A novel bioinformatics strategy to uncover the active ingredients and molecular mechanisms of Bai Shao in the treatment of non-alcoholic fatty liver disease.

Introduction: As a new discipline, network pharmacology has been widely used to disclose the material basis and mechanism of Traditional Chinese Medicine in recent years. However, numerous researches indicated that the material basis of TCMs identified based on network pharmacology was the mixtures of beneficial and harmful substances rather than the real material basis. In this work, taking the anti-NAFLD (non-alcoholic fatty liver disease) effect of Bai Shao (BS) as a case, we attempted to propose a novel bioinformatics strategy to uncover the material basis and mechanism of TCMs in a precise manner. Methods: In our previous studies, we have done a lot work to explore TCM-induced hepatoprotection. Here, by integrating our previous studies, we developed a novel computational pharmacology method to identify hepatoprotective ingredients from TCMs. Then the developed method was used to discover the material basis and mechanism of Bai Shao against Non-alcoholic fatty liver disease by combining with the techniques of molecular network, microarray data analysis, molecular docking, and molecular dynamics simulation. Finally, literature verification method was utilized to validate the findings. Results: A total of 12 ingredients were found to be associated with the anti-NAFLD effect of BS, including monoterpene glucosides, flavonoids, triterpenes, and phenolic acids. Further analysis found that IL1-ß, IL6, and JUN would be the key targets. Interestingly, molecular docking and molecular dynamics simulation analysis showed that there indeed existed strong and stable binding affinity between the active ingredients and the key targets. In addition, a total of 23 NAFLD-related KEGG pathways were enriched. The major biological processes involved by these pathways including inflammation, apoptosis, lipid metabolism, and glucose metabolism. Of note, there was a great deal of evidence available in the literature to support the findings mentioned above, indicating that our method was reliable. Discussion: In summary, the contributions of this work can be summarized as two aspects as follows. Firstly, we systematically elucidated the material basis and mechanism of BS against NAFLD from multiple perspectives. These findings further enhanced the theoretical foundation of BS on NAFLD. Secondly, a novel computational pharmacology research strategy was proposed, which would assist network pharmacology to uncover the scientific connotation TCMs in a more precise manner.

Genomic Epidemiology and Antimicrobial Resistance Profiles of Clostridioides difficile from Multi-Hospitals in a City in Eastern China.

Background: Clostridioides difficile is an important pathogen causing approximately 20-30% of the cases-with antibiotic-associated diarrhea and 90% of those with Pseudomembranous enteritis. However, limited surveillance of C. difficile infections (CDI) in China is done at present, especially in terms of multi-hospital epidemiological reports. Methods: Between June 2020 and November 2020, we conducted a prospective study addressing antimicrobial susceptibility profiles and genomic epidemiology of C. difficile strains isolated from inpatients with diarrhea in seven tertiary hospitals in the same city. Results: In total, 177 strains of toxin-producing C. difficile were isolated, and the dominant toxin gene profiles were tcdA+tcdB+ (84.2%, 149/177) and tcdA-tcdB+ (15.8%, 28/177). Furthermore, 130 isolates were successfully analyzed for antimicrobial susceptibility phenotype in which the rates of resistance to clindamycin, erythromycin, levofloxacin, and moxifloxacin were higher than to other antibiotics. All strains were susceptible to metronidazole and vancomycin. Fluoroquinolone-associated mutations (such as gyrA) were the most frequently found ones in the analyzed genomes. Moreover, 24 different sequence types (STs) were identified in the 130 isolates, and the most prevalent types were ST3 (26.2%, 34/130) followed by ST54 (16.9%, 22/130) and ST2 (10%, 13/130). The so-called highly virulent strain ribotyping 027 (B1/NAP1/ST1) was not identified. In addition, we also compared single nucleotide polymorphisms (SNPs) among the isolates and carried out genomic epidemiological studies on the isolates. We found that ST3 and ST54 could cause transmission in both intra- and inter-hospital settings. Conclusion: Although it is the so-called hypervirulent epidemic strain, ribotyping 027 (ST1), was not detected. ST3 and ST54 can be transmitted through different hospitals. Therefore, it is necessary to conduct further molecular epidemiological monitoring of C. difficile and screening of patients admitted to key departments.

Deep brain stimulation in the globus pallidus alleviates motor activity defects and abnormal electrical activities of the parafascicular nucleus in parkinsonian rats.

Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD). The most common sites targeted for DBS in PD are the globus pallidus internal (GPi) and subthalamic nucleus (STN). However, STN-DBS and GPi-DBS have limited improvement in some symptoms and even aggravate disease symptoms. Therefore, discovering new targets is more helpful for treating refractory symptoms of PD. Therefore, our study selected a new brain region, the lateral globus pallidus (GP), as the target of DBS, and the study found that GP-DBS can improve motor symptoms. It has been reported that the thalamic parafascicular (PF) nucleus is strongly related to PD pathology. Moreover, the PF nucleus and GP have very close direct and indirect fiber connections. However, whether GP-DBS can change the activity of the PF remains unclear. Therefore, in this study, we monitored the activity changes in the PF nucleus in PD rats during a quiet awake state after GP-DBS. We found that GP-DBS could reverse the electrical activity of the PF nucleus in PD model rats, including the discharge pattern of the neurons and the local field potential (0.7-12 and 12-70 Hz). Based on the results mentioned above, PF activity in PD model rats could be changed by GP-DBS. Thus, the normalization of PF neuronal activity may be a potential mechanism for GP-DBS in the treatment of PD; these findings lay the foundation for PD treatment strategies.

Identification of hepatoprotective traditional Chinese medicines based on the structure-activity relationship, molecular network, and machine learning techniques.

The efforts focused on discovering potential hepatoprotective drugs are critical for relieving the burdens caused by liver diseases. Traditional Chinese medicine (TCM) is an important resource for discovering hepatoprotective agents. Currently, there are hundreds of hepatoprotective products derived from TCM available in the literature, providing crucial clues to discover novel potential hepatoprotectants from TCMs based on predictive research. In the current study, a large-scale dataset focused on TCM-induced hepatoprotection was established, including 676 hepatoprotective ingredients and 205 hepatoprotective TCMs. Then, a comprehensive analysis based on the structure-activity relationship, molecular network, and machine learning techniques was performed at molecular and holistic TCM levels, respectively. As a result, we developed an in silico model for predicting the hepatoprotective activity of ingredients derived from TCMs, in which the accuracy exceeded 85%. In addition, we originally proposed a material basis and a drug property-based approach to identify potential hepatoprotective TCMs. Consequently, a total of 12 TCMs were predicted to hold potential hepatoprotective activity, nine of which have been proven to be beneficial to the liver in previous publications. The high rate of consistency between our predictive results and the literature reports demonstrated that our methods were technically sound and reliable. In summary, systematical predictive research focused on the hepatoprotection of TCM was conducted in this work, which would not only assist screening of potential hepatoprotectants from TCMs but also provide a novel research mode for discovering the potential activities of TCMs.

The efficacy of therapies for post-stroke depression in aging: An umbrella review.

Post-stroke depression (PSD) is a common complication after stroke. PSD is associated with emotional disorders and psychological dependence, which are potential risk factors for stroke recurrence and suicidality. This study aimed to perform an umbrella review of therapies for PSD through a comprehensive literature search. A systematic search was conducted in the PubMed and Web of Science by two independent authors. We examined the Hamilton Depression Scale (HAMD), Activities of daily living (ADL), Neurologic function as efficacy endpoints, and the incidence of adverse events as safety profiles. Seventeen eligible studies, including 267 clinical trials were included in this study. The results showed that High-Frequency Repetitive Transcranial Magnetic Stimulation (HfrTMS), Acupuncture/EA+conventional treatment, Escitalopram, Modified Sini San, Moxibustion, Xiaoyao Formula, Paroxetine, Chinese herbal medicine, Exercise, Citalopram, and Cognitive behavioral therapy are beneficial for improving the depression symptoms of patients with PSD. HfrTMS and Sertraline may have an impact on slowing the scores of activities of daily living or neurologic function. In addition, Acupuncture/EA+conventional, Escitalopram, Citalopram, Sertraline, and Fluoxetine showed no serious adverse events in PSD patients. Our study demonstrated that 11 treatment methods can effectively improve the condition of PSD patients.

Investigating the active compounds and mechanism of HuaShi XuanFei formula for prevention and treatment of COVID-19 based on network pharmacology and molecular docking analysis.

Traditional Chinese medicine (TCM) has exerted positive effects in controlling the COVID-19 pandemic. HuaShi XuanFei Formula (HSXFF) was developed to treat patients with mild and general COVID-19 in Zhejiang Province, China. The present study seeks to explore its potentially active compounds and pharmacological mechanisms against COVID-19 based on network pharmacology, molecular docking, and molecular dynamics (MD) simulation. All components of HSXFF were harvested from the pharmacology database of the TCMSP system. COVID-19-related targets were retrieved from using OMIM and GeneCards databases. The herb-compound-targets network was constructed by Cytoscape. The target protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to discover the potential key target genes and mechanism. The main active compounds of HSXFF were docked with 3C-like (3CL) protease hydrolase and angiotensin-converting enzyme 2 (ACE2). The MD simulation confirmed the binding stability of docking results. The herbs-targets network mainly contained 52 compounds and 70 corresponding targets, including key targets such as RELA, TNF, TP53, IL6, MAPK1, CXCL8, IL-1ß, and MAPK14. The GO and KEGG indicated that HSXFF may be mainly acting on the IL-17 signaling pathway, TNF signaling pathway, NF-κB signaling pathway, etc. The molecular docking results indicated that isovitexin and procyanidin B1 showed the highest affinity with 3CL and ACE2, respectively, which were confirmed by MD simulation. These findings suggested HSXFF exerted therapeutic effects involving "multi-compounds and multi-targets." It might be working through directly inhibiting the virus, improving immune function, and reducing the inflammatory in response to anti-COVID-19. In summary, the present study would provide a valuable direction for further research of HSXFF.

Preselection TCR repertoire predicts CD4+ and CD8+ T-cell differentiation state.

T cells must display diversity regarding both the cell state and T-cell receptor (TCR) repertoire to provide effective immunity against pathogens; however, the generation and evolution of cellular T-cell heterogeneity in the adaptive immune system remains unclear. In the present study, a combination of multiplex PCR and immune repertoire sequencing (IR-seq) was used for a standardized analysis of the TCR ß-chain repertoire of CD4+ naive, CD4+ memory, CD8+ naive and CD8+ memory T cells. We showed that the T-cell subsets could be distinguished from each another with regard to the TCR ß-chain (TCR-ß) diversity, CDR3 length distribution and TRBV usage, which could be observed both in the preselection and in the post-selection repertoire. Moreover, the Dß-Jß and Vß-Dß combination patterns at the initial recombination step, template-independent insertion of nucleotides and inter-subset overlap were consistent between the pre- and post-selection repertoires, with a remarkably positive correlation. Taken together, these results support differentiation of the CD4+ and CD8+ T-cell subsets prior to thymic selection, and these differences survived both positive and negative selection. In conclusion, these findings provide deeper insight into the generation and evolution of TCR repertoire generation.

Using chemical bond-based method to predict site of metabolism for five biotransformations mediated by CYP 3A4, 2D6, and 2C9.

Although it has been proposed for decades to predict site of metabolism (SOM) by in silico methods, identifying SOM correctly remains an unsolved fundamental problem and is an active area of research. In our prior works, we proposed a chemical bond-based approach to construction of SOM prediction models by integrating chemical bond descriptors and drug-metabolizing enzymes data. Although it has been evaluated with both 10-fold cross-validation and independent validation, we believe comparisons between this method and prior methods using publicly accessible external datasets are indispensable and more desirable. In the current study, based on chemical bond-based method, metabolism data released by Sheridan et al. and Zaretzki et al. was utilized to establish metabolite prediction models for CYP450 3A4, 2D6, and 2C9. Five major reaction types were involved, including Aliphatic C-hydroxylation, Aromatic C-hydroxylation, N-dealkylation, O-dealkylation, and S-Oxidation. Consequently, all our five models showed impressive performance on predicting SOMs, with accuracy and area under curve exceeded 0.940 and 0.953, respectively. Compared to prior works, our models were better than SOMP both in "SOM-scale" and "molecule-scale". In conclusion, comparisons between chemical-bond based method and prior works were conducted for the first time, which demonstrated that chemical-bond based method is better than or at least comparable to prior works.

Elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in schizophrenia patients.

BACKGROUND: Psychiatric diseases are usually accompanied by immune dysregulation and activation of the inflammatory response system. However, the characteristics of immunoinflammatory markers in psychiatric diseases are not well defined. METHODS: Seventy-three patients with psychiatric diseases were divided into four groups, including a schizophrenia group, an anxiety disorder group, a unipolar depression group, and a bipolar disorder group, according to the ICD-10 and DSM-IV codes. Neutrophil gelatinase-associated lipocalin (NGAL) and associated classical immunoinflammatory markers including C-reactive protein (CRP), Th1/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ), total leukocyte count (TLC), and neutrophilic granulocyte percentage (NEU%) were analysed; patients with physical diseases were excluded to avoid confounders. Fifteen healthy, age- and gender-matched individuals served as controls. RESULTS: Compared with the corresponding values in the control group, the level of CRP in each psychiatric disease group, the levels of IFN-γ and NGAL in the schizophrenia group, and the NEU% in the depression group were significantly elevated (P < 0.05). Compared with the levels in the schizophrenia group, the levels of CRP in the bipolar disorder and depression groups, the level of IFN-γ in the bipolar disorder group, and the levels of NGAL in the anxiety disorder and depression groups were significantly decreased (P < 0.05). Compared with the depression group, the bipolar disorder group showed significant elevation the NGAL level. LIMITATION: The sample size was relatively small. CONCLUSIONS: Immunoinflammatory markers were elevated in patients with psychiatric diseases, especially schizophrenia. We are the first to report that the level of NGAL is significantly increased in schizophrenia patients.

Decreased absolute numbers of CD3+ T cells and CD8+ T cells during aging in herpes zoster patients.

Herpes zoster (HZ) is an infectious dermatosis with high incidence worldwide. Age is a key risk factor for HZ, and postherpetic neuralgia (PHN) is the main sequelae. Until now, no index has been available to predict the pathogenesis of PHN, and rare reports have focused on the immune response during aging and PHN. In this study, we selected immunoglobulin and complement proteins as markers for humoral immunity, while T lymphocyte subsets and natural killer (NK) cells were selected as markers for cell immunity, to systematically study the characteristics of immune responses in the peripheral blood of HZ patients. Our data showed that the absolute number of CD3+ T cells and CD8+ T cells decreased during aging and PHN. This implies that more attention should be paid to prevent the occurrence of PHN, especially in the aged population.

Predictive value of serum ALT and T-cell receptor beta variable chain for HBeAg seroconversion in chronic hepatitis B patients during tenofovir treatment.

Effective antiviral therapy plays a key role in slowing the progression of chronic hepatitis B (CHB). Identification of serum indices, including hepatitis B e antigen (HBeAg) expression and seroconversion, will facilitate evaluation of the efficacy of antiviral therapy in HBeAg-positive CHB patients. The biochemical, serological, virological parameters, and the frequency of circulating CD4CD25 regulatory T cell (Treg) in 32 patients were measured at baseline and every 12 weeks during 96 weeks of tenofovir disoproxil fumarate (TDF) treatment. The relationship between the hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and Treg and alanine aminotransferase (ALT) levels was analyzed, respectively. The molecular profiles of T-cell receptor beta variable chain (TRBV) were determined using gene melting spectral pattern. For the seroconverted 12 patients, ALT declined to normal levels by week 24 and remained at this level in subsequent treatment; moreover, the predictive cutoff value of ALT for HBeAg seroconversion (SC) was 41.5 U/L at week 24. The positive correlation between HBV DNA and Treg and ALT was significant in SC patients, but not in non-SC patients. Six TRBV families (BV3, BV11, BV12, BV14, BV20, and BV24) were predominantly expressed in SC patients at baseline. The decline of ALT could be used to predict HBeAg seroconversion for CHB patients during TDF treatment. In addition, the profile of Tregs and TRBVs may be associated with HBeAg seroconversion and could also be a potential indicator for predicting HBeAg SC and treatment outcome for CHB patients.

[Mechanism of anti-aging therapy on Parkinson's disease].

Many studies have shown that anti-aging treatment has value to prevention and treatment of some diseases. For the treatment of Parkinson' s disease, clinical and experimental researches have proved the potential value of anti-aging treatment, yet the mechanism remains unclear. For this reason, this work used the anti-aging prescriptions of Buyang Huanwu decoction in traditional Chinese medicines example to discover the anti-aging treatment mechanism on Parkinson's disease. The results showed that the mechanism of mitochondrial damage, apoptosis, free radicals and oxidative stress could contribute to the treatment of Parkinson' s disease. Buyang Huanwu decoction is more than as the carrier in this article, the discovered anti-aging treatment mechanism Parkinson's disease is not confined to Buyang Huanwu decoction, could also be used to understand the anti-aging treatment mechanism using other prescription. The main contribution of this paper is to clarify the mechanism of anti-aging treatment of Parkinson's disease, and provide a new strategy for the treatment and prevention of Parkinson's disease.

Curcumin treatment suppresses CCR7 expression and the differentiation and migration of human circulating fibrocytes.

BACKGROUND/AIM: Recent studies have demonstrated that circulating fibrocytes contribute to the formation and development of fibrosis. Curcumin, a polyphenolic compound isolated from turmeric, has been shown to have anti-fibrotic effects in various organs. We and others have demonstrated that curcumin beneficially affects the development of fibrosis. However the effect of curcumin on circulating fibrocytes has not been reported. METHODS: Human circulating fibrocytes were isolated from leukocyte concentrates of healthy human donors and identified based on the expression of CD34, CD45, collagen I (COLI), and chemokine receptor CCR7 (CCR7) via flow cytometry. Cell Counting Kit-8 was used to evaluate cell viability. The effect of curcumin on the differentiation and migration of human circulating fibrocytes was evaluated by immunofluorescence staining, flow cytometry and a transwell migration assay. Transforming growth factor (TGF)-ß1 secretion was examined by ELISA. RESULTS: Curcumin treatment (72 h; 20 µM) significantly decreased the expression of COL I, α-SMA and CCR7, as well as TGF-ßl secretion, in human circulating fibrocytes. The inhibitory effect of curcumin on the differentiation and migration of human circulating fibrocytes is likely via regulating the CCR7/CCL21 signaling pathway, in particular by reducing CCR7 expression. These observed effects may be beneficial in resolving fibrosis by suppressing TGF-ß1 secretion. CONCLUSION: Our results suggest that curcumin has the potential to suppress the differentiation and migration of circulating fibrocytes, which would provide new explanation for curcumin's application in the development of fibrosis in various organs.