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Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1β, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.
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A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with β-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C β-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of β-lactamase-producing MDR Gram-negative bacterial infections.
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Objective To Investigate the cause of a food poisoning incident in a city in Dehong Prefecture， determine the scope of the incident， and to formulate effective prevention and control measures. Methods Field epidemiology and case-control study methods were used to formulate case definition； carry out case search； find suspicious food combined with clinical manifestations， dining history and other information； and collect samples from the suspicious food， cases and environment for laboratory testing. Results A total of 160 cases were found and the incidence rate was 26.02% （160/615）. The main clinical manifestations were diarrhea， leukocytosis， vomiting， nausea and abdominal pain. The average incubation period was 10.89±5.09 h， with 2 h as the shortest and 28 h as the longest. The epidemiological curve suggested the point source exposure mode. The results of case-control study showed that eating roast pork with green shoots was an independent risk factor （OR=13.09， 95%CI： 3.26‒52.54）.16 samples were tested by the local CDC laboratory. Proteus mirabilis was detected in two the anal swabs of two patients He and Chen. Both proteus pani and proteus mirabilis were detected in anal swab of patient Zhou and Proteus pani was detected in roast meat. There was no detection of pathogenic bacteria in other samples. Conclusion Based on the field epidemiological investigation and laboratory test results， we conclude that the food poisoning incident is caused by suspected proteus bacteria. We suggest that the market supervision department should strengthen the supervision of local food hygiene； clarify the sampling rights， responsibilities and technical procedures when medical institutions treat patients with foodborne diseases； ensure finding the causes in time； and take effective prevention and control measures to avoid similar food poisoning events.
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Objective:To understand the clinical characteristics of pregnant women infected with dengue virus (DENV) in Ruili City, Yunnan Province, so as to provide basis for formulating effective diagnosis and treatment protocol of dengue fever in pregnant women.Methods:A total of 18 pregnant women infected with DENV hospitalized in Ruili People's Hospital in 2017 and 2018 were selected as observation group, and 18 non-pregnant women infected with DENV were selected as control group according to the age range of the observation group, and epidemiological and clinical data of patients in the two groups were retrospectively collected. Epidemiological characteristics, clinical symptoms and laboratory biochemical indexes of the two groups were compared and analyzed.Results:There were no significant differences ( t = - 0.032, 0.495, P > 0.05) in age [(27.9 ± 5.3) vs (27.9 ± 5.1) years old] and hospitalization stay [(6.8 ± 1.6) vs (6.6 ± 2.0) d] between the observation group and control group. One pregnant woman in observation group had early pregnancy abortion. Patients of both groups had fever in 18 cases (100.0%), headache, muscle aches, and chills in 14 cases (77.8%), anorexia in 15 cases (83.3%), and nausea and vomiting in 5 cases (27.8%); fatigue in 14 cases (77.8%) and 16 cases (88.9%), respectively; there was 1 case of rash in observation group (5.6%), and no rash in control group. There were no significant differences in the above mentioned clinical symptoms distribution between the two groups ( P > 0.05). On the first day of admission, the reduction proportions in red blood cells [61.1% (11/18) vs 5.6% (1/18)], hemoglobin [50.0% (9/18) vs 16.7% (3/18)], and hematocrit [61.1% (11/18) vs 16.7% (3/18)] in observation group were significantly higher than those in control group ( P < 0.05); on the fifth day of admission, the reduction proportions in hemoglobin [33.3% (6/18) vs 5.6% (1/18)] and hematocrit [33.3% (6/18) vs 5.6% (1/18)] in observation group were significantly higher than those in control group ( P < 0.05). Conclusions:The red blood cells, hemoglobin and hematocrit of pregnant women infected with DENV are significantly reduced, and there is a risk of miscarriage in early pregnancy. It is suggested that relevant departments should strengthen the training of medical staff to diagnose and treat pregnant women infected with DENV early.
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We investigated the molecular characteristics of the full-length genome of 14 dengue serotype 1 virus (DENV-1)strains isolated in Sino-Myanmar border region in Yunnan Province,China during 2013-2015.Isolation of dengue virus was using C6/36 cell culture method.Viral RNA was extracted from virus isolates,and then the full-length genome was amplified by RT-PCR.The homology and phylogenetic analysis was made on the nucleotide and deduced amino acid sequences by bioinformatics software including ClastalX1.83 and MEGA6 etc.Results showed that fourteen strains of DENV-1 isolated from dengue fever cases,of these,9 strains from Ruili City of Dehong Prefecture,3 from Lincang Prefecture,2 from Kunming City.RT-PCR and sequencing indicated that the full-length genes (10 735 nt) of 14 DENV-1 strains were obtained,and their open reading frame (95-10 271) were coded 3 392 amino acid residues.The genotypes of DENV-1 were revealed by homology and phylogenetic analysis based on structural and non-structural proteins.Thirteen were genotype Ⅰ (G-Ⅰ) (7 from indigenous cases in Ruili and Lincang and 6 from imported case from Myanmar to Ruili,Lincang and Kunming),and 1 G-Ⅲ from imported case from India to Kunming.The phylogenic analysis indicated that the 13 isolates from Yunnan divided into 2 phylogenic subgroups,and they had a closer genetic relationship with the strains isolated from Southeast Asia.The gene sequences of the 13 G-Ⅰ strains have been acquired,the rate of their nucleotide homology and amino acid homology were 97.02 ％-100 ％ and 98.78 ％100 ％ respectively.Compared with 6 strains from Southeast Asia,nucleotide homology and amino acid homology were 96.53％-99.53％ and 97.33％-100％ respectively.Compared with prototype strain (US_Hawaii) of DENV-1,nucleotide homology and amino acid homology were 93.76％-94.45 ％ and 95.86 ％-96.91％ respectively.Compared with US_Hawaii strain,there were 44 and 150 different sites in amino acid of structural and non-structural proteins,respectively.The G-1 of DENV-1 have been popular in Sino-Myanmar border region in Yunnan,2013-2015.They have genetic diversity but multiple transmission sources were from Myanmar,and should strengthen control cross-border spread of dengue fever in this region.It is necessary to further study that change of the amino acid sites of Yunnan strains of DENV-1 is related to its antigenicity and pathogenicity.
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Objective To observe the effects of Jiuxieling Granules on the expressions of MyD88 and IRAK1 in ulcerative colitis model rats with spleen-kidney yang deficiency; To discuss its mechanism of action. Methods Animal models were established by compound methods. 90 Wistar rats were randomly divided into blank group, model group, positive medicine group, and Jiuxieling Granules high-, medium-, and low-dose groups. Each administration group was given relevant medicine for gavage. RT-qPCR, SP immunohistochemistry and Western blot were used to detect mRNA and proteins of MyD88 and IRAK1 in colon tissues. Results Compared with the blank group, mRNA and proteins of MyD88 and IRAK1 in the model group increased (P<0.01). Compared with the model group, mRNA and proteins of MyD88 and IRAK1 in each administration group decreased (P<0.01), especially in Jiuxieling Granules high-dose group. Conclusion Jiuxieling Granules can reduce the expressions of MyD88 and IRAK1, and then influence the transmission of MyD88 signaling pathway and block the release of downstream inflammatory factors to achieve the result of treating ulcerative colitis with spleen-kidney yang deficiency.
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Objective To explore the mechanism of tripterygium wilfordii polyglycoside tablets for elderly patients with relapsing refractory immune thrombocytopenic purpura (ITP),and to seek the theoretical basis for Chinese medicine treatment of this disease.Methods The clinical data of 79 patients with relapsing refractory ITP were retrospectively analyzed.According to whether the combined use of tripterygium wilfordii polyglycoside,they were divided into the control group (35 cases) and the observation group (44 cases).The control group was treated with platelet and tranexamic acid,sulfasalazine,sulforaphane sodium,hemagglutinin and other symptomatic hemostasis treatment.The observation group in symptomatic hemostasis support on the basis of treatment with tripterygium wilfordii polyglycoside tablets.The CD4+/CD8+ ratio and CD4+ CD25+ Treg expression were compared between the two groups.Results The CD4+/CD8+ ratio,CD4+ CD25+ Treg and platelet count in the control group before treatmentwere (0.96 ± 0.36),(1.21 ± 0.67) ％,(13.14 ± 6.92) × 109/L,respectively,which of the observation group were (0.92 ± 0.37),(1.19 ± 0.59) ％,(11.51 ± 6.21) × 109/L,respectively,there were no statistically significant differences between the two groups (all P ＞ 0.05).The CD4+/CD8+ ratios in peripheral blood of the observation group at 2 weeks,3 weeks and 4 weeks after treatmentwere (1.04 ±0.56),(1.55 ±0.34),(1.59 ±0.41),respectively,there were statistically significant differences between the two groups (t =9.994,9.797,all P ＜ 0.05).The CD4+ CD25+ Treg proportions in the observation group at 2 weeks,3 weeks and 4 weeks after treatmentwere (1.01 ± 0.61) ％,(1.06:±:0.57) ％,(5.92 ± 0.65) ％,respectively,there was statistically significant difference between the 4 weeks after treatment and before treatment(t =5.378,P ＜ 0.05).The CD4+/CD8+ ratios in the peripheral blood of the control group were (1.01 ±0.60),(0.89 ±0.50) and (0.96 ±0.51),respectively,and the CD4+ CD25+ Treg in control group at 2 weeks,3 weeks and 4 weeks after treatment proportions were (0.99 ±0.72)％,(1.15 ±0.66)％,(1.22 ±0.56)％,respectively,there were no statistically significant differences between before and after treatment (all P ＞0.05).There were statistically significant differences in the CD4+/CD8+ ratio and CD4+ CD25+ Treg expression between the observation group and control group at 4 weeks after treatment (t =8.589,P ＜ 0.01;t =2.369,P ＜ 0.05).There was no statistically significant difference in the platelet count between the two groups(P ＞ 0.05),but the symptoms of bleeding of the observation group was lighter at 3 weeks after treatment.Conclusion Tripterygium wilfordii polyglycoside improves the expression of CD4+/CD8+ and CD4+ CD25+ Treg in peripheral blood of elderly patients with relapsed or refractory ITP.It is an ideal drug for the treatment of relapsed and refractory ITP in the elderly,it is worth further study.
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Objective To explore the change and value of interleukin (IL)-2,IL-6 and tumor necrosis factor (TNF)-α in the serum samples of patients with brucellosis.Methods The levels of serum IL-2,IL-6 and TNF-α were measured using the enzyme linked immunosorbent assay (ELISA) method in 155 patients with brucellosis in different clinical stages (including 69 cases in acute,34 cases in subacute and 52 cases in chronic periods) and 50 healthy controls.IL-2 was used to represent the helper T cell (Th)-type 1 cytokines,IL-6 represent Th2 type cytokines,and the Th1/Th2 ratio in different clinical stages was compared.Results The expression level of serum IL-2 in patients with brucellosis was different (ng/L:acute:10.15 ± 2.01;subacute:9.53 ± 1.68;chronic:6.76± 1.31;control:47.25 ± 5.68),the differences were statistically significant (F =74.921,P ＜ 0.05).The expression levels of serum IL-2 in acute,subacute and chronic periods of brucellosis patients were significantly lower than that of healthy controls (all P ＜ 0.05).The expression levels of serum IL-2 in acute and subacute periods of brucellosis patients were higher than that of chronic period patients (all P ＜ 0.05).The expression of IL-6 and TNF-α in serum of patients in different clinical stages were different (ng/L:acute:615.22± 341.07,802.55 ± 479.53;subacute:478.45 ± 105.33,680.21 ± 366.95;chronic:306.37 ± 96.12,455.36 ± 176.27;control:121.45 ± 30.16,87.51 ± 24.03),the differences were statistically significant (F =57.692,63.210,all P ＜ 0.05).The levels of serum IL-6 and TNF-o were significantly higher in patients with brucellosis in acute,subacute and chronic clinical stages than that of healthy controls (all P ＜ 0.05).Serum IL-6 and TNF-α levels in acute period of brucellosis patients were higher than those of subacute and chronic periods patients (all P ＜ 0.05);the levels of serum IL-6 and TNF-α in subacute period of brucellosis patients were also significantly higher than that of chronic period patients (all P ＜ 0.05).The Th1/Th2 ratio was different (acute:0.02 ± 0.00;subacute:0.02 ± 0.00;chronic:0.23 ± 0.02;control:0.41 ± 0.06) in clinical patients with brucellosis,the differences were statistically significant (F =17.843,P ＜ 0.05),the value of Th1/Th2 in acute and subacute period patients were lower than that of chronic period (all P ＜ 0.05).Conclusion IL-2,IL-6 and TNF-α may play an important role in the pathogenesis of brucellosis,and their dynamic changes can reflect the progression and outcome of brucellosis.
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Objective To explore the effects of clarithromycin on the expressions of histone deacetylase-2 (HDAC2) and glucocorticoid receptor (GR) of cigarette smoke-exposed asthmatic mice.Methods BALB/c mice were chosen to be the subjects of this study.They were raised to establish asthma model (OVA group);and mice in one asthma group were exposed to smoke (SEA group), one asthma group were treated with clarithromycin (CAM group) after smoke exposure.Control group mice were used as parallel comparison.The histopathological changes were studied to assess lung tissue inflammation.Cell counts in bronchoalveolar lavage fluid were also tested for airway inflammation.Histone deacelytase2 (HDAC2) activity of lung tissues was measured by qRT-PCR.HDAC2 and GR expressions in the lung tissue were detected by Western blot.Results Histopathologic observation showed massive infiltration of inflammatory cells in both OVA group and SEA group, while inflammation infiltration attenuated in CAM group.Compared with those in CAM group, the levels of IL-4 and IL-8 in bronchoalveolar lavage fluid of SEA group increased significantly (104.36±14.39 vs.65.49±10.82, 681.35±66.18 vs.321.49±90.37;P=0.031, 0.017).The expression of HDAC2 mRNA in CAM group was significantly higher than that in SEA group (0.062±0.013 vs.0.031±0.015, P=0.032).The expressions of HDAC2 protein (0.23±0.017 vs.0.49±0.022, P=0.033) and GR protein (0.19±0.014 vs.0.64±0.023, P=0.011) were significantly lower in SEA group than in CAM group.Conclusion Clarithromycin could attenuate airway inflammation in smoke-exposed asthmatic mice.The mechanism of action may be related to the expression of HDAC2 gene in the lower reaches by combining with GR.
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Objective@#To understand the serotypes, genotypes and transmission source of dengue viruses(DENV) isolated in Yunnan from 2013 to 2015.@*Methods@#Viral RNA was extracted from serum samples of dengue fever(DF) cases at the acute stage in Yunnan, then the gene fragments of envelope protein(E) region were amplified by RT-PCR. The homology and phylogenetic analysis was made on the nucleotide and deduced amino acid sequences by bioinformatics softwares including Clustal X, DNAStar and MEGA5.@*Results@#Viral nucleic acid detection and sequencing indicated that 40 E genes of DENV were obtained. The serotypes and genotypes of DENV were revealed by homology and phylogenetic analysis based on E genes of DENV. Fifteen virus strains belonged to DENV serotype 1(DENV-1), of these, 14(11 from Ruili, 1 from Lincang and 2 from Kunming) were genotype I(G-I), 1 from Kunming was G-V. Twenty-two virus strains belonged to DENV serotype 2(DENV-2), of these, 10 from Ruili were G-I and 12 from Xishuangbanna were G-IV. Two virus strains belonged to DENV serotype 3(DENV-3) and G-II. One virus strain belonged to DENV serotype 4(DENV-4) and G-I. All detected DENV genotypes were mainly predominant in Southeast Asia. All the 40 Yunnan DENV strains shared high homology with the DENV strains in Southeast Asia countries.@*Conclusions@#Four serotypes and multiple genotypes of DENV had been co-circulating in Yunnan from 2013 to 2015. The DENV transmitted from Southeast Asia countries was the main cause of DF in Yunnan. It is necessary to strengthen the surveillance and management on the imported cases of DF in Yunnan.