total of 280 patients were included in the study. Patient's use of vasopressin and norepinephrine, respiratory rate (RR), temperature, mean corpuscular volume (MCV), and MELD score were included in the nomogram. The area under the curve (AUC), NRI, IDI, and DCA of the nomogram showed that it performs better than the MELD alone. CONCLUSION: A nomogram was created that outperformed the MELD score in forecasting the risk of 28-day mortality in individuals with bleeding esophageal varices.

The impact of the COVID-19 pandemic on Staphylococcus aureus infections in pediatric patients admitted with community acquired pneumonia.

The COVID-19 pandemic has significantly transformed the infection spectrum of various pathogens. This study aimed to evaluate the impact of the COVID-19 pandemic on Staphylococcus aureus (S. aureus) infections among pediatric patients with community acquired pneumonia (CAP). We retrospectively reviewed pediatric CAP admissions before (from 2018 to 2019) and during (from 2020 to 2022) the COVID-19 pandemic. The epidemiology and antimicrobial resistance (AMR) profiles of S. aureus isolates were examined to assess the pandemic's effect. As a result, a total of 399 pediatric CAP patients with S. aureus infections were included. The positivity rate, gender, and age distribution of patients were similar across both periods. There was a marked reduction in respiratory co-infections with Haemophilus influenzae (H. influenzae) during the COVID-19 pandemic, compared to 2019. Additionally, there were significant changes in the resistance profiles of S. aureus isolates to various antibiotics. Resistance to oxacillin and tetracycline increased, whereas resistance to penicillin, gentamicin, and quinolones decreased. Notably, resistance to erythromycin significantly decreased in methicillin-resistant S. aureus (MRSA) strains. The number of S. aureus isolates, the proportion of viral co-infections, and the number of resistant strains typically peaked seasonally, primarily in the first or fourth quarters of 2018, 2019, and 2021. However, shifts in these patterns were noted in the first quarter of 2020 and the fourth quarter of 2022. These findings reveal that the COVID-19 pandemic has significantly altered the infection dynamics of S. aureus among pediatric CAP patients, as evidenced by changes in respiratory co-infections, AMR patterns, and seasonal trends.

Impact of the COVID-19 pandemic on Haemophilus influenzae infections in pediatric patients hospitalized with community acquired pneumonia.

The COVID-19 pandemic has altered the infection landscape for many pathogens. This retrospective study aimed to compare Haemophilus influenzae (H. influenzae) infections in pediatric CAP patients hospitalized before (2018-2019) and during (2020-2022) the COVID-19 pandemic. We analyzed the clinical epidemiology and antimicrobial resistance (AMR) patterns of H. influenzae from a tertiary hospital in southwest China. A total of 986 pediatric CAP patients with H. influenzae-associated infections were included. Compared to 2018, the positivity rate increased in 2019 but dropped significantly in 2020. Although it rose in the following 2 years, the rate in 2022 remained significantly lower than in 2019. Patients' age during the pandemic was significantly higher than in 2018 and 2019, while gender composition remained similar across both periods. Notably, there were significant changes in co-infections with several respiratory pathogens during the pandemic. Resistance rates of H. influenzae isolates to antibiotics varied, with the highest resistance observed for ampicillin (85.9%) and the lowest for cefotaxime (0.0%). Resistance profiles to various antibiotics underwent dramatic changes during the COVID-19 pandemic. Resistance to amoxicillin-clavulanate, cefaclor, cefuroxime, trimethoprim-sulfamethoxazole, and the proportion of multi-drug resistant (MDR) isolates significantly decreased. Additionally, MDR isolates, alongside isolates resistant to specific drugs, were notably prevalent in ampicillin-resistant and ß-lactamase-positive isolates. The number of pediatric CAP patients, H. influenzae infections, and isolates resistant to certain antibiotics exhibited seasonal patterns, peaking in the winter of 2018 and 2019. During the COVID-19 pandemic, sharp decreases were observed in February 2020, and there was no resurgence in December 2022. These findings indicate that the COVID-19 pandemic has significantly altered the infection spectrum of H. influenzae in pediatric CAP patients, as evidenced by shifts in positivity rate, demographic characteristics, respiratory co-infections, AMR patterns, and seasonal trends.

Changes in the epidemiology and antimicrobial resistance patterns of Streptococcus pneumoniae from pediatric community acquired pneumonia patients attended in a Chinese hospital during the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic has altered the infection dynamics of numerous pathogens. This study aimed to elucidate its impact on Streptococcus pneumoniae (S. pneumoniae) infections in children with community acquired pneumonia (CAP). METHODS: A retrospective analysis was conducted in pediatric CAP patients admitted before (2018-2019) and during (2020-2022) the COVID-19 pandemic. The epidemiology and antimicrobial resistance (AMR) patterns of S. pneumoniae were compared to reveal the impact of the pandemic. RESULTS: A total of 968 S. pneumoniae-associated pediatric CAP patients were enrolled. Although the positivity rate and gender of patients were stable across both periods, the age notably increased in 2021 and 2022. Additionally, significant changes were observed in the co-infections with several pathogens and the resistance rates to certain antibiotics during the COVID-19 pandemic. The resistance rate to clindamycin and quinupristin-dalfopristin increased, whereas the resistance rate to tetracycline, trimethoprim-sulfamethoxazole, telithromycin, and proportion of multi-drug resistant isolates decreased. The number of S. pneumoniae strains and resistant isolates exhibited similar seasonal patterns in 2018 and 2019, peaking in November or December with another minor peak in March or April. During the COVID-19 pandemic, there was a sharp decrease in February 2020 and no resurgence was observed at the end of 2022. Additionally, the minor peak was absent in 2020 and shifted to other months in 2021 and 2022. CONCLUSIONS: The COVID-19 pandemic has markedly altered the infection spectrum of S. pneumoniae in pediatric CAP patients, as evidenced by shifts in the age of patients, respiratory co-infections, AMR patterns, and seasonal trends.

Network Pharmacology and Molecular Docking Identify the Potential Mechanism and Therapeutic Role of Scutellaria baicalensis in Alzheimer's Disease.

Aim: Scutellaria baicalensis, a traditional Chinese medicinal herb renowned for its anti-inflammatory, antioxidant, and anti-tumor properties, has shown promise in alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Scutellaria baicalensis against Alzheimer's disease remains unclear. In this study, network pharmacology was employed to explore the possible mechanisms by which Scutellaria baicalensis protects against Alzheimer's disease. Methods: The active compounds of Scutellaria baicalensis were retrieved from the TCMSP database, and their corresponding targets were identified. Alzheimer's disease-related targets were obtained through searches in the GeneCards and OMIM databases. Cytoscape 3.6.0 software was utilized to construct a regulatory network illustrating the "active ingredient-target" relationships. Subsequently, the target genes affected by Scutellaria baicalensis in the context of Alzheimer's disease were input into the String database to establish a PPI network. GO analysis and KEGG analysis were conducted using the DAVID database to predict the potential pathways associated with these key targets. Following this, the capacity of these active ingredients to bind to core targets was confirmed through molecular docking. In vitro experiments were then carried out for further validation. Results: A total of 36 active ingredients from Scutellaria baicalensis were screened out, which corresponded to 365 targets. Molecular docking results demonstrated the robust binding abilities of Baicalein, Wogonin, and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to key target proteins (SRC, PIK3R1, and STAT3). In vitro experiments showed that the active components of Scutellaria baicalensis can inhibit STAT3 expression by downregulating the PIK3R1/SRC pathway in Neuro 2A cells. Conclusion: In summary, these findings collectively suggest that Scutellaria baicalensis holds promise as a viable treatment option for Alzheimer's disease.

Comparison of Mycoplasma pneumoniae infection in children admitted with community acquired pneumonia before and during the COVID-19 pandemic: a retrospective study at a tertiary hospital of southwest China.

PURPOSE: The COVID-19 pandemic has notably altered the infection dynamics of various pathogens. This study aimed to evaluate the pandemic's impact on the infection spectrum of Mycoplasma pneumoniae (M. pneumoniae) among children with community acquired pneumonia (CAP). METHODS: We enrolled pediatric CAP patients admitted to a tertiary hospital in southwest China to compare the prevalence and characteristics of M. pneumoniae infections before (2018-2019) and during (2020-2022) the COVID-19 pandemic. Detection of M. pneumoniae IgM antibodies in serum were conducted using either indirect immunofluorescence or passive agglutination methods. RESULTS: The study included 1505 M. pneumoniae-positive and 3160 M. pneumoniae-negative CAP patients. Notable findings were the higher age and frequency of pneumonia-associated symptoms in M. pneumoniae-positive patients, alongside a lower male proportion and fewer respiratory co-infections. The year 2019 saw a notable increase in M. pneumoniae infections compared to 2018, followed by a decline from 2020 to 2022. The COVID-19 pandemic period witnessed significant alterations in age distribution, male proportion, and co-infections with specific pathogens in both M. pneumoniae-positive and negative patients. The M. pneumoniae infections were predominantly seasonal, peaking in autumn and winter during 2018 and 2019. Although there was a sharp drop in February 2020, the infection still peaked in cold months of 2020 and 2021. However, the typical seasonal pattern was nearly absent in 2022. CONCLUSIONS: The COVID-19 pandemic has markedly changed the infection landscape of M. pneumoniae in pediatric CAP patients, with shifts observed in infection rates, demographic profiles, co-infections, and seasonal patterns.

Identification of Plasma Inflammatory Markers of Adolescent Depression Using the Olink Proteomics Platform.

Purpose: The quality of life of worldwide adolescents has been seriously affected by depression. Notably, the inflammatory response is closely associated with the pathophysiology of depression. The present study applied a novel targeted proteomics technology, Olink proximity extension assay (PEA), to profile circulating immune-related proteins in adolescents with depression. Methods: In the present study, the expression levels of 92 inflammation-related proteins were compared between adolescents with depression (ADs) (n=15) and healthy controls (HCs) (n=15), using the OLINK PEA inflammation panel. We further validated 5 top proteins that were identified through KEGG and GO analyses between 40 HCs and 50 ADs, including CCL4, CXCL5, CXCL6, CXCL11, and IL-18 using enzyme linked immunosorbent assay (ELISA). Results: We identified 13 differentially expressed proteins between the two cohorts, including 5 up-regulated and 8 down-regulated proteins. Among them, the TRAIL protein levels were significantly negatively correlated with the HAMA-14 score (r=-0.538, p= 0.038), and the levels of transforming growth factor α (TGF-α) were significantly associated with a change in appetite (r = -0.658, p = 0.008). After validation by ELISA, CCL4, CXCL5, CXCL11, and IL-18 showed significant changes between ADs and HCs (p < 0.05), while CXCL6 showed an up-regulated tendency in ADs (p=0.0673). The pooled diagnostic efficacy (area under the curve [AUC]) of these five inflammation markers in clinical diagnosis for adolescent depression was 0.819 (95% CI: 0.735-0.904). Conclusion: We report a number of inflammation-related plasma biomarkers, which uncover a potential involvement of chemokines, cytokines, and cytokine receptors in adolescent depression. Their roles in the pathophysiology of depression need to be further elucidated.

Enhanced Biohomogeneous Composite Membrane-Encapsulated Nanoplatform with Podocyte Targeting for Precise and Safe Treatment of Diabetic Nephropathy.

Diabetic nephropathy (DN), associated with high mobility and disability, is the leading cause of end-stage kidney disease worldwide. Dysfunction of the mammalian target of the rapamycin (mTOR) pathway and reactive oxygen species (ROS) activation in the glomeruli is the main hypnosis for DN progression. However, the use of mTOR inhibitors for DN treatment remains controversial. In this study, we built a multifunctional selective mechanistic target of rapamycin complex 1 (mTORC1) inhibiting nanoplatform (naming as ESC-HCM-B) that targets the release of mTOR and ROS inhibitors near podocytes, aiming to confirm whether combination therapy is an alternative method for DN treatment. The results showed that ESC-HCM-B achieved high drug loading because of the core mesoporous silica nanoparticles (MSNPs), and the enhanced biohomogeneous composite membrane endowed ESC-HCM-B with the characteristics of avoiding immune phagocytosis, automatic valve-type slow-release drug, and high stability. In vitro, the nanoplatform showed high efficiency in podocyte targeting but no significant cytotoxicity or apoptotic promotion. In particular, the quantum dots carried by ESC-HCM-B further amplified the effect of "nanoenzyme"; this mechanism reduced the ROS level in podocytes induced by high glucose, protected mitochondrial damage, and restored mitochondrial energy metabolism. In vivo, the nanoplatform specifically targeted the glomerular and podocyte regions of the kidney. After treatment, the nanoplatform significantly reduced urinary protein levels and delayed glomerulosclerosis in DN rats. This nanoplatform provides a safe and effective strategy for DN treatment.

A retrospective analysis of factors associated with the length of hospital stay in COVID-19 patients treated with Nirmatrelvir / Ritonavir.

Objectives: This study reviewed factors influencing the length of hospital stay in adult inpatients with confirmed Coronavirus disease (COVID-19) who were treated with Nirmatrelvir/Ritonavir. Methods: We did a retrospective analysis of data from a cohort of inpatients with confirmed diagnosis of Omicron variant of SARS-CoV-2 infection who were treated with Nirmatrelvir/Ritonavir. We included patients who were treated from 13th March 2022 to 6th May 2022 in various in-patient treatment units in Quanzhou, Fujian Province, China. The primary study outcome was the length of hospital stay. Secondary study outcome was viral elimination defined as negative for ORF1ab and N genes [cycle threshold (Ct) value ≥35 in real-time PCR], according to local guidelines. Hazard ratios (HR) of event outcomes were analyzed using Multivariate Cox regression models. Results: We studied 31 inpatients with high risk for severe COVID-19 who were treated with Nirmatrelvir/Ritonavir. We found that inpatients with shorter length of hospital stay (≤17 days) were mostly females with lower body mass index (BMI) and Charlson Comorbidity Index (CCI) index. Their treatment regimen with Nirmatrelvir/Ritonavir was started within 5 days of diagnosis (p < 0.05). Multivariate Cox regression indicated that inpatients starting treatment of Nirmatrelvir/Ritonavir within 5 days had a shorter length of hospital stay (HR 3.573, p = 0.004) and had a faster clearance of viral load (HR 2.755, p = 0.043). Conclusion: This study assumes relevance during the Omicron BA.2 epidemic as our findings suggest that early treatment with Nirmatrelvir/Ritonavir within 5 days of diagnosis (≤5 days) was highly effective in shortening the length of hospital stay and faster viral load clearance.

Polymorphism in genes encoding two fatty acid binding proteins increases risk of ischemic stroke in a Chinese Han population.

Background: Dyslipidemia is an independent predictor of ischemic stroke (IS). Genetic variations in lipid-metabolism related genes may increase the risk of IS. Fatty acid-binding protein 1 (FABP1) and fatty acid-binding protein 2 (FABP2) are lipid chaperones responsible for lipid transport and metabolism. The present study aimed to determine the association between FABP1 or FABP2 and ischemic stroke. Methods: A total of 251 participants were recruited composed of 138 patients with ischemic stroke and 113 healthy subjects. DNA was extracted from peripheral blood samples. The rs2241883 polymorphism in FABP1 and rs1799883 polymorphism in FABP2 were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Generalized multifactor dimensionality reduction (GMDR) was used to find out the interaction combinations between two SNPs and environmental factors. Results: The GA genotype of FABP2 rs1799883 increased susceptibility to ischemic stroke under overdominant inheritance model (p = 0.042). After adjusting for the risk factors of IS, it was associated with a significantly higher risk of IS in the codominant inheritance model (adjust OR = 3.431, 95%CI = 1.060-11.103, p = 0.04). The interactions of FABP1 rs2241883 and FABP2 rs1799883 were not associated with IS risk (p = 0.172). Moreover, interaction analysis of two genes (rs1799883 and rs2241883) and two environmental factors (smoking and alcohol consumption) was associated with an increased risk of IS (p = 0.011). Conclusion: The GA genotype of FABP2 rs1799883, interactions between rs1799883, rs2241883 and smoking and alcohol consumption were associated with IS risk in Chinese Han populations.

Lipid Alteration Signature in the Blood Plasma of Individuals With Schizophrenia, Depression, and Bipolar Disorder.

Importance: No clinically applicable diagnostic test exists for severe mental disorders. Lipids harbor potential as disease markers. Objective: To define a reproducible profile of lipid alterations in the blood plasma of patients with schizophrenia (SCZ) independent of demographic and environmental variables and to investigate its specificity in association with other psychiatric disorders, ie, major depressive disorder (MDD) and bipolar disorder (BPD). Design, Setting, and Participants: This was a multicohort case-control diagnostic analysis involving plasma samples from psychiatric patients and control individuals collected between July 17, 2009, and May 18, 2018. Study participants were recruited as consecutive and volunteer samples at multiple inpatient and outpatient mental health hospitals in Western Europe (Germany and Austria [DE-AT]), China (CN), and Russia (RU). Individuals with DSM-IV or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnoses of SCZ, MDD, BPD, or a first psychotic episode, as well as age- and sex-matched healthy controls without a mental health-related diagnosis were included in the study. Samples and data were analyzed from January 2018 to September 2020. Main Outcomes and Measures: Plasma lipidome composition was assessed using liquid chromatography coupled with untargeted mass spectrometry. Results: Blood lipid levels were assessed in 980 individuals (mean [SD] age, 36 [13] years; 510 male individuals [52%]) diagnosed with SCZ, BPD, MDD, or those with a first psychotic episode and in 572 controls (mean [SD] age, 34 [13] years; 323 male individuals [56%]). A total of 77 lipids were found to be significantly altered between those with SCZ (n = 436) and controls (n = 478) in all 3 sample cohorts. Alterations were consistent between cohorts (CN and RU: [Pearson correlation] r = 0.75; DE-AT and CN: r = 0.78; DE-AT and RU: r = 0.82; P < 10-38). A lipid-based predictive model separated patients with SCZ from controls with high diagnostic ability (area under the receiver operating characteristic curve = 0.86-0.95). Lipidome alterations in BPD and MDD, assessed in 184 and 256 individuals, respectively, were found to be similar to those of SCZ (BPD: r = 0.89; MDD: r = 0.92; P < 10-79). Assessment of detected alterations in individuals with a first psychotic episode, as well as patients with SCZ not receiving medication, demonstrated only limited association with medication restricted to particular lipids. Conclusions and Relevance: In this study, SCZ was accompanied by a reproducible profile of plasma lipidome alterations, not associated with symptom severity, medication, and demographic and environmental variables, and largely shared with BPD and MDD. This lipid alteration signature may represent a trait marker of severe psychiatric disorders, indicating its potential to be transformed into a clinically applicable testing procedure.

Elevated plasma intestinal fatty acid binding protein and aberrant lipid metabolism predict post-stroke depression.

Post-stroke depression (PSD) is the most common mood disorder caused by stroke. Stroke might bring about increased intestinal permeability accompanied by gut microbiota changes. According to the "gut-brain" axis hypothesis, increased intestinal permeability may contribute to PSD. Therefore, we investigated the association between increased intestinal permeability and the occurrence of PSD. Intestinal fatty acid binding protein (iFABP) is responsible for intestinal fatty acid absorption and transport and is often considered a biomarker of gut hyperpermeability, also known as leaky gut. We enrolled 48 healthy controls (HCs), 48 stroke patients without depression, and 48 PSD patients in this study. Plasma iFABP was measured in the three groups. CRP, LBP, and sCD14 were quantified for bacterial infection assessment. In addition, clinical laboratory indicators of lipid metabolism were assessed. The PSD patients exhibited higher iFABP levels compared with HCs and non-depressed stroke patients. Using OPLS discriminant analysis, four proteins (ApoA1, HDL-C, iFABP, and Lp(a)) were identified as potential biomarkers for distinguishing PSD patients from non-depression stroke patients. Our study discovered that elevated plasma iFABP levels in PSD patients correlated with the degree of depression, along with disturbed lipid metabolism. These findings also suggested the need to consider the role of a leaky gut in depression after stroke.

Reduced plasma levels of RGM-A predict stroke-associated pneumonia in patients with acute ischemic stroke: A prospective clinical study.

Background: Stroke-induced immunodepression syndrome is considered the major etiology of stroke-associated pneumonia (SAP). Repulsive guidance molecule A (RGM-A) is an immunomodulatory protein that is closely related to inflammation and immune responses. To explore the relationship between RGM-A and SAP and facilitate the early identification of patients at high risk of developing SAP, we investigated the predictive value of RGM-A in SAP. Methods: We enrolled 178 patients with acute ischemic stroke (AIS) and finally analyzed 150 patients, among whom 69 had SAP and 81 had non-SAP. During the same period, 40 patients with community-acquired pneumonia and 40 healthy participants were included as controls. SAP was defined according to the modified US Centers for Disease Control and Prevention criteria. Blood samples were collected at 24 h, 48 h, 3 days, 4 to 7 days, and 8 to 14 days after stroke onset. An enzyme-linked immunosorbent assay was used to detect the plasma levels of RGM-A and interleukin-6. Results: The plasma RGM-A levels were significantly decreased in both patients with community-acquired pneumonia and those with AIS, and the decline was most pronounced in patients with SAP (P < 0.001). RGM-A started to decline within 24 h after stroke in the SAP group, and the lowest levels were detected on day 3 and days 4 to 7 (P < 0.001). The RGM-A levels in the SAP group were lower than those in the non-SAP group at all blood collection time points (P < 0.05). In the logistic regression analyses, RGM-A was a protective factor for SAP after adjusting for confounders (adjusted odds ratio = 0.22, 95% confidence interval = 0.091-0.538, P = 0.001). Receiver operating characteristic curve analysis showed that the area under the curve for RGM-A was 0.766 (0.091-0.538; P = 0.001), the cutoff value was 4.881 ng/mL, and the sensitivity and specificity were 80.00 and 76.36%, respectively. Conclusions: We demonstrated that reduced plasma levels of RGM-A might help in the early identification of high-risk patients with SAP and predict the occurrence of SAP in patients with AIS. RGM-A might provide new clues to a potential alternative therapy for SAP.

Differential Gut Microbiota Compositions Related With the Severity of Major Depressive Disorder.

Objective: Increasing evidence shows a close relationship between gut microbiota and major depressive disorder (MDD), but the specific mechanisms remain unknown. This study was conducted to explore differential gut microbiota compositions related to the severity of MDD. Methods: Healthy controls (HC) (n = 131) and MDD patients (n = 130) were included. MDD patients with Hamilton Depression Rating Scale (HDRS) score <25 and ≥25 were assigned into moderate (n = 72) and severe (n = 58) MDD groups, respectively. Univariate and multivariate analyses were used to analyze the gut microbiota compositions at the genus level. Results: Thirty-six and 27 differential genera were identified in moderate and severe MDD patients, respectively. The differential genera in moderate and severe MDD patients mainly belonged to three (Firmicutes, Actinobacteriota, and Bacteroidota) and two phyla (Firmicutes and Bacteroidota), respectively. One specific covarying network from phylum Actinobacteriota was identified in moderate MDD patients. In addition, five genera (Collinsella, Eggerthella, Alistipes, Faecalibacterium, and Flavonifractor) from the shared differential genera by two MDD groups had a fair efficacy in diagnosing MDD from HC (AUC = 0.786). Conclusions: Our results were helpful for further exploring the role of gut microbiota in the pathogenesis of depression and developing objective diagnostic methods for MDD.

The GR-FKBP51 interaction modulates fear memory but not spatial or recognition memory.

The glucocorticoid receptor (GR) forms a protein complex with FKBP51 that is increased in post-traumatic stress disorder (PTSD) and by fear conditioned learning. Disrupting the GR-FKBP51 complex with a synthetic peptide can block the storage or retrieval of fear conditioned memories, which could be a novel approach to the alleviate fear associated memory in PTSD. However, a potential unacceptable side effect could be the impairment of other types of memory. Thus, we investigated the effect of disrupting the GR-FKBP51 complex on recognition memory using the novel object and displaced object recognition tasks, spatial memory in the Morris water maze, and on social interaction in Crawley's three-chamber social interaction test. We did not observe adverse effects on these other types of memory and conclude that the GR-FKBP51 interaction remains a promising target for treating psychiatric disorders characterized by unwanted aversive memories such as in PTSD.

Associations Between Disordered Microbial Metabolites and Changes of Neurotransmitters in Depressed Mice.

Backgrounds: Many pieces of evidence demonstrated that there were close relationships between gut microbiota and depression. However, the specific molecular mechanisms were still unknown. Here, using targeted metabolomics, this study was conducted to explore the relationships between microbial metabolites in feces and neurotransmitters in prefrontal cortex of depressed mice. Methods: Chronic unpredictable mild stress (CUMS) model of depression was built in this study. Targeted liquid chromatography-mass spectrometry analysis was used to detect the microbial metabolites in feces and neurotransmitters in prefrontal cortex of mice. Both univariate and multivariate statistical analyses were applied to identify the differential microbial metabolites and neurotransmitters and explore relationships between them. Results: Ninety-eight differential microbial metabolites (mainly belonged to amino acids, fatty acids, and bile acids) and 11 differential neurotransmitters (belonged to tryptophan pathway, GABAergic pathway, and catecholaminergic pathway) were identified. Five affected amino acid-related metabolic pathways were found in depressed mice. The 19 differential microbial metabolites and 10 differential neurotransmitters were found to be significantly correlated with depressive-like behaviors. The two differential neurotransmitters (tyrosine and glutamate) and differential microbial metabolites belonged to amino acids had greater contributions to the overall correlations between microbial metabolites and neurotransmitters. In addition, the significantly decreased L-tyrosine as microbial metabolites and tyrosine as neurotransmitter had the significantly positive correlation (r = 0.681, p = 0.0009). Conclusions: These results indicated that CUMS-induced disturbances of microbial metabolites (especially amino acids) might affect the levels of neurotransmitters in prefrontal cortex and then caused the onset of depression. Our findings could broaden the understanding of how gut microbiota was involved in the onset of depression.

Altered Metabolism of the Microbiota-Gut-Brain Axis Is Linked With Comorbid Anxiety in Fecal Recipient Mice of Myasthenia Gravis.

Myasthenia gravis (MG) comorbid anxiety seriously affects the progress of MG. However, the exact relationship remains poorly understood. Recently, our preliminary study has revealed that intestinal microbe disturbance is closely related to MG. Therefore, further exploration of whether the microbiome is involved in MG comorbid anxiety is warranted. In this study, gas chromatography-mass spectrometry metabolomics analysis was used to characterize the metabotype of feces, serum, and three brain regions involved in emotion (i.e., the prefrontal cortex, hippocampus, and striatum), which were obtained from mice that were colonized with fecal microbiota from patients with MG (MMb), healthy individuals (HMb), or co-colonization of both patients and healthy individuals (CMb). Functional enrichment analysis was used to explore the correlation between the "microbiota-gut-brain" (MGB) axis and anxiety-like behavior. The behavioral test showed that female MMb exhibited anxiety-like behavior, which could be reversed by co-colonization. Moreover, metabolic characterization analysis of the MGB axis showed that the metabotype of gut-brain communication was significantly different between MMb and HMb, and 146 differential metabolites were jointly identified. Among these, 44 metabolites in feces; 12 metabolites in serum; 7 metabolites in hippocampus; 2 metabolites in prefrontal cortex; and 6 metabolites in striatum were reversed by co-colonization. Furthermore, the reversed gut microbiota mainly belonged to bacteroides and firmicutes, which were highly correlated with the reversed metabolites within the MGB axis. Among three emotional brain regions, hippocampus was more affected. Therefore, disturbances in gut microbiota may be involved in the progress of anxiety-like behavior in MG due to the MGB axis.

MicroRNA-Messenger RNA Regulatory Network Mediates Disrupted TH17 Cell Differentiation in Depression.

Accumulating evidence indicates an important role for microRNA (miRNA)-messenger RNA (mRNA) regulatory networks in human depression. However, the mechanisms by which these networks act are complex and remain poorly understood. We used data mining to identify differentially expressed miRNAs from GSE81152 and GSE152267 datasets, and differentially expressed mRNAs were identified from the Netherlands Study of Depression and Anxiety, the GlaxoSmithKline-High-Throughput Disease-specific target Identification Program, and the Janssen-Brain Resource Company study. We constructed a miRNA-mRNA regulatory network based on differentially expressed mRNAs that intersected with target genes of differentially expressed miRNAs, and then performed bioinformatics analysis of the network. The key candidate genes were assessed in the prefrontal cortex of chronic social defeat stress (CSDS) depression mice by quantitative real-time polymerase chain reaction (qRT-PCR). Three differentially expressed miRNAs were commonly identified across the two datasets, and 119 intersecting differentially expressed mRNAs were identified. A miRNA-mRNA regulatory network including these three key differentially expressed miRNAs and 119 intersecting differentially expressed mRNAs was constructed. Functional analysis of the intersecting differentially expressed mRNAs revealed that an abnormal inflammatory response characterized by disturbed T-helper cell 17 (Th17) differentiation was the primary altered biological function. qRT-PCR validated the decreased expression of Th17 cell differentiation-related genes, including interleukin (IL)17A, IL21, IL22, and IL1ß, and the increased expression of retinoic acid receptor-related orphan receptor gamma-t (RORγt) in CSDS mice, which showed significant depressive- and anxiety-like behaviors. This study indicates that an abnormal inflammatory response characterized by disturbed Th17 cell differentiation is the primary altered biological process in major depressive disorder. Our findings indicate possible biomarkers and treatment targets and provide novel clues to understand the pathogenesis of major depressive disorder.

Proteomics analysis of the gut-brain axis in a gut microbiota-dysbiosis model of depression.

Major depressive disorder (MDD) is a serious mental illness. Increasing evidence from both animal and human studies suggested that the gut microbiota might be involved in the onset of depression via the gut-brain axis. However, the mechanism in depression remains unclear. To explore the protein changes of the gut-brain axis modulated by gut microbiota, germ-free mice were transplanted with gut microbiota from MDD patients to induce depression-like behaviors. Behavioral tests were performed following fecal microbiota transplantation. A quantitative proteomics approach was used to examine changes in protein expression in the prefrontal cortex (PFC), liver, cecum, and serum. Then differential protein analysis and weighted gene coexpression network analysis were used to identify microbiota-related protein modules. Our results suggested that gut microbiota induced the alteration of protein expression levels in multiple tissues of the gut-brain axis in mice with depression-like phenotype, and these changes of the PFC and liver were model specific compared to chronic stress models. Gene ontology enrichment analysis revealed that the protein changes of the gut-brain axis were involved in a variety of biological functions, including metabolic process and inflammatory response, in which energy metabolism is the core change of the protein network. Our data provide clues for future studies in the gut-brain axis on protein level and deepen the understanding of how gut microbiota cause depression-like behaviors.