Discovery of natural multi-targets neuraminidase inhibitor glycosides compounds against influenza A virus through network pharmacology, virtual screening, molecular dynamics simulation, and in vitro experiment.

Influenza virus continually challenges both human and animal health. Moreover, influenza viruses are easy to mutate. In a certain degree, vaccines may not catch up with rapid mutant paces of viruses. Anti-influenza drugs NIs (neuraminidase inhibitors) are one of the best choices. Therefore, based on ADMET properties, eight optimal natural multi-targets NIs glycosides compounds (IC50 = 0.094-97.275 µM) are found from radix glycyrrhizae, flos sophorae, caulis spatholobi, radix astragali, radix glycyrrhizae, semen astragali complanati, and common fenugreek seed through network pharmacology, molecular docking, dynamics simulation, quantum chemistry, and in vitro experiment. Moreover, mechanism research illustrates these natural compounds treat influenza A virus through key targets TLR4, TNF, and IL6 (high fever, acute respiratory distress syndrome), MAPK1, and MAPK3 (MAPK signaling pathway, viral RNP export, and viral protein expression), IL1B (NOD-like receptor signaling pathway, suppressed maturation of pro-IL-1ß and pro-IL-18), CASP3 (apoptosis), AKT1 (inhibited premature apoptosis), and EP300 (viral myocarditis, chemoattraction of monocytes and macrophages, T-cell activation antibody response).

Panax notoginseng saponins inhibits NLRP3 inflammasome-mediated pyroptosis by downregulating lncRNA-ANRIL in cardiorenal syndrome type 4.

OBJECTIVE: Cardiorenal syndrome type 4 (CRS4) is a complication of chronic kidney disease. Panax notoginseng saponins (PNS) have been confirmed to be efficient in cardiovascular diseases. Our study aimed to explore the therapeutic role and mechanism of PNS in CRS4. METHODS: CRS4 model rats and hypoxia-induced cardiomyocytes were treated with PNS, with and without pyroptosis inhibitor VX765 and ANRIL overexpression plasmids. Cardiac function and cardiorenal function biomarkers levels were measured by echocardiography and ELISA, respectively. Cardiac fibrosis was detected by Masson staining. Cell viability was determined by cell counting kit-8 and flow cytometry. Expression of fibrosis-related genes (COL-I, COL-III, TGF-ß, α-SMA) and ANRIL was examined using RT-qPCR. Pyroptosis-related protein levels of NLRP3, ASC, IL-1ß, TGF-ß1, GSDMD-N, and caspase-1 were measured by western blotting or immunofluorescence staining. RESULTS: PNS improved cardiac function, and inhibited cardiac fibrosis and pyroptosis in a dose-dependent manner in model rats and injured H9c2 cells (p < 0.01). The expression of fibrosis-related genes (COL-I, COL-III, TGF-ß, α-SMA) and pyroptosis-related proteins (NLRP3, ASC, IL-1ß, TGF-ß1, GSDMD-N, and caspase-1) was inhibited by PNS in injured cardiac tissues and cells (p < 0.01). Additionally, ANRIL was upregulated in model rats and injured cells, but PNS reduced its expression in a dose-dependent manner (p < 0.05). Additionally, the inhibitory effect of PNS on pyroptosis in injured H9c2 cells was enhanced by VX765 and reversed by ANRIL overexpression, respectively (p < 0.05). CONCLUSION: PNS inhibits pyroptosis by downregulating lncRNA-ANRIL in CRS4.

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation.

BACKGROUND: Traumatic brain injury (TBI) is a common brain injury with a high morbidity and mortality. The complex injury cascade triggered by TBI can result in permanent neurological dysfunction such as cognitive impairment. In order to provide new insights for elucidating the underlying molecular mechanisms of TBI, this study systematically analyzed the transcriptome data of the rat hippocampus in the subacute phase of TBI. METHODS: Two datasets (GSE111452 and GSE173975) were downloaded from the Gene Expression Omnibus (GEO) database. Systematic bioinformatics analyses were performed, including differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network construction, and hub gene identification. In addition, hematoxylin and eosin (HE), Nissl, and immunohistochemical staining were performed to assess the injured hippocampus in a TBI rat model. The hub genes identified by bioinformatics analyses were verified at the mRNA expression level. RESULTS: A total of 56 DEGs were shared in the two datasets. GSEA results suggested significant enrichment in the MAPK and PI3K/Akt pathways, focal adhesion, and cellular senescence. GO and KEGG analyses showed that the common DEGs were predominantly related to immune and inflammatory processes, including antigen processing and presentation, leukocyte-mediated immunity, adaptive immune response, lymphocyte-mediated immunity, phagosome, lysosome, and complement and coagulation cascades. A PPI network of the common DEGs was constructed, and 15 hub genes were identified. In the shared DEGs, we identified two transcription co-factors and 15 immune-related genes. The results of GO analysis indicated that these immune-related DEGs were mainly enriched in biological processes associated with the activation of multiple cells such as microglia, astrocytes, and macrophages. HE and Nissl staining results demonstrated overt hippocampal neuronal damage. Immunohistochemical staining revealed a marked increase in the number of Iba1-positive cells in the injured hippocampus. The mRNA expression levels of the hub genes were consistent with the transcriptome data. CONCLUSIONS: This study highlighted the potential pathological processes in TBI-related hippocampal impairment. The crucial genes identified in this study may serve as novel biomarkers and therapeutic targets, accelerating the pace of developing effective treatments for TBI-related hippocampal impairment.

Effects of acupuncture on microglial polarization and the TLR4/TRIF/MyD88 pathway in a rat model of traumatic brain injury.

OBJECTIVE: Neuroinflammation caused by traumatic brain injury (TBI) can lead to neurological deficits. Acupuncture can inhibit neuroinflammation and promote nerve repair; however, the specific mechanism is still unclear. The purpose of this study was to explore whether acupuncture could modulate the M1 and M2 phenotypic polarization of microglia in a rat model of TBI via the toll-like receptor 4 (TLR4)/intracellular toll-interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-ß (TRIF)/myeloid differentiation factor 88 (MyD88) pathway. METHODS: A total of 90 adult male Sprague-Dawley (SD) rats, SPF grade, were randomly divided into a normal group, model group and acupuncture group. Each group was further divided into three subgroups (first, third, and fifth day groups) according to the treatment time (n = 10 rats/subgroup). We used the modified neurological severity score (mNSS) method to quantify neurological deficits before and after modeling. We used Nissl staining to observe the pathological changes in brain tissue, flow cytometry to detect the proportion of M1 and M2 polarized microglia in the injured area on the first, third and fifth day, and co-immunoprecipitation (Co-IP) to examine TLR4/TRIF/MyD88 expression in microglia on the first, third and fifth day, as well as expression of the amount of binding of TLR4 with TRIF and MyD88. RESULTS: Compared to the model group, mNSS in the acupuncture group gradually decreased and pathological morphology improved. The proportion of CD11b/CD86 positive cells was decreased, while that of CD11b/CD206 was increased in the acupuncture group. Expression of IP TLR4, IP TRIF and IP MyD88 also decreased in the acupuncture group. CONCLUSION: The results of this study demonstrate that one of the mechanisms through which acupuncture mitigates neuroinflammation and promotes nerve repair in TBI rats may be inhibition of M1 phenotypic polarization and promotion of M2 phenotypic polarization through inhibition of the TLR4/TRIF/MyD88 signaling pathway.

Acupuncture promotes nerve repair through the benign regulation of mTOR-mediated neuronal autophagy in traumatic brain injury rats.

AIMS: Recent investigations have already proved the neuroprotective efficacy of acupuncture in clinical practice in the treatment of neurological diseases, such as traumatic brain injury (TBI). Since growing evidence has suggested that neuronal autophagy was involved in multiple stages of TBI, this study aims to clarify the autophagy mediating mechanism underlying the neuroprotective effect of acupuncture in TBI rats. METHODS: Three experiments were carried out to detect changes in neuronal autophagy and identify the potential molecular mechanism underlying the neuroprotective effect of acupuncture for TBI treatment. Feeney's free-falling epidural impingement method was used to establish the moderate TBI rat model; modified neurological severity scoring (mNSS) was used for neurological recovery evaluation. Nissl and HE staining were used to examine the histopathological changes. Immunofluorescence was used to detect the LC3-positive cell rate. The transmission electron microscope (TEM) was used to investigate the morphology and quantity of autophagosomes. Western blotting was used to determine the protein expressions of LC3, p62, beclin1, mTOR, ULK1, p-mTOR, and p-ULK1. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for gene expressions analysis of LC3 mRNA and p62 mRNA. Co-immunoprecipitation (CO-IP) method was used to identify the protein interaction of mTOR and ULK1. RESULTS: On Day 3 after TBI, acupuncture accelerated the removal of damaged cellular structures by promoting neuronal autophagy; on Day 7 and Day 14 after TBI, acupuncture inhibited neuronal autophagy, preventing excessive autophagy and thus alleviated nerve damage. In addition, the simultaneous treatment with 3-MA or rapamycin at different stages after TBI attenuated the effect of acupuncture. CONCLUSION: Acupuncture has a benign regulatory effect on neuronal autophagy in different stages of TBI, possibly through the mTOR/ULK1 pathway.

LncRNA ANRIL-mediated miR-181b-5p/S1PR1 axis is involved in the progression of uremic cardiomyopathy through activating T cells.

This study aimed to explore the regulatory role of lncRNA ANRIL/miR-181b-5p/S1PR1 in UC. UC mouse model was established by 5/6th nephrectomy. We detected body weight, serum levels of renal function and inflammatory factors (biochemical analyzer/ELISA), and cardiac parameters (echocardiography). HE and Masson staining showed the pathological changes and fibrosis in myocardial and nephridial tissues. The expression of ANRIL, miR-181b-5p, and S1PR1 were detected by qRT-PCR or Western blot/immunofluorescence. T cells activation was analyzed by Flow cytometry. ANRIL/S1PR1 were up-regulated and miR-181b-5p was down-regulated in UC mice. ANRIL silencing up-regulated miR-181b-5p and down-regulated S1PR1 (a target of miR-181b-5p). ANRIL silencing increased the body weight, recovered renal function [decreased blood urea nitrogen (BUN) and serum creatinine (Scr)] and cardiac function [decreased left ventricular end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), LV systolic anterior wall thickness (LVAWS), LV end-diastolic anterior wall thickness (LVAWD), myocardial performance index (MPI), and isovolumic relaxation time (IVRT); increased LV ejection fraction (LVEF), LVEF/MPI, fractional shortening (FS), and E- and A-waves (E/A)], inhibited the inflammation [decreased interferon (IFN)-γ, interleukin (IL)-2, IL-10, and tumor necrosis factor (TNF)-α], and relieved pathological injuries and fibrosis. ANRIL silencing also recovered the viability and inhibited the inflammation of activated T cells in vitro, and inhibited T cell activation in UC mice in vivo. In addition, miR-181b-5p overexpression exhibited same effects with ANRIL silencing in UC. ANRIL silencing inhibited T cell activation through regulating miR-181b-5p/S1PR1, contributing to the remission of UC.

The Influence of Acupuncture Parameters on Efficacy and the Possible Use of Acupuncture in Combination with or as a Substitute for Drug Therapy in Patients with Ulcerative Colitis.

Background: Ulcerative colitis (UC) is an inflammatory disease of the colonic mucosa, which is accompanied by chronic, idiopathic characteristics. Acupuncture may be an effective therapy for UC. Here we focused on manual acupuncture and electroacupuncture (MA/EA), two widely used and studied acupuncture interventions, to probe the effects of acupuncture parameters on clinical efficacy in patients with UC and the use of MA/EA alone or with other drugs to support their wider adoption in clinical practice. Methods: The PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure Database, and Wanfang databases were searched from inception to April 27, 2021. Randomized clinical trials (RCTs) published in Chinese or English were included, and subgroup analyses were performed according to acupuncture parameter, acupuncture type, and control medicine type. The risk of bias was assessed using the Cochrane Risk of Bias tool and modified Jadad scale, and Review Manager 5.4 and Stata 14.0 were used to perform a meta-analysis. Sources of heterogeneity were explored; sensitivity analysis was performed; and the GRADE methodology was used to assess the evidence level. Results: Sixteen studies (1454 individuals) were included. Retention of the needle [10-30 minutes (RR 1.18, 95% CI [1.11, 1.26], P < 0.01; heterogeneity: χ 2 = 6.25, df = 6 (P=0.40), I2 = 4%)], the frequency of MA [once every other day (RR 1.21, 95% CI [1.08, 1.35], P < 0.01; heterogeneity: χ 2 = 0.80, df = 1 (P=0.37), I2 = 0%)], and the length of treatment [8 weeks (RR 1.35, 95% CI [1.01, 1.81], P=0.04)] improved clinical efficacy at the end of treatment compared with medications alone. MA (RR 1.18, 95% CI [1.11, 1.25], P < 0.01; heterogeneity: χ 2 = 6.19, df = 7 (P=0.52), I2 = 0%) increased clinical efficacy compared with medications. Furthermore, MA plus medications (RR 1.26, 95% CI [1.13, 1.40], P < 0.01; heterogeneity: χ 2 = 0.95, df = 2 (P=0.62), I2 = 0%) and EA plus medications (RR 1.36, 95% CI [1.13, 1.63], P < 0.01; heterogeneity: χ 2 = 0.13, df = 1 (P=0.72), I2 = 0%) both dramatically improved clinical efficacy. The clinical efficacy of MA plus mesalazine or MA plus metronidazole and sulfasalazine was greater than with mesalazine or metronidazole and sulfasalazine alone. Similarly, EA plus sulfasalazine was more effective than sulfasalazine alone. MA/EA resulted in fewer adverse reactions than medical therapies. The use of MA plus medications significantly reduced Baron scores. GRADE evaluations indicated that the evidence strength was moderate to low but mostly low. Conclusions: Our study provides the latest evidence to allow us to speculate about the possible optimal MA parameters to treat patients with UC. The low number of adverse reactions and high efficacy make MA/EA a possible supplement to or replacement for traditional UC drugs. The variable parameter settings preferred by patients and acupuncturists may be an important factor limiting the wider clinical deployment of acupuncture as a potential UC therapy.

Inhibiting DNA Methylation Improves Survival in Severe Sepsis by Regulating NF-κB Pathway.

Organ dysfunction caused by sepsis is life-threatening and results in high mortality. Therapeutic options for sepsis are limited. Pathogenic factors are considered as components of environmental pressure that modify DNA methylation patterns thereby enhancing disease progression. Here, we found that sepsis patients exhibited higher levels of genomic DNA methylation patterns and hypermethylated genes associated with the NF-kB signaling pathway. Therefore, we hypothesized that a DNA methyl transferase inhibitor, Decitabine, may mitigate inflammation and improve survival by inhibiting the NF-κB signaling pathway. To test the hypothesis, mice challenged with caecal ligation and puncture (CLP) were subcutaneously injected with Decitabine solution (0.5, 1, and 1.5 mg/kg) 2 h following operation. Our results indicated that Decitabine reduces DNA methyltransferases (DNMTs), attenuates NF-κB activation, downregulates inflammatory cytokine levels, and inhibits the progression of sepsis. Thus, DNA methylation may be indispensable for sepsis and serve as a predicting factor. The use of Decitabine could represent a novel strategy in the treatment of sepsis.

Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism.

BACKGROUND: Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism. METHODS: We contrasted the release of neutrophil NETs from mice with telomere dysfunction, mice with DNA damage and wide-type mice. Neutrophil telomere length, the expression of LL37, and the formation of NETs were measured in SVV patients and healthy controls (HCs). The co-expression of γH2AX, LL37, and NETs were detected in SVV patients to evaluate the association of the immune aging of neutrophils and pro-inflammatory conditions. LL37 inhibitor was used to verify its key role in NETs release in SVV patients and DNA damage mice. RESULTS: We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils. CONCLUSIONS: Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.

Manual acupuncture relieves microglia-mediated neuroinflammation in a rat model of traumatic brain injury by inhibiting the RhoA/ROCK2 pathway.

OBJECTIVE: To investigate the regulatory mechanism of manual acupuncture (MA) on microglial polarization-mediated neuroinflammation after traumatic brain injury (TBI), focusing on the RhoA/Rho-associated coiled coil-forming protein kinase (ROCK2) pathway. METHODS: Sprague Dawley (SD) rats were used to generate a TBI model using Feeney's freefall epidural impact method. MA was performed on half of the TBI model rats, while the others remained untreated. Acupuncture was administered at GV15, GV16, GV20, GV26, and LI4. At the end of the intervention, rat brain tissue samples were collected, and the microglial M1 polarization status was observed by immunofluorescence labeling of CD86, an M1 microglia-specific protein. RhoA/ROCK2 signaling components were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. An enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of inflammatory factors. RESULTS: Compared with normal rats, the CD86 expression density in the untreated TBI model rats was high and showed an aggregated expression pattern. The genes and proteins of the RhoA/ROCK2 signaling pathway were highly expressed, and inflammatory factors were significantly increased. The CD86 expression density in TBI rats after MA was reduced compared to that in untreated TBI rats and showed a scattered distribution. The expression of RhoA/ROCK2 signaling pathway genes and proteins was also significantly reduced, and inflammatory factors were decreased. CONCLUSION: These results show that MA may inhibit M1 polarization of microglia by regulating the RhoA/ROCK2 signaling pathway, thereby reducing neuroinflammation in TBI.

Acupuncture Reduces Apoptosis of Granulosa Cells in Rats with Premature Ovarian Failure Via Restoring the PI3K/Akt Signaling Pathway.

Acupuncture is widely recognized as an effective therapy for premature ovarian failure (POF) in clinical, but information about its potential mechanisms is rarely explored. To investigate the mechanism, fifty SD female rats were randomly divided into normal group, POF group, POF+estradiol-valerate group (abbreviated as estradiol group), and POF+acupuncture group (abbreviated as acupuncture group). The estrous cycle of the rats was tracked by vaginal smears. Their ovaries morphology was observed by hematoxylin-eosin staining. The apoptotic level of granulosa cells was detected by in situ TUNEL fluorescence staining assay. Serum follicle-stimulating hormone (FSH) and estrogen (E2) levels were measured by enzyme-linked-immunosorbent-assay (ELISA). Protein and gene expression of PI3K, Akt, bcl-2, and bax were detected by Western blotting and qPCR. In the acupuncture and estradiol groups, compared with the POF group as controls, the apoptosis number of granulosa cells was significantly decreased (p < 0.05). FSH levels were decreased, while E2 levels were increased (p > 0.05). The gene and protein expression levels of PI3K, Akt, and bcl-2 were increased, while the expression levels of bax were decreased (p < 0.05), and the protein expression level of p-Akt increased. There was no significant difference between the acupuncture group and the estradiol group (p > 0.05). Acupuncture was able to regulate hormone levels in POF rats, up-regulate PI3K/Akt signaling pathway, and reduce the apoptosis of granulosa cells. This may be one of the mechanisms of acupuncture treating premature ovarian failure.

Compound Kushen Injection as an Adjunctive Therapy for the Treatment of Non-Small-Cell Lung Cancer: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To evaluate the efficacy and safety of compound Kushen injection (CKI) combined with chemo treatment (chemo) for non-small-cell lung cancer (NSCLC). METHODS: We systematically searched the literature published in seven databases, including Embase, PubMed, central, MEDLINE, CNKI, Wanfang, and VIP, from their inception to April 2019 for all randomized controlled trials (RCTs) comparing CKI plus chemo with chemo alone in patients with NSCLC. Our main end point was clinical efficiency and the secondary outcomes were Karnofsky performance score (KPS), immune function, and adverse events. The Cochrane risk of bias tool was applied for quality assessment. RESULTS: 10 studies involving 1019 participants were included. The clinical response rate (relative risk (RR) = 1.21, 95% confidence interval (CI): 1.06 to 1.37; P=0.003), KPS (RR = 2.18, 95% CI: 1.49 to 3.17; P < 0.0001), immune function (mean differences (MD) = 0.82, 95% CI: 0.12 to 1.52; P=0.02) and adverse effects (RR = 0.67, 95% CI: 0.60 to 0.74; P < 0.00001) in the CKI plus chemo group showed significant differences when compared with chemo alone. CONCLUSIONS: CKI combined with chemo can improve clinical efficiency, KPS, and immune function and reduce adverse reactions in patients with NSCLC when compared with chemo alone. However, more rigorously designed RCTs are needed to validate this benefit, as some of the included RCTs are of low methodological quality.

Effect of acupuncture on the TLR2/4-NF-κB signalling pathway in a rat model of traumatic brain injury.

OBJECTIVE: To study the effect of acupuncture on the TLR2/4-NF-κB signalling pathway in the cortex of Sprague-Dawley rats following traumatic brain injury (TBI), and investigate the possible mechanism underlying the effects of acupuncture on scar repair. METHODS: TBI was established using Feeney's free-falling epidural percussion model. In total, 108 rats were randomly divided into a normal group (n=18), untreated TBI model group (TBI group, n=36) and manual acupuncture-treated TBI group (TBI+MA, n=36). Each group of rats was subdivided into three time groups: 3-day (3d), 7-day (7d) and 14-day (14d). No treatment was given to rats in the normal and TBI groups. The TBI+MA group received manual acupuncture at GV20, GV26, GV16 through GV15, and bilateral LI4. mRNA expression of TLR2, TLR4, NF-κB and protein in the rat cortices was quantified using real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blot analyses. RESULTS: The modified neurological severity score (mNSS) scores of the TBI+MA group were improved compared with baseline scores 12 hours after modelling, and improved at 7d and 14d compared with the TBI group (P<0.05), while the score of the TBI group did not improve until 14d compared to baseline. mRNA and protein expression of TLR2, TLR4 and NF-κB in the TBI group were higher than the normal group at 3d (P<0.05), reached a peak at 7d, then began to decrease at 14d. mRNA and protein expression of TLR2, TLR4 and NF-κB were higher in the TBI+MA group compared with the TBI group at 3d (P<0.05), were significantly down-regulated at 7d (P<0.01), and decreased to normal levels at 14d. CONCLUSIONS: Acupuncture has a bidirectional regulatory effect on the TLR2/4-NF-κB signalling pathway-related genes TLR2, TLR4 and NF-κB in the TBI rat cortex, promoting their expression in the early stage and inhibiting it in the later stage.

Whole-Genome Analysis of an Extensive Drug-Resistant Acinetobacter Baumannii ST195 Isolate from a Recipient After DCD Renal Transplantation in China.

BACKGROUND/AIMS: Infection with Acinetobacter baumannii was emerging as one of the leading causes of mortality after donation after cardiac death transpalantion. METHODS: We reported a case of a recipient who underwent DCD renal transplantation and later got infected by A.baumannii. Etests were done to verify the susceptibility test results in clinic. Whole-genome analysis was applied to investigate the resistant mechanism at gene level. RESULTS: The pathogen was isolated from his draining liquid the day after the surgery, and susceptibility test reavealed that it was sensitive to tigecycline. However, the isolate obtained from the draining liquid became tigecycline-resistant after fifteen-day administration of tigecycline. The Susceptibility tests showed that the pathogen recovered from tigecycline resistance and became intermediated to tigecycline. Whole-Genome analysis revealed the genetic level change leading to tigecycline resistance and we identified the location of mutation by comparing the whole genome sequence of the isolates. Three loci were figured out which may contribute to drug resistance, including genes encoding HTH domain protein, MFS transporter and AdeS. CONCLUSION: Understanding the genetic characteristics associated with drug resistance mechanism and antimicrobial profiles of pathogen is important in controlling infection outbreak and preventing serious complications and gives a new insight into the development of antimicrobial agents.

Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta-analysis.

Thiazide diuretics are widely used for the management of hypertension. In recent years, it has been actively debated that there is interchangeability of thiazide-type diuretics hydrochlorothiazide and thiazide-like diuretics including indapamide and chlorthalidone for the treatment of hypertension. With the purpose of seeking out the best thiazide diuretic for clinicians, we summarized the existing evidence on the two types of drugs and conducted a meta-analysis on their efficacy in lowering blood pressure and effects on blood electrolyte, glucose and total cholesterol. Twelve trials were identified: five based on the comparison of indapamide versus hydrochlorothiazide and seven based on the chlorthalidone versus hydrochlorothiazide. In the meta-analysis of blood pressure reduction, thiazide-like diuretics seemed to further reduce systolic BP ([95% CI]; -5.59 [-5.69, -5.49]; P < 0.001) and diastolic BP ([95% CI]; -1.98 [-3.29, -0.66]; P = 0.003). Meanwhile, in the analysis of side effects, the incidence of hypokalemia ([95% CI]; 1.58 [0.80, 3.12]; P = 0.19), hyponatremia ([95% CI]; -0.14 [-0.57, 0.30], P = 0.54), change of blood glucose ([95% CI];0.13 [-0.16, 0.41], P = 0.39) and total cholesterol ([95% CI]; 0.13 [-0.16, 0.41], P = 0.39) showed that there is no statistical significant differences between the two groups of drugs. In conclusion, using thiazide-like diuretics is superior to thiazide-type diuretics in reducing blood pressure without increasing the incidence of hypokalemia, hyponatraemia and any change of blood glucose and serum total cholesterol.

Evolution of Drug-resistant Acinetobacter baumannii After DCD Renal Transplantation.

Infection after renal transplantation remains a major cause of morbidity and death, especially infection from the extensively drug-resistant bacteria, A. baumannii. A total of fourteen A. baumannii isolates were isolated from the donors' preserved fluid from DCD (donation after cardiac death) renal transplantation and four isolates in the recipients' draining liquid at the Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, from March 2013 to November 2014. An outbreak of A. baumannii emerging after DCD renal transplantation was tracked to understand the transmission of the pathogen. PFGE displayed similar DNA patterns between isolates from the same hospital. Antimicrobial susceptibility tests against thirteen antimicrobial agents were determined using the K-B diffusion method and eTest. Whole-genome sequencing was applied to investigate the genetic relationship of the isolates. With the clinical data and research results, we concluded that the A. baumannii isolates 3R1 and 3R2 was probably transmitted from the donor who acquired the bacteria during his stay in the ICU, while isolate 4R1 was transmitted from 3R1 and 3R2 via medical manipulation. This study demonstrated the value of integration of clinical profiles with molecular methods in outbreak investigation and their importance in controlling infection and preventing serious complications after DCD transplantation.

Evaluation of crescent formation as a predictive marker in immunoglobulin A nephropathy: a systematic review and meta-analysis.

The 2009 Oxford Classification of immunoglobulin A (IgA) nephropathy (IgAN) identifies four histological features as predictors of renal prognosis: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). However, the clinical and prognostic significance of crescent formation still remains controversial. Therefore, we performed a meta-analysis to evaluate the association between crescents and kidney outcome in IgAN. A total of 20 studies published from January 2009 to July 2016 involving 5,285 patients were included after systematic searches of PubMed and EMBASE databases. Pooled results showed that crescent lesions were associated with kidney failure (HR, 1.93; 95% CI, 1.49-2.50; P < 0.001). IgAN patients with crescents had lower eGFR levels (SMD, -0.21; 95% CI, -0.40--0.03; P = 0.023); higher proteinuria levels (SMD, 0.87; 95% CI, 0.11-1.63; P = 0.024); a larger number of patients with M1 (RR, 1.22; 95% CI, 1.07-1.40; P = 0.003), E1 (RR, 4.83; 95% CI, 3.04-7.66;P < 0.001), S1 (RR, 1.76; 95% CI, 1.11-2.80; P = 0.016) and T1/2 (RR, 2.74; 95% CI, 2.10-3.57; P < 0.001) lesions; and received immunosuppressive therapy more frequently (RD, 0.17; 95% CI, 0.11-0.23; P < 0.001). Our results suggest that crescent formation represents an efficient prognostic factor associated with progression to kidney failure and thus could be considered into the new Oxford Classification.

Effect of remote ischemic preconditioning on postoperative acute kidney injury among patients undergoing cardiac and vascular interventions: a meta-analysis.

It is currently controversial whether remote ischemic preconditioning (RIPC) reduces the incidence of acute kidney injury (AKI) in patients undergoing cardiovascular interventions. The main objective of this meta-analysis was to investigate whether RIPC provides renal protection for patients undergoing cardiac or vascular surgery. We searched the PubMed database (1966-Oct 2015), Embase database (1966-Oct 2015), Google Scholar, Cochrane Library, ClinicalTrials Database and Open Grey. Then we conducted a meta-analysis of the randomized controlled trials that met the inclusion criteria of our study. The interventions included use of an inflatable tourniquet around the limbs or cross-clamping of the iliac arteries before surgery (RIPC groups) and general cardiovascular intervention (control groups). The main outcomes examined included the incidence of AKI; changes in acute kidney injury biomarkers; and use of renal replacement therapy. Other outcomes examined included in-hospital mortality and the lengths of hospital stay and intensive care unit (ICU) stay. Finally, we screened 26 eligible studies containing 6699 patients who underwent cardiac or vascular interventions with RIPC (n = 3343) or without RIPC (n = 3356). The AKI incidence was decreased in the RIPC group as was the length of ICU stay. There were no differences in the changes in AKI biomarkers, use of renal replacement therapy or in-hospital mortality between the two groups. Remote ischemic preconditioning may decrease the occurrence of AKI in cardiovascular surgery patients. Since studies included have a significant heterogeneity, meta-analyses using a stricter inclusion criteria are needed to clarify the renoprotection effect of RIPC.