The clinical value of serum-related indexes in differentiating simple premature thelarche from idiopathic central precocious puberty.

Objective: To explore the changes of serum-related indexes at different time points, so as to identify the critical time of converting from simple premature thelarche (PT) to idiopathic central precocious puberty (ICPP). Methods: This is a retrospective study. The subjects of the study were 50 girls with PT who were admitted to the Children's Hospital of Hebei Province from January 2019 to September 2020. The enrolled 50 children were divided into the conversion group(n=12) and the non-conversion group(n=38) according to whether PT was converted into ICPP during follow-up. Furthermore, the levels of serum-related indexes and uterine and ovarian volumes were compared after the diagnosis of PT. Results: The IGF-1 and IGFBP-3 levels of children in the conversion group began to change significantly from six months after the diagnosis, with statistically significant differences when compared with the levels of children at the initial diagnosis, three months and those of the non-conversion group at the same time points (p<0.05). The levels of vitamin-D, DHEA and leptin began to change significantly at nine months after the diagnosis (p<0.05). Besides, uterine and ovarian volumes in the conversion group began to increase significantly six months after the diagnosis, with statistically significant differences when compared with those in the non-conversion group (p<0.05). Conclusion: Findings in our study suggest that regular monitoring of vitamin-D, IGF-1, IGFBP-3, DHEA and leptin levels, and uterine and ovarian volumes can predict the conversion from PT to ICPP at an early stage.

The Distribution, Drug Susceptibility, and Dynamic Trends of Pseudomonas aeruginosa Infection in a Tertiary Hospital in China During 2016‒2022.

Background: Drug-resistant Pseudomonas aeruginosa infections rapidly increased and contributed to life-threatening nosocomial infections; however, the distribution, species, drug susceptibility and dynamic trends of P. aeruginosa infection in China remained unclear. This study was conducted to better understand the epidemiological data of increased P. aeruginosa infections from 2016 to 2022 in a hospital in China. Methods: This study involved 3301 patients infected with P. aeruginosa, diagnosed using a nosocomial infection surveillance system in a tertiary hospital between 2016 and 2022. The P. aeruginosa infections from 2016 to 2022 were assessed according to the hospital department and species, and the drug susceptibility was evaluated using 16 antimicrobial agents. Results: The P. aeruginosa infection prevalence in the hospital department was: Neurosurgery (14.30%), Emergency (13.30%), and Critical Care Medicine (11.69%). Samples for P. aeruginosa infection identification were from sputum (72.52%) and other secreta (9.91%). The P. aeruginosa infections demonstrated a greater sensitivity to amikacin (AMK, 91.82%), tobramycin (TOB, 82.79%), and gentamycin (GEN, 82.01%); however, P. aeruginosa infection demonstrated greater resistance to ticarcillin (22.57%), levofloxacin (21.63%), and ciprofloxacin (18.00%). Conclusion: The P. aeruginosa infections were commonly observed in the Neurosurgery, Emergency, and Critical Care Medicine departments and demonstrated greater sensitivity to AMK, TOB, and GEN than the other drugs.

How we treat primary immune thrombocytopenia in adults.

Primary immune thrombocytopenia (ITP) is an immune-mediated bleeding disorder characterized by decreased platelet counts and an increased risk of bleeding. Multiple humoral and cellular immune abnormalities result in accelerated platelet destruction and suppressed platelet production in ITP. The diagnosis remains a clinical exclusion of other causes of thrombocytopenia. Treatment is not required except for patients with active bleeding, severe thrombocytopenia, or cases in need of invasive procedures. Corticosteroids, intravenous immunoglobulin, and anti-RhD immunoglobulin are the classical initial treatments for newly diagnosed ITP in adults, but these agents generally cannot induce a long-term response in most patients. Subsequent treatments for patients who fail the initial therapy include thrombopoietic agents, rituximab, fostamatinib, splenectomy, and several older immunosuppressive agents. Other potential therapeutic agents, such as inhibitors of Bruton's tyrosine kinase and neonatal Fc receptor, are currently under clinical evaluation. An optimized treatment strategy should aim at elevating the platelet counts to a safety level with minimal toxicity and improving patient health-related quality of life, and always needs to be tailored to the patients and disease phases. In this review, we address the concepts of adult ITP diagnosis and management and provide a comprehensive overview of current therapeutic strategies under general and specific situations.

Erratum: CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway: Erratum.

[This corrects the article DOI: 10.7150/ijbs.66915.].

[New eudesmane sesquiterpenoids from Atractylodis Macrocephalae Rhizoma and their inhibitory activities against SREBPs].

Three sesquiterpenoids were isolated and purified from the 95% ethanol extract of Atractylodis Macrocephalae Rhizoma by column chromatography on silica gel, Sephadex LH-20, ODS, and high-performance liquid chromatography(HPLC). Their chemical structures were identified on the basis of spectroscopic analysis and physiochemical properties as(7Z)-8ß,13-diacetoxy-eudesma-4(15),7(11)-diene(1), 7-oxo-7,8-secoeudesma-4(15),11-dien-8-oic acid(2), and guai-10(14)-en-11-ol(3). Compounds 1 and 2 are new compounds and compound 3 was obtained from Compositae family for the first time. Compounds 1, 2, and 3 showed weak inhibitory activities against sterol regulatory element-binding proteins(SREBPs).

CircCCNB1 silencing acting as a miR-106b-5p sponge inhibited GPM6A expression to promote HCC progression by enhancing DYNC1I1 expression and activating the AKT/ERK signaling pathway.

Background: Circular RNAs (circRNAs), which generally act as microRNA (miRNA) sponges to competitively regulate the downstream target genes of miRNA, play an essential role in cancer biology. However, few studies have been reported on the role of circRNA based competitive endogenous RNA (ceRNA) network in hepatocellular carcinoma (HCC). Herein, we aimed to screen and establish the circRNA/miRNA/mRNA networks related to the prognosis and progression of HCC and further explore the underlying mechanisms of tumorigenesis. Methods: GEO datasets GSE97332, GSE108724, and GSE101728 were utilized to screen the differentially expressed circRNAs (DE-circRNAs), DE-miRNAs, and DEmRNAs between HCC and matched para-carcinoma tissues. After six RNA-RNA predictions and five intersections between DE-RNAs and predicted RNAs, the survival-related RNAs were screened by the ENCORI analysis tool. The ceRNA networks were constructed using Cytoscape software, based on two models of up-regulated circRNA/down-regulated miRNA/up-regulated mRNA and down-regulated circRNA/up-regulated miRNA/down-regulated mRNA. The qRT-PCR assay was utilized for detecting the RNA expression levels in HCC cells and tissues. The apoptosis, Edu, wound healing, and transwell assays were performed to evaluate the effect of miR-106b-5p productions on the proliferation, invasion, and metastasis of HCC cells. In addition, the clone formation, cell cycle, and nude mice xenograft tumor assays were used to investigate the influence of hsa_circ_0001495 (circCCNB1) silencing and overexpression on the proliferation of HCC cells in vitro and in vivo. Furthermore, the mechanism of downstream gene DYNC1I1 and AKT/ERK signaling pathway via the circCCNB1/miR-106b-5p/GPM6A network in regulating the cell cycle was also explored. Results: Twenty DE-circRNAs with a genomic length less than 2000bp, 11 survival-related DE-miRNAs, and 61 survival-related DE-mRNAs were screened out and used to construct five HCC related ceRNA networks. Then, the circCCNB1/miR-106b-5p/GPM6A network was randomly selected for subsequent experimental verification and mechanism exploration at in vitro and in vivo levels. The expression of circCCNB1 and GPM6A were significantly down-regulated in HCC cells and cancer tissues, while miR-106b-5p expression was up-regulated. After transfections, miR-106b-5p mimics notably enhanced the proliferation, invasion, and metastasis of HCC cells, while the opposite was seen with miR-105b-5p inhibitor. In addition, circCCNB1 silencing promoted the clone formation ability, the cell cycle G1-S transition, and the growth of xenograft tumors of HCC cells via GPM6A downregulation. Subsequently, under-expression of GPM6A increased DYNC1I1 expression and activated the phosphorylation of the AKT/ERK pathway to regulate the HCC cell cycle. Conclusions: We demonstrated that circCCNB1 silencing promoted cell proliferation and metastasis of HCC cells by weakening sponging of oncogenic miR-106b-5p to induce GPM6A underexpression. DYNC1I1 gene expression was up-regulated and further led to activation of the AKT/ERK signaling pathway.

Two new sesquiterpenes from the rhizomes of Atractylodes macrocephala and their biological activities.

Two new sesquiterpenes, named selina-4(14),7,11-trien-9-ol (1) and selina-4(14),11-dien-7-ol (2), along with two known compounds were isolated from rhizomes of Atractylodes macrocephala Koidz. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configuration of 1 was established by TDDFT-ECD calculations. Compound 1 was found to moderately inhibit LSD1 activity with IC50 value of 34.0 µM. Compounds 1 and 4 exhibited a regulate effect on Keap1-Nrf2-ARE pathway.[Formula: see text].

Structure, synthesis, biosynthesis, and activity of the characteristic compounds from Ginkgo biloba L.

Covering: 1928-2021Ginkgo biloba L. is one of the most distinctive plants to have emerged on earth and has no close living relatives. Owing to its phylogenetic divergence from other plants, G. biloba contains many compounds with unique structures that have served to broaden the chemical diversity of herbal medicine. Examples of such compounds include terpene trilactones (ginkgolides), acylated flavonol glycosides (ginkgoghrelins), biflavones (ginkgetin), ginkgotides and ginkgolic acids. The extract of G. biloba leaf is used to prevent and/or treat cardiovascular diseases, while many ginkgo-derived compounds are currently at various stages of preclinical and clinical trials worldwide. The global annual sales of G. biloba products are estimated to total US$10 billion. However, the content and purity of the active compounds isolated by traditional methods are usually low and subject to varying environmental factors, making it difficult to meet the huge demand of the international market. This highlights the need to develop new strategies for the preparation of these characteristic compounds from G. biloba. In this review, we provide a detailed description of the structures and bioactivities of these compounds and summarize the recent research on the development of strategies for the synthesis, biosynthesis, and biotechnological production of the characteristic terpenoids, flavonoids, and alkylphenols/alkylphenolic acids of G. biloba. Our aim is to provide an important point of reference for all scientists who research ginkgo-related compounds for medicinal or other purposes.

Abnormalities of bone marrow B cells and plasma cells in primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoantibody-mediated hemorrhagic disorder in which B cells play an essential role. Previous studies have focused on peripheral blood (PB), but B cells in bone marrow (BM) have not been well characterized. We aimed to explore the profile of B-cell subsets and their cytokine environments in the BM of patients with ITP to further clarify the pathogenesis of the disease. B-cell subpopulations and their cytokine/chemokine receptors were detected by using flow cytometry. Plasma concentrations of cytokines/chemokines were measured by using enzyme-linked immunosorbent assay. Messenger RNA levels of B cell-related transcription factors were determined by using quantitative polymerase chain reaction. Regulatory B cell (Breg) function was assessed by quantifying their inhibitory effects on monocytes and T cells in vitro. Decreased proportions of total B cells, naive B cells, and defective Bregs were observed in patients with ITP compared with healthy controls (HCs), whereas an elevated frequency of long-lived plasma cells was found in BM of autoantibody-positive patients. No statistical difference was observed in plasmablasts or in short-lived plasma cells between patients with ITP and HCs. The immunosuppressive capacity of BM Bregs from patients with ITP was considerably weaker than HCs. An in vivo study using an active ITP murine model revealed that Breg transfusion could significantly alleviate thrombocytopenia. Moreover, overactivation of CXCL13-CXCR5 and BAFF/APRIL systems were found in ITP patient BM. Taken together, B-cell subsets in BM were skewed toward a proinflammatory profile in patients with ITP, suggesting the involvement of dysregulated BM B cells in the development of the disease.

Yeast MED2 is involved in the endoplasmic reticulum stress response and modulation of the replicative lifespan.

Saccharomyces cerevisiae MED2/YDL005C is a subunit of the mediator complex (Mediator), which is responsible for tightly controlling the transcription of protein-coding genes by mediating the interaction of RNA polymerase II with gene-specific transcription factors. Although a high-throughput analysis in yeast showed that the MED2 protein exhibits altered cellular localization under hypoxic stress, no specific function of MED2 has been described to date. In this study, we first provided evidence that MED2 is involved in the endoplasmic reticulum (ER) stress response and modulation of the replicative life span. We showed that deletion of MED2 leads to sensitivity to the ER stress inducer tunicamycin (TM) as well as a shortened replicative lifespan (RLS), accompanied by increased intracellular ROS levels and hyperpolarization of mitochondria. On the other hand, overexpression of MED2 in wild-type (WT) yeast enhanced TM resistance and extended the RLS. In addition, the IRE1-HAC1 pathway was essential for the TM resistance of MED2-overexpressing cells. Moreover, we showed that MED2 deficiency enhances ER unfolded protein response (UPR) activity compared to that in WT cells. Collectively, these results suggest the novel role of MED2 as a regulator in maintaining ER homeostasis and longevity.

Investigation of immune escape-associated mutations of hepatitis B virus in patients harboring hepatitis B virus drug-resistance mutations.

BACKGROUND: It is unclear whether immune escape-associated mutations in the major hydrophilic region of hepatitis B virus surface antigen (HBsAg) are associated with nucleoside/nucleotide analog resistance. AIM: To evaluate the association between immune escape-associated mutations and nucleoside/nucleotide analog resistance mutations. METHODS: In total, 19440 patients with chronic hepatitis B virus infection, who underwent resistance testing at the Fifth Medical Center of Chinese PLA General Hospital between July 2007 and December 2017, were enrolled. As determined by sequence analysis, 6982 patients harbored a virus with resistance mutations and 12458 harbored a virus lacking resistance mutations. Phenotypic analyses were performed to evaluate HBsAg production, replication capacity, and drug-induced viral inhibition of patient-derived drug-resistant mutants with or without the coexistence of sA159V. RESULTS: The rate of immune escape-associated mutation was significantly higher in 9 of the 39 analyzed mutation sites in patients with resistance mutations than in patients without resistance mutations. In particular, these mutations were sQ101H/K/R, sS114A/L/T, sT118A/K/M/R/S/V, sP120A/L/Q/S/T, sT/I126A/N/P/S, sM133I/L/T, sC137W/Y, sG145A/R, and sA159G/V. Among these, sA159V was detected in 1.95% (136/6982) of patients with resistance mutations and 1.08% (134/12,458) of patients lacking resistance mutations (P < 0.05). The coexistence of sA159V with lamivudine (LAM) and entecavir (ETV)-resistance mutations in the same viral genome was identified during follow-up in some patients with drug resistance. HBsAg production was significantly lower and the replication capacity was significantly higher, without a significant difference in LAM/ETV susceptibility, in sA159V-containing LAM/ETV-resistant mutants than in their sA159V-lacking counterparts. CONCLUSION: In summary, we observed a close link between the increase in certain immune escape-associated mutations and the development of resistance mutations. sA159V might increase the fitness of LAM/ETV-resistant mutants under environmental pressure in some cases.

High-dose dexamethasone plus recombinant human thrombopoietin vs high-dose dexamethasone alone as frontline treatment for newly diagnosed adult primary immune thrombocytopenia: A prospective, multicenter, randomized trial.

We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus recombinant human thrombopoietin (rhTPO), vs HD-DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4-day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD-DXM plus rhTPO arm and 96 patients in the HD-DXM monotherapy arm were included in the full analysis set. So, HD-DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs 66.7%, P < .001) and complete response (CR, 75.0% vs 42.7%, P < .001) compared with HD-DXM monotherapy. Response rate at 6 months was also higher in the HD-DXM plus rhTPO arm than that in the HD-DXM monotherapy arm (51.0% vs 36.5%, P = .02; sustained CR: 46.0% vs 32.3%, P = .043). Throughout the follow-up period, the overall duration of response was greater in the HD-DXM plus rhTPO arm compared to the HD-DXM monotherapy arm (P = .04), as estimated by the Kaplan-Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD-DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044.

Comprehensive chemical profiling of Jia-Wei-Qi-Fu-Yin and its network pharmacology-based analysis on Alzheimer's disease.

Jia-Wei-Qi-Fu-Yin (JWQFY) is a newly developed anti-Alzheimer's disease (AD) prescription modified from a classical traditional Chinese medicine formula, Qi-Fu-Yin (QFY). However, a systematic understanding of its chemical constituents and molecular mechanisms is still elusive. To address this problem, comprehensive chemical profiling followed by network pharmacology-based analysis of JWQFY was performed. Firstly, a total of 136 compounds were characterized by high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF MS), 17 of them were specifically identified in JWQFY comparing with QFY. Seventy compounds were further quantified via a validated HPLC coupled with triple quadrupole tandem mass spectrometry (QQQ MS) method. Then the protein targets of the seventy compounds were gathered from public databases for network construction. As a result, fifty-seven compounds were filtered, which interacted with 655 targets. Thirty-four of them were mapped into the KEGG pathway of AD, indicating JWQFY might exert anti-AD effects by anti-inflammation, neuronal apoptosis intervening, Aß production inhibition and phosphorylating tau protein moderating. Furthermore, in the compound-target-AD network, a list of hub compounds and hub targets was identified based on their topological features, including the degree, node betweenness and closeness. Four of the hub compounds were specifically originated from JWQFY, supporting the modification rationality of this formula. This study provided a scientific basis for understanding the bioactive compounds and the multi-target mechanism of JWQFY.

Aberrant expression of two miRNAs promotes proliferation, hepatitis B virus amplification, migration and invasion of hepatocellular carcinoma cells: evidence from bioinformatic analysis and experimental validation.

BACKGROUND: As key negative regulators of gene expression, microRNAs (miRNAs) play an important role in the onset and progression of hepatocellular carcinoma (HCC). This study aimed to identify the miRNAs involved in HCC carcinogenesis and their regulated genes. METHODS: The Gene Expression Omnibus (GEO) dataset (GSE108724) was chosen and explored to identify differentially expressed miRNAs using GEO2R. For the prediction of potential miRNA target genes, the miRTarBase was explored. Enrichment analysis of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed by the DAVID online tool. The hub genes were screened out using the CytoHubba plug-in ranked by degrees. The networks between miRNAs and hub genes were constructed by Cytoscape software. MiRNA mimics and negative control were transfected into HCC cell lines and their effects on proliferation, hepatitis B virus DNA (HBV-DNA) replication, TP53 expression, migration, and invasion were investigated. The following methods were employed: MTT assay, quantitative PCR (qPCR) assay, western blotting, wound healing assay, and transwell assay. RESULTS: A total of 50 differentially expressed miRNAs were identified, including 20 upregulated and 30 downregulated miRNAs, in HCC tumor tissues compared to matched adjacent tumor-free tissues. The top three upregulated (miR-221-3p, miR-222-3p, and miR-18-5p) and downregulated (miR-375, miR-214-3p and miR-378d) miRNAs, ranked by |log2 fold change (log2FC)|, were chosen and their potential target genes were predicted. Two gene sets, targeted by the upregulated and the downregulated miRNAs, were identified respectively. GO and KEGG pathway analysis showed that the predicted target genes of upregulated and downregulated miRNAs were mainly enriched in the cell cycle and cancer-related pathways. The top ten hub nodes of gene sets ranked by degrees were identified as hub genes. Analysis of miRNA-hub gene network showed that miR-221-3p and miR-375 modulated most of the hub genes, especially involving regulation of TP53. The q-PCR results showed that miR-221-3p and miR-375 were markedly upregulated and downregulated, respectively, in HCC cells and HCC clinical tissue samples compared to non-tumoral tissues. Furthermore, miR-221-3p overexpression significantly enhanced proliferation, HBV-DNA replication, as well as the migration and invasion of HCC cells, whereas miR-375 overexpression resulted in opposite effects. Western blotting analysis showed that the overexpression of miR-221-3p and miR-375 reduced and increased TP53 expression, respectively. CONCLUSION: The present study revealed that miR-211-3p and miR-375 may exert vital effects on cell proliferation, HBV-DNA replication, cell migration, and invasion through the regulation of TP53 expression in HCC.

Overexpression of Progerin Results in Impaired Proliferation and Invasion of Non-Small Cell Lung Cancer Cells.

PURPOSE: The accumulation of progerin (PG) in patients is responsible for the pathogenesis of Hutchinson-Gilford Progeria Syndrome (HGPS) because it triggers accelerated aging of cells. However, there are few studies on the effects of progerin on tumor cells. Lung cancer is one of the most common malignant cancers with high global morbidity and mortality rates; non-small cell lung cancer accounts for the majority of cases. The purpose of this study was to determine the effects of progerin on A549 cell proliferation, cell cycle, invasion, migration, sensitivity to DNA damaging agents, senescence and apoptosis with a goal of exploring new ideas for lung cancer treatment. METHODS: A549 cells overexpressing progerin (A549-PG) and a corresponding blank control (A549-GFP) were constructed by lentiviral infection. A nuclear staining assay was utilized to detect abnormal nuclear morphology. The proliferation, cell cycle, colony formation, invasion and migration abilities of A549-PG were compared with those of A549-GFP via EdU assays, flow cytometry, colony formation experiments, and Matrigel invasion and migration assays, respectively. SA-ß-gal staining was used to measure senescence in cells. RESULTS: The expression of progerin was significantly higher in A549-PG than A549-GFP. About 20% of A549-PG possessed abnormal nuclei. Overexpression of progerin in A549 cells inhibited cell proliferation, migration and invasion, and associated proteins (CDK4, pRB, ANLN, MMP7 and MMP9) were downregulated. DNA damage repair was also impaired. Progerin did not cause cells to senesce, and there was no difference in apoptosis. CONCLUSION: A549-PG generated some cellular changes, including the nuclear skeleton, the cell cycle, DNA damage repair, and migration and invasion abilities. Our data indicate that progerin could cause an imbalance in the steady state in A549 cells and increase their sensitivity to chemotherapeutic drugs.

The association between antinuclear antibody and response to rituximab treatment in adult patients with primary immune thrombocytopenia.

Background: Antinuclear antibodies (ANAs) can be detected in about 30% of patients with primary immune thrombocytopenia (ITP), yet their relationship with treatment response to rituximab remains elusive.Methods: we retrospectively reviewed the clinical records of hospitalized adult ITP patients who were treated with rituximab from three medical centers across China. Rituximab was given intravenously at 100 mg weekly for 4 weeks, or at a single dose of 375 mg/m2. All included patients had their ANAs tested before rituximab treatment.Results: A total of 287 patients fulfilled the inclusion criteria and were eligible for analysis. ANAs were positive in 98 (34.1%) of the included patients. The incidence of overall response and complete response (CR) in ANA-positive patients was significantly higher than that in ANA-negative patients (overall response: 76.5% vs. 55.0%, P < 0.001; CR: 46.9% vs. 29.1%, P = 0.003). However, sustained response (SR) rates in ANA-positive patients at 6, 12 and 24 months were all lower compared with ANA-negative patients (all P < 0.05). The overall duration of response (DOR) estimated by Kaplan-Meier analysis in ANA-negative patients was greater than that in ANA-positive patients (P < 0.001).Conclusion: ITP patients with positive ANA test were likely to achieve a better initial response to rituximab treatment, while their long-term outcome was unfavorable. Therefore, ANA test could be useful for predicting rituximab response in ITP.

PCK1 Deficiency Shortens the Replicative Lifespan of Saccharomyces cerevisiae through Upregulation of PFK1.

The cytosolic isozyme of phosphoenolpyruvate carboxykinase (PCK1) was the first rate-limiting enzyme in the gluconeogenesis pathway, which exerted a critical role in maintaining the blood glucose levels. PCK1 has been established to be involved in various physiological and pathological processes, including glucose metabolism, lipid metabolism, diabetes, and tumorigenesis. Nonetheless, the association of PCK1 with aging process and the detailed underlying mechanisms of PCK1 on aging are still far to be elucidated. Hence, we herein constructed the PCK1-deficient (pck1Δ) and PCK1 overexpression (PCK1 OE) Saccharomyces cerevisiae. The results unveiled that PCK1 deficiency significantly shortened the replicative lifespan (RLS) in the S. cerevisiae, while overexpression of PCK1 prolonged the RLS. Additionally, we noted that the ROS level was significantly enhanced in PCK1-deficient strain and decreased in PCK1 OE strain. Then, a high throughput analysis by deep sequencing was performed in the pck1Δ and wild-type strains, in an attempt to shed light on the effect of PCK1 on the lifespan of aging process. The data showed that the most downregulated mRNAs were enriched in the regulatory pathways of glucose metabolism. Fascinatingly, among the differentially expressed mRNAs, PFK1 was one of the most upregulated genes, which was involved in the glycolysis process and ROS generation. Thus, we further constructed the pfk1Δpck1Δ strain by deletion of PFK1 in the PCK1-deficient strain. The results unraveled that pfk1Δpck1Δ strain significantly suppressed the ROS level and restored the RLS of pck1Δ strain. Taken together, our data suggested that PCK1 deficiency enhanced the ROS level and shortened the RLS of S. cerevisiae via PFK1.

Chemical profiling of Callicarpa nudiflora and its effective compounds identification by compound-target network analysis.

Callicarpa nudiflora, belonging to the family Verbenaceae, is widely used to treat inflammation caused by bacterial infection.However, the underlying active substances of C. nudiflora against inflammation remains obscure. In this work, an ultra high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight mass spectrometry method was developed to characterize the ingredients in C. nudiflora, and a validated UHPLC coupled with triple quadrupole tandem mass spectrometry method was applied to quantify major components. As a result, a total of 96 chemical compounds were identified in C. nudiflora, and 26 compounds of them were further quantified in 34 batches of C. nudiflora. Based on the identified components from C. nudiflora, a compound-target network for the anti-inflammation effect was constructed by reverse docking target prediction, disease associated genes screening in DisGeNET and the protein-protein interaction from STRING. The compound-target network showed that C. nudiflora might exert anti-inflammation effect on the target of complement 3 and 5 in the pathway of cells and molecules involved in local acute inflammatory response, and 16 effective candidate compounds were found such as catalpol, acteoside, rutin, etc. This study provided an opportunity to deepen the understanding of the chemical composition and the potential anti-inflammatory mechanism of C. nudiflora.

Interleukin-36 receptor antagonist alleviates airway inflammation in asthma via inhibiting the activation of Interleukin-36 pathway.

BACKGROUNDS: Asthma is characterized as an inflammatory disorder in the respiratory system with increasing tendency. Most of the asthma patients suffered from the disease since childhood. Thus, developing novel therapeutic targets of pediatric asthma is necessary. Here, we conducted the present study to investigate the effects of IL-36RN (Interleukin-36 receptor antagonist), a newly identified anti-inflammatory factor, on asthma. METHODS: Sixty asthmatic children (30 moderate and 30 mild) were recruited. The levels of IL-36RN in peripheral blood mononuclear cells (PBMCs), serum and induced sputum (IS) samples from asthma patients and healthy controls (HCs) were measured by qPCR and ELISA. The anti-inflammatory effects of IL-36RN were determined in vitro and potential therapeutic effect on asthma was evaluated in the mouse model of asthma. RESULTS: The mRNA and protein levels of IL-36RN were significant down-regulated in asthmatics than HCs. The IL-36RN significantly suppressed the expression of pro-inflammatory factors in PBMCs and sputum cells from asthma patients in vitro. And delivering IL-36RN into the mouse model of asthma showed disease alleviation. Pathway analysis showed that the IL-36RN may alleviate airway inflammation in asthma through suppressing the activation of IL-36 pathway. CONCLUSION: Our data here indicated that IL-36RN may alleviate airway inflammation in asthma through suppressing the activation of IL-36 pathway.