Exploring the mechanism of Corbrin capsules in the intervention of AKI-COVID-19 based on network pharmacology combined with GEO dataset.

AIM: of the study: This study used network pharmacology and the Gene Expression Omnibus (GEO) database to investigate the therapeutic effects of Corbrin capsules on acute kidney injury (AKI)-COVID-19 (coronavirus disease 2019). MATERIALS AND METHODS: The active constituents and specific molecular targets of Corbrin capsules were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Swiss Target Prediction databases. The targets related to AKI and COVID-19 disease were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, and GEO databases. A protein-protein interaction (PPI) network was constructed by utilizing Cytoscape. To enhance the analysis of pathways associated with the pathogenesis of AKI-COVID-19, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Furthermore, immune infiltration analysis was performed by using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. Molecular docking was used to assess interactions between differentially expressed genes and active ingredients. Verification was performed by utilizing GEO databases and in vivo assays. RESULTS: This study revealed an overlap of 18 significantly differentially expressed genes between the Corbrin capsules group and the AKI-COVID-19 target group. Analysis of the PPI network identified TP53, JAK2, PIK3CA, PTGS2, KEAP1, and MCL1 as the top six core protein targets with the highest degrees. The results obtained from GO and KEGG analyses demonstrated that the target genes were primarily enriched in the apoptosis and JAK-STAT signaling pathways. Moreover, the analysis of immune infiltration revealed a notable disparity in the percentage of quiescent memory CD4 + T cells. Western blot analyses provided compelling evidence suggesting that the dysregulation of 6 core protein targets could be effectively reversed by Corbrin capsules. CONCLUSION: This study revealed the key components, targets, and pathways involved in treating AKI-related COVID-19 using Corbrin capsules. This study also provided a new understanding of the molecular mechanisms underlying this treatment.

Arene-Arene Coupled Disulfamethazines (or Sulfadiazine)-Phenanthroline-Metal(II) Complexes were Synthesized by In Situ Reactions and Inhibited the Growth and Development of Triple-Negative Breast Cancer through the Synergistic Effect of Antiangiogenesis, Anti-Inflammation, Pro-Apoptosis, and Cuproptosis.

The novel metal(II)-based complexes HA-Cu, HA-Co, and HA-Ni with phenanthroline, sulfamethazine, and aromatic-aromatic coupled disulfamethazines as ligands were synthesized and characterized. HA-Cu, HA-Co, and HA-Ni all showed a broad spectrum of cytotoxicity and antiangiogenesis. HA-Cu was superior to HA-Co and HA-Ni, and even superior to DDP, showing significant inhibitory effect on the growth and development of tripe-negative breast cancer in vivo and in vitro. HA-Cu exhibited observable synergistic effects of antiproliferation, antiangiogenesis, anti-inflammatory, pro-apoptosis, and cuproptosis to effectively inhibited tumor survival and development. The molecular mechanism was confirmed that HA-Cu could downregulate the expression of key proteins in the VEGF/VEGFR2 signaling pathway and the expression of inflammatory cytokines, enhance the advantage of pro-apoptotic protein Bax, and enforce cuproptosis by weakening the expression of FDX1 and enhancing the expression of HSP70. Our research will provide a theoretical and practical reference for the development of metal-sulfamethazine and its derivatives as chemotherapy drugs for cancer treatment.

Extending the Grading of Recommendations Assessment, Development and Evaluation (GRADE) in Traditional Chinese Medicine (TCM): The GRADE-TCM.

AIM: To extend and form the "Grading of Recommendations Assessment, Development and Evaluation in Traditional Chinese Medicine" (GRADE-TCM). METHODS: Methodologies were systematically reviewed and analyzed concerning evidence-based TCM guidelines worldwide. A survey questionnaire was developed based on the literature review and open-end expert interviews. Then, we performed expert consensus, discussion meeting, opinion collection, external examination, and the GRADE-TCM was formed eventually. RESULTS: 265 Chinese and English TCM guidelines were included and analyzed. Five experts completed the open-end interviews. Ten methodological entries were summarized, screened and selected. One round of consensus was conducted, including a total of 22 experts and 220 valid questionnaire entries, concerning 1) selection of the GRADE, 2) GRADE-TCM upgrading criteria, 3) GRADE-TCM evaluation standard, 4) principles of consensus and recommendation, and 5) presentation of the GRADE-TCM and recommendation. Finally, consensus was reached on the above 10 entries, and the results were of high importance (with voting percentages ranging from 50 % to 81.82 % for "very important" rating) and strong reliability (with the Cr ranging from 0.93 to 0.99). Expert discussion meeting (with 40 experts), opinion collection (in two online platforms) and external examination (with 14 third-party experts) were conducted, and the GRADE-TCM was established eventually. CONCLUSION: GRADE-TCM provides a new extended evidence-based evaluation standard for TCM guidelines. In GRADE-TCM, international evidence-based norms, characteristics of TCM intervention, and inheritance of TCM culture were combined organically and followed. This is helpful for localization of the GRADE in TCM and internationalization of TCM guidelines.

Structural identification and combination mechanism of iron (II)-chelating Atlantic salmon (Salmo salar L.) skin active peptides.

In order to utilize salmon skin for high value, and investigate the structural identification and combination mechanism of iron (II)-chelating peptides systemically, Atlantic salmon (Salmo salar L.) skin, a by-product of Atlantic salmon processing, was treated by two-step enzymatic hydrolysis to obtain salmon skin active peptides (SSAP). Then they reacted with iron (II) to obtain iron (II)-chelating salmon skin active peptides (SSAP-Fe) with a high iron (II) chelating ability of 98.84%. The results of Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD) spectroscopy, 8-anilino-1-naphthalenesulfonic acid ammonium salt hydrate (ANS) combined fluorescence measurement, isothermal titration calorimetry (ITC) and full wavelength ultraviolet (UV) scanning showed that the structural characteristics of SSAP changed before and after chelating iron (II). Reverse phase high performance liquid chromatography (RP-HPLC) and mass spectrometry were used to identify and quantify the peptides in SSAP-Fe. Four peptide sequences (STEGGG, GIIKYGDDFMH, PGQPGIGYDGPAGPPGPPGPPGAP and QNQRESWTTCRSQSSLPDG) were identified. The content of PGQPGIGYDGPAGPPGPPGPPGAP was the highest, at 25.17 µg/mg. The pharmacokinetic and pharmacodynamic properties of these four peptides were also investigated, and the results indicated that they have satisfactory predicted ADMET properties. Molecular docking technology was used to analyze the binding sites between iron (II) and SSAP, and it was found that PGQPGIGYDGPAGPPGPPGPPGAP had the lowest predicted binding energy with iron (II) and the most stable predicted binding energy with iron (II). This results showed that the stability of SSAP-Fe were closely related to the number of covalent bonds and the types of amino acids. This study revealed the structure and combination mechanism of SSAP-Fe, and indicated that SSAP-Fe prepared by chelation may be used as a Fe supplement that can be applied in functional foods or ingredients.

Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies.

OBJECTIVES: As a novel type of theta burst stimulation (TBS), continuous TBS (cTBS) has been shown to have mixed therapeutic effects for major depressive disorder (MDD) or bipolar depression (BD). Thus, we performed a meta-analysis of randomized controlled trials (RCTs) of cTBS for treating major depressive episodes in patients with MDD or BD. METHODS: A systematic search of four major bibliographic databases (PubMed, EMBASE, Cochrane Library, and PsycINFO) was conducted from inception dates to February 3, 2023 to identify eligible studies. The data were analyzed using a random-effects model. RESULTS: Three RCTs (n = 78, active cTBS = 37 and sham cTBS = 41) were included the meta-analysis. No significant differences were found in terms of change in Hamilton Depression Rating Scale (HAMD) scores (3 RCTs, n = 78, SMD = -0.09, 95 % CI: -0.53 to 0.36; I2 = 0 %; P = 0.71) and study-defined response (2 RCTs, n = 58, 26.7 % versus 21.4 %, RR = 1.20, 95 % CI: 0.48 to 2.96; I2 = 0 %; P = 0.70) between active and sham cTBS groups. Similarly, no group differences were found in the rates of adverse events and discontinuation due to any reason (P > 0.05). LIMITATIONS: Meta-analysis had small sample sizes and low number of included studies. CONCLUSIONS: Although cTBS appeared to be a safe and well-tolerated option for treating major depressive episodes in MDD or BD patients, no advantage in treatment effects was found in this meta-analysis. Future large-scale studies are warranted to assess the efficacy of cTBS for MDD or BD patients with a major depressive episode.

Endoscopic retrograde cholangiopancreatography for diagnosing and treating pediatric biliary and pancreatic diseases.

BACKGROUND: This study evaluated the safety and effectiveness of endoscopic retrograde cholangiopancreatography (ERCP) in pediatric patients with biliary and pancreatic diseases. A retrospective analysis was conducted on 57 ERCP procedures performed in 41 children, primarily for treating pancreatic diseases. The overall success rate was 91.2%, with no major complications observed. Post-ERCP pancreatitis (PEP) occurred in 8.8% of cases. Follow-up examinations over one year showed no recurrence of biliary or pancreatic diseases. Notably, endoscopic treatment led to a significant increase in body mass index (BMI). These findings demonstrate the valuable role of ERCP in managing such conditions. AIM: To evaluate the safety and efficacy of ERCP for the management of biliary and pancreatic diseases in pediatric patients. METHODS: We conducted a retrospective analysis of data from children aged 1-18 years who underwent ERCP for biliary and pancreatic diseases at Beijing Children's Hospital between January 2021 and December 2022. The collected data included procedure time, endoscopic treatment, success rate, and postoperative complications. RESULTS: Forty-one children underwent 57 ERCP procedures, including 14 with biliary duct disease and 27 with pancreatic disease. The mean age of the patients was 7.48 ± 3.48 years. Biliary duct-related treatments were performed 18 times, and pancreatic disease treatments were performed 39 times. ERCP was primarily used to treat pediatric pancreatic diseases [68.4% (39/57) of the procedures]. The overall success rate was 91.2% (52/57 patients). PEP was noted in five patients (8.8%, 5/57), and no instances of bleeding, perforation, or cholangitis were observed. The patients were followed up for over one year, and no recurrence of biliary or pancreatic diseases was detected. Importantly, BMI significantly increased after endoscopic treatment compared to that before treatment (P = 0.001). CONCLUSION: The high success rate and lack of major complications support the valuable role of ERCP in the management of pediatric biliary and pancreatic diseases in the pediatric population.

A novel chiral oxazoline copper(II)-based complex inhibits ovarian cancer growth in vitro and in vivo by regulating VEGF/VEGFR2 downstream signaling pathways and apoptosis factors.

A novel chiral oxazoline copper(II)-based complex {[Cu(C13H14NO3S)2]}2 (Cu-A) was synthesized by an in situ reaction using L-methioninol, 4-hydroxyisophthalaldehyde, sodium hydroxide and copper(II) nitrate trihydrate as reactants. Its crystal structure was characterized. In vitro, Cu-A was superior to cis-dichlorodiammineplatinum (DDP) in cytotoxicity and angiogenesis inhibition. Cu-A significantly induced apoptosis of ovarian cancer cells (SKOV3) and human umbilical vein endothelial cells (HUVECs), showing significant anti-ovarian cancer and anti-angiogenesis effects. Notably, Cu-A significantly inhibits the growth of ovarian cancer in nude mice xenografted with SKOV3 cells, and it is less renal toxic than DDP. The molecular mechanism of anti-ovarian cancer and anti-angiogenesis is possibly that it down-regulates the expression of the proteins ERK1/2, AKT, FAK, and VEGFR2 and their phosphorylated proteins p-ERK1/2, p-AKT, p-FAK, and p-VEGFR2 in the VEGF/VEGFR2 signal transduction pathway to inhibit SKOV3 cell and HUVEC proliferation, induce apoptosis, suppress migration and metastasis, and inhibit angiogenesis. What's more, Cu-A significantly inhibits ovarian tumor growth in vivo by inhibiting tumor cells from inducing vascular endothelial cells to form their own vasculature and by inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expression of the pro-apoptotic proteins Caspase-9 and Bax to induce apoptosis of tumor cells.

Accelerated intermittent theta burst stimulation for major depressive disorder or bipolar depression: A systematic review and meta-analysis.

We aimed to systematically evaluate the clinical efficacy and safety of accelerated intermittent theta burst stimulation (aiTBS) for patients with major depressive disorder (MDD) or bipolar depression (BD). A random-effects model was adopted to analyze the primary and secondary outcomes using the Review Manager, Version 5.3 software. This meta-analysis (MA) identified five double-blind randomized controlled trials (RCTs) comprising 239 MDD or BD patients with a major depressive episode. Active aiTBS overperformed sham stimulation in the study-defined response. This MA found preliminary evidence that active aiTBS resulted in a greater response in treating major depressive episodes in MDD or BD patients than sham stimulation.

Comparison of Efficacy and Safety of Magnetic Seizure Therapy and Electroconvulsive Therapy for Depression: A Systematic Review.

OBJECTIVES: As a new physical therapeutic technique, magnetic seizure therapy (MST) has established efficacy in the treatment of depression with few cognitive side effects, and thus appears to be a potential alternative to electroconvulsive therapy (ECT). The findings of randomized controlled trials (RCTs) examining the efficacy and safety of MST versus ECT for depression are inconsistent. This systematic review of RCTs was designed with the aim of assessing the safety and efficacy of MST versus ECT for patients with depression. METHODS: The WanFang, Chinese Journal Net (CNKI), EMBASE, PubMed, Cochrane Library, and PsycINFO databases were systematically searched by three independent investigators, from their inceptions to July 24, 2021. RESULTS: In total, four RCTs (n = 86) were included and analyzed. Meta-analyses of study-defined response (risk ratio (RR) = 1.36; 95% CI = 0.78 to 2.36; p = 0.28; I2 = 0%), study-defined remission (RR = 1.17; 95% CI = 0.61 to 2.23; p = 0.64; I2 = 0%), and the improvement in depressive symptoms (standardized mean difference (SMD) = 0.21; 95% CI = -0.29 to 0.71; p = 0.42; I2 = 0%) did not present significant differences between MST and ECT. Three RCTs evaluated the cognitive effects of MST compared with ECT using different cognitive measuring tools, but with mixed findings. Only two RCTs reported adverse drug reactions (ADRs), but these lacked specific data. Only one RCT reported discontinuation due to any reason. CONCLUSIONS: This preliminary study suggests that MST appears to have a similar antidepressant effect as ECT for depression, but mixed findings on adverse cognitive effects were reported.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor.

OBJECTIVE: This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR). METHODS: Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway. RESULTS: Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon. CONCLUSION: Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke.

Ischemic stroke can cause blood-brain barrier (BBB) injury, which worsens brain damage induced by stroke. Abnormal expression of tight junction proteins in endothelial cells (ECs) can increase intracellular space and BBB leakage. Selective inhibition of mitogen-activated protein kinase, the negative regulatory substrate of mitogen-activated protein kinase phosphatase (MKP)-1, improves tight junction protein function in ECs, and genetic deletion of MKP-1 aggravates ischemic brain injury. However, whether the latter affects BBB integrity, and the cell type-specific mechanism underlying this process, remain unclear. In this study, we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke. We found that overexpression of MKP-1 in ECs reduced infarct volume, reduced the level of inflammatory factors interleukin-1ß, interleukin-6, and chemokine C-C motif ligand-2, inhibited vascular injury, and promoted the recovery of sensorimotor and memory/cognitive function. Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase (ERK) 1/2 and the downregulation of occludin expression. Finally, to investigate the mechanism by which MKP-1 exerted these functions in ECs, we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose, and pharmacologically inhibited the activity of MKP-1 and ERK1/2. Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death, cell monolayer leakage, and downregulation of occludin expression, and that inhibiting ERK1/2 can reverse these effects. In addition, co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2. These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2, thereby protecting the integrity of BBB, alleviating brain injury, and improving post-stroke prognosis.

A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

BACKGROUND: Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described. METHODS: Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review. RESULTS: The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome. CONCLUSIONS: The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment. IMPACT: First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

The potential role of N6-methyladenosine modification of LncRNAs in contributing to the pathogenesis of chronic glomerulonephritis.

BACKGROUND: Increasing evidence indicates that N6-methyladenosine (m6A) modification of mRNAs has been shown to play a critical role in the occurrence and development of many diseases, while little is known about m6A modification in long non-coding RNAs (LncRNAs). Our study aims to investigate the potential functions of LncRNA m6A modifications in lipopolysaccharide (LPS)-induced mouse mesangial cells (MMCs), providing us with a new perspective on the molecular mechanisms of chronic glomerulonephritis (CGN) pathogenesis. METHODS: Differentially methylated LncRNAs were identified by Methylated RNA immunoprecipitation sequencing (MeRIP-seq). LncRNA-mRNA and LncRNA-associated LncRNA-miRNA-mRNA (CeRNA) networks were constructed by bioinformatics analysis. Furthermore, we utilized gene ontology (GO) and pathway enrichment analyses (KEGG) to explore target genes from co-expression networks. In addition, the total level of m6A RNA methylation and expression of methyltransferase and pro-inflammatory cytokines were detected by the colorimetric quantification method and western blot, respectively. Cell viability and cell cycle stage were detected by cell counting kit-8 (CCK-8) and flow cytometry. RESULTS: In total, 1141 differentially m6A-methylated LncRNAs, including 529 hypermethylated LncRNAs and 612 hypomethylated LncRNAs, were determined by MeRIP-seq. The results of GO and KEGG analysis revealed that the target mRNAs were mainly enriched in signal pathways, such as the NF-kappa B signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway, and apoptosis signaling pathway. In addition, higher METTL3 expression was found in CGN kidney tissues using the GEO database. METTL3 knockdown in MMC cells drastically reduced the levels of m6A RNA methylation, pro-inflammatory cytokines IL6 and TNF-α, and inhibited cell proliferation and cycle progression. CONCLUSIONS: Our findings provide a basis and novel insight for further investigations of m6A modifications in LncRNAs for the pathogenesis of CGN.

High-throughput data on circular RNA reveal novel insights into chronic glomerulonephritis.

BACKGROUND: Circular RNAs (circRNAs), a unique novel type of RNA, have been widely reported to be involved in physiologic and pathologic processes in humans. However, the exact molecular pathogenesis of circRNAs in chronic glomerulonephritis (CGN) is far from clear. OBJECTIVE: This paper aims to evaluate the specific expression profile of circRNAs in renal cortex tissues from Adriamycin-induced CGN rats. METHODS: CircRNAs were screened in renal cortex tissues from 3 CGN rats and 3 control rats by using high-throughput sequencing (HTS). Then, 4 circRNAs were selected randomly for verification by quantitative real-time polymerase chain reaction (qRT-PCR). In addition, the differentially expressed (DE) circRNAs were analyzed by bioinformatics methods. RESULTS: In total, 31 significantly DE circRNAs were identified, which revealed their potential roles in CGN; in particular, we found that 4 confirmed altered circRNAs (rno-circ-RNAs 689, 3217, 1327, and 5001) might play important roles in the development of CGN. CONCLUSION: This study reveals a cluster of circRNAs that are DE in Adriamycin-induced CGN rats, which brings us closer to understanding the pathogenic mechanisms and may provide new potential targets for clinical treatment.

Simple and Efficient Synthesis of Diamino Derivatives of bis-1,2,4-oxadiazole via Tandem Staudinger/aza-Wittig Reaction.

Two efficient, scalable routes to bis-1,2,4-oxadiazole have been developed by tandem Staudinger/aza-Wittig reaction from the same starting material diaziglyoxime, isocyanates and triphenylphosphonium in good yields. BACKGROUND: Two convenient and efficient routes for synthesizing diamino derivatives of bis-1,2,4- oxadiazoles were described. OBJECTIVE: This study provides a simple protocol for the synthesis of bis-1,2,4-oxadiazoles. METHODS: The two procedures were based on a tandem Staudinger/aza-Wittig reaction from the same starting material of diaziglyoxime, isocyanates and triphenylphosphonium. RESULTS: In synthesis method I, diaziglyoxime 1 was treated with various aromatic or aliphatic isocyanates to give diazioxalimides 2 a high yield. Diazioxalimides 2 reacted with Ph3P to produce the iminophosphoranes 4; the reaction was directly heated from room temperature to 115 ℃ to get the desired diamino derivatives of bis-1,2,4-oxadiazole 4 in 72-92% yields. In synthesis method II, the same target compounds 4 were synthesized in a one-pot reaction by Ph3P and aromatic or aliphatic isocyanates in toluene for 10 h under 115 ℃ in 53-71% yields. CONCLUSION: The two procedures provide proficient methods of making nitrogen-containing heterocyclic rings. The structures of target compounds 4 were identified by IR, 1HNMR, 13CNMR and HRMS.

[Correlation Analysis of Fâ §Gene Mutation and the Production of Fâ § Inhibitor with Severe Hemophilia A Patients in a Single Medical Center].

OBJECTIVE: To investigate the relationship between the type of FⅧgene mutation and the development of FⅧ inhibitors in patients with severe haemophilia A (HA). METHODS: The medical records of 172 patients with severe hemophilia A from January 2009 to September 2020 were reviewed. The types of FⅧgene mutations and the production of factor Ⅷ inhibitors were collected and divided into high-risk mutation group ( intron 1 inversions, large deletions, nonsense mutations), low-risk mutation group (missense mutations, small deletions and insertions, splice site mutations) and intron 22 inversions group. The correlation of FⅧgenotype and the production of FⅧ inhibitors in patients with HA were analyzed. RESULTS: Among 172 patients with severe HA, 21 cases(12.21%) developed FⅧ inhibitors. The cumulative incidence of FⅧ inhibitor development was 32%(10/31) in high risk group (75% patients with large deletions, 43% patients with intron 1 inversions, 20% patients with nonsense mutations) and 5%(2/43) in low risk group(6% patients with missense mutations, 5% patients with small deletions or insertions and 0% patient with a splice site mutation) and 9%(9/98) in intron 22 inversions group. Compared with the risk of FⅧ inhibitor development in intron 22 inversions group, the risk of FⅧ inhibitor development in high risk group was higher (OR＝4.7, 95% CI： 1.7-13.0), the risk of FⅧ inhibitor development in low risk group was equal (OR＝0.5, 95% CI： 0.1-2.3). Compared with the risk of inhibitor development in low risk group, the risk of FⅧ inhibitor development in high risk group was higher (OR＝9.8, 95% CI： 2.0-48.7). CONCLUSION: Gene mutations of patients with severe HA in high-risk group which include intron 1 inversions, large deletions, nonsense mutations are a risk factor for FⅧ inhibitor production.

Microwave-assisted degradation of ß-D-glucan from Ganoderma lucidum and the structural and immunoregulatory properties of oligosaccharide fractions.

Microwave-assisted degradation of ß-(1 â†’ 3,1 â†’ 6)-D-glucan from Ganoderma lucidum and correlated immunoregulatory activities were investigated in this study. The optimal temperature and degradation time for microwave hydrothermal hydrolysis were 140 °C and 40 min, respectively. Under these conditions, a high yield of degradation rate (98.4 %) and abundant ß-oligosaccharide products (GLOS) with different degrees of polymerization (DP 2-24) were obtained. Four fractions including F1 (DP 2-8), F2 (DP 6-19), F3 (DP 8-24) and F4 (high DPs) with different average ratios of ß-(1 â†’ 3) to ß-(1 â†’ 6)-linked glucose units were isolated from GLOS. The structures of oligosaccharides with DP (2-6) in F1 were identified as linear ß-(1 â†’ 3)-linked glucooligosaccharides without or with ß-(1 â†’ 6)-linked glucose residues based on MS/MS analysis. The immunoregulation activity of ß-glucooligosaccharides was correlated with their DPs and the average ratios of ß-(1 â†’ 3) to ß-(1 â†’ 6)-linked glucose units. F4 fraction with high DPs and ratio of 3.29:1 exhibited higher immunoenhancing activity on inducing NF-κB activation through binding to dectin-1. Surface plasmon resonance (SPR) analysis indicated that ß-glucooligosaccharides could bind to Dectin-1 directly and the binding affinity increased with the increase of DPs and the ratios of ß-(1 â†’ 3)-linked glucose.

Head Acupuncture Plus Schuell's Language Rehabilitation for Post-Stroke Aphasia: A Systematic Review and Meta-Analysis of 32 Randomized Controlled Trials.

OBJECTIVE: To evaluate the existing randomized controlled trials (RCTs) for evidence of the efficacy and safety of head acupuncture (HA) plus Schuell's language rehabilitation (SLR) in post-stroke aphasia. METHODS: Seven databases including Embase, PubMed, Cochrane Library, Technology Periodical Database, the China National Knowledge Infrastructure, SinoMed and Wanfang Data Information Site were searched for RCTs published from database inception until November 14, 2021. RCTs that compared HA plus SLR with sham (or blank) control, acupuncture therapy alone, certain language rehabilitation therapy alone or other therapies for post-stroke aphasia were included. Data were extracted and assessed, and the quality of RCTs was evaluated. Fixed-effects model was used, with meta-inflfluence analysis, meta-regression, and regression-based sub-group analyses applied for exploration of heterogeneity. Publication bias was estimated by funnel plots and Egger's tests. RESULTS: A total of 32 RCTs with 1,968 patients were included and 51 comparisons were conducted classified as types of strokes and aphasia. (1) For patients with aphasia after ischemic stroke, HA plus PSA showed significantly higher accumulative markedly effective rate [relative risk (RR)=1.55, 95% confidence interval (CI): 1.19-2.02, I2=0%] and accumulative effective rate (RR=1.22, 95% CI: 1.09-1.36, I2=0%). (2) For patients with comprehensive types of stroke, HA plus PSA was more effective in increasing recovery rate (RR=1.89, 95% CI: 1.39-2.56, I2=0%), accumulative markedly effective rate (RR=1.53, 95% CI: 1.36-1.72, I2=9%) and accumulative effective rate (RR=1.14, 95% CI: 1.09-1.19, I2=34%). (3) For patients with aphasia after stroke, HA plus PSA was superior to PSA alone with statistical significance in increasing recovery rate (RR=2.08, 95% CI: 1.24-3.46, I2=0%), accumulative markedly effective rate (RR=1.49, 95% CI: 1.24-1.78, I2=0%) and accumulative effective rate (RR=1.15, 95% CI: 1.06-1.24, I2=39%). (4) For patients with multiple types of aphasia, HA plus PSA also demonstrated significantly higher recovery rate (RR=1.86, 95% CI: 1.28-2.72, I2=0%), accumulative markedly effective rate (RR=1.55, 95% CI: 1.35-1.78, I2=22%), and accumulative effective rate (RR=1.17, 95% CI: 1.11-1.23, I2=41%). (5) For patients with motor aphasia after ischemic stroke, compared with PSA alone, HA plus PSA showed significantly higher accumulative markedly effective rate (RR=1.38, 95% CI: 1.06-1.79, I2=0%) and accumulative effective rate (RR=1.20, 95% CI: 1.05-1.37, I2=0%). Meta-regression analyses were performed without significant difference, and publication bias was found in some comparisons. CONCLUSION: HA plus SLR was significantly associated with better language ability and higher effective rate for patients with post-stroke aphasia, and HA should be operated cautiously especially during acupuncture at eye and neck. (Registration No. CRD42020154475).

Polymorphisms and AR: A Systematic Review and Meta-Analyses.

Background: Allergic rhinitis (AR) is an especially common disorder associated with both environmental and genetic factors, and a lot of researchers have attempted to find polymorphisms which predisposed to the disease. We conducted a meta-analysis of the most frequently researched polymorphisms to find those genes which may be susceptible to AR and then may be of value in diagnosis. Methods: Pubmed and China National Knowledge Infrastructure (CNKI) databases were searched to screen out eligible studies focusing on the correlation between polymorphisms and AR susceptibility, and then polymorphisms cited in at least 3 studies were selected. Results: The 142 papers originally selected cited 78 genes. Twelve genes (coinciding with 23 polymorphisms) were reported in more than three papers. Twenty-three polymorphisms were involved in the meta-analysis. Among the 23 polymorphisms, only 4 were found to be related to the risk of AR: IL-13 rs20541, CTLA-4 rs11571302, IL-4R RS1801275 and ACE (I/D). The remaining 19 of the 23 polymorphisms were not associated with AR. Conclusion: We found polymorphisms that could be used for AR diagnosing and those that were unrelated to AR. This may be the first step in detecting polymorphic combinations susceptible to AR (IL-13 RS20541, CTLA-4 RS11571302, IL-4R RS1801275 and ACE (I/D). In addition, our results may improve AR diagnosis and contribute to the intensive study of AR.

MicroRNA-339-5p inhibits lipopolysaccharide-induced rat mesangial cells by regulating the Syk/Ras/c-Fos pathway.

Chronic glomerulonephritis (CGN) is a disease occurred in glomeruli. The mechanism of CGN is regarded to be involved in a range of inflammatory responses. MicroRNA-339-5p (miR-339-5p) has been reported to be involved in inflammatory responses in many diseases. However, the role of miR-339-5p in CGN remains unclear. The purpose of this study was to investigate the role of miR-339-5p in lipopolysaccharide (LPS)-induced nephritis injury in vitro. The real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot (WB) were used to detect the expression of miR-339-5p and Syk/Ras/c-Fos pathway. Double luciferase was performed to identify targeted binding of miR-339-5p to Syk. Cell counting kit-8 (CCK-8) and flow cytometry were used to observe cell viability and cell cycle. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the concentrations of inflammatory cytokines IL-1ß, IL-10, IL-6, and TNF-α. Lipopolysaccharide (LPS) could increase HBZY-1 (rat mesangial cells) cell viability, decrease the G2 phase, and promote cell proliferation and accelerate inflammatory cytokine. However, overexpression of miR-339-5p could inhibit LPS-induced HBZY-1 cell viability, decrease the expression of Syk/Ras/c-Fos signaling pathway, downregulate the expression level of inflammatory cytokines, increase the G2 phase, and inhibit cell proliferation. miR-339-5p could inhibit the proliferation and inflammation of the rat mesangial cells through regulating Syk/Ras/c-Fos signaling pathway.