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Clostridioides difficile infection (CDI) causes severe diarrhea and colitis, leading to significant morbidity, mortality, and high medical costs worldwide. Oral vancomycin, a first-line treatment for CDI, is associated with a high risk of recurrence, necessitating novel therapies for primary and recurrent CDI. A novel small-molecule compound, CDBN-YGXZ, was synthesized by modifying the benzene ring of nitazoxanide with lauric acid. The mechanism of action of CDBN-YGXZ was validated using a pyruvate:ferredoxin/flavodoxin oxidoreductase (PFOR) inhibition assay. The efficacy of CDBN-YGXZ was evaluated using the MIC test and CDI infection model in mice and hamsters. Furthermore, metagenomics was used to reveal the underlying reasons for the effective reduction or prevention of CDI after CDBN-YGXZ treatment. The inhibitory activity against PFOR induced by CDBN-YGXZ. MIC tests showed that the in vitro activity of CDBN-YGXZ against C. difficile ranging from 0.1 to 1.5 µg/mL. In the mouse and hamster CDI models, CDBN-YGXZ provided protection during both treatment and relapse, while vancomycin treatment resulted in severe relapse and significant clinical scores. Compared with global effects on the indigenous gut microbiota induced by vancomycin, CDBN-YGXZ treatment had a mild influence on gut microbes, thus resulting in the disappearance or reduction of CDI recurrence. CDBN-YGXZ displayed potent activity against C. difficile in vitro and in vivo, reducing or preventing relapse in infected animals, which could merit further development as a potential drug candidate for treating CDI.
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Clostridioides difficile , Infecções por Clostridium , Cricetinae , Animais , Camundongos , Vancomicina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/prevenção & controle , RecidivaRESUMO
A different regioselective three-component reaction of alkenes, oxygen sources, and hydroperoxides mediated by ammonium iodine to α-oxyperoxidates has been developed. Mechanistic studies demonstrated that regioselective radical addition and subsequent SN2 nucleophilic substitution were possible for the formation of products. In addition to the traditional pathway of SN2 reaction, that is, where nucleophiles attack the α-C atoms at the back side, an additional unusual transition configuration with the H2O molecule attacking the α-C atom at the front side was obtained.
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An environment-friendly and efficient dioxygenation of aryl alkenes for the construction of vicinal diols has been developed in water with iodine as the catalyst and tert-butylhydroperoxides (TBHPs) as the oxidant. The protocol was efficient, sustainable, and operationally simple. Detailed mechanistic studies indicated that one of the hydroxyl groups is derived from water and the other one is derived from TBHP. Additionally, the bisperoxides could be obtained in good yields with iodine as the catalyst, Na2CO3 as the additive, and propylene carbonate as the solvent, instead.
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SIGNIFICANCE: The use of antiobesity drugs is becoming more widespread, and the resulting adverse effects are also increasing. Visual impairments caused by weight-loss pills need a timely and accurate diagnosis and treatment. Prompt diagnosis and treatment can achieve a satisfactory prognosis. PURPOSE: This report describes a case of a significant decline in bilateral visual acuity caused by taking diet pills and explores the possible pathogenesis. CASE REPORT: A 32-year-old Chinese woman showed shallow anterior chambers, and intraocular pressure (IOP) was 38 mmHg bilaterally after taking Korean prescription diet pills for 6 days. The best-corrected visual acuity of both eyes was 0.03. The ultrasound biomicroscopy showed complete ciliary body detachment accompanied with angle closure. The central anterior chamber depths were 1.70 mm in the right eye and 1.61 mm in the left eye. The patient was diagnosed with ciliary body detachment with secondary elevated IOP. The patient was treated with pilocarpine, carteolol hydrochloride, brinzolamide, mannitol, and dexamethasone sodium phosphate. The patient had rewarding prognosis after treatment with discontinuation of diet pills, control of IOP, and glucocorticoids. CONCLUSIONS: Extensive publicity and education are needed to ensure that consumers do not abuse diet pills; meanwhile, a timely diagnosis and withdrawal are crucial for a desirable prognosis. Clinicians need to consider the possibility of drug-secondary ocular diseases.
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Corpo Ciliar , Pressão Intraocular , Adulto , Dieta , Feminino , Humanos , Microscopia Acústica , Tonometria OcularRESUMO
Primary pulmonary lymphoma (PPL) is a rare neoplasm. We report a case of 45-year-old men who was admitted to hospital for multiple nodules and masses in both lungs. The contrast enhanced chest CT scans revealed multiple nodules and masses of varying sizes in right upper and middle lobes and both lower lobes. CT-guided percutaneous transthoracic needle biopsy was performed. The diagnosis of PPL was confirmed by histopathological examination and Immunohistochemical staining. PPL should be included in the differential diagnoses in symptomless patients with multiple pulmonary nodules and masses.
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Neoplasias Pulmonares , Linfoma , Nódulos Pulmonares Múltiplos , Humanos , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Linfoma/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Background: Adolescents differ from adults in certain aspects, but the differences in the etiology of chronic cough between adolescents and adults have not been specifically investigated. The purpose of this study is to evaluate the causes of chronic cough in adolescent patients in comparison with those in adult patients. Methods: The electronic medical records were retrospectively screened for patients with the initial diagnosis of chronic cough from 2016 to 2018. Clinical variables and the causes of chronic cough were collected in patients who met inclusion criteria. Patients were assigned to adolescent (13 to 18 years) and adult (> 18 years) group based on age. The distribution of causes of chronic cough was compared by t-test and χ2 tests between adolescent and adult groups using SPSS. Significant level was set at 0.05. Results: The enrolled patients consisted of 16 adolescents and 73 adults with chronic cough. The most common causes of chronic cough were cough-variant asthma and upper airway cough syndrome in both adolescents and adults. The frequency of post infectious cough in adolescents was significantly higher than that in adults (12.5% vs. 1.36%; p= 0.024). Although no significant difference between the two groups was found, there was a trend that suggested that habitual cough was more common in the adolescent group (6.25%:1.36%); while gastroesophageal reflux disease (GERD) did not show similar results (6.25%:20.54%). Conclusion: There are moderate differences in the causes of chronic cough between adolescent and adult patients. Realizing those differences would be helpful for clinicians to establish an appropriate differential diagnosis and make referral decisions.
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OBJECTIVE: This study aims to investigate the effects of hybrid blood purification treatment on secondary hyperparathyroidism for maintenance hemodialysis (HD) patients. METHODS: A total of 40 patients were randomly divided into 2 groups: HD combined with hemoperfusion (HD + HP) group (n = 20) and HD group (n = 20). Changes in intact parathyroid hormone (iPTH) in these 2 groups were compared before and after treatment, and iPTH levels in the HD + HP group were monitored before and after treatment. RESULTS: iPTH, ß2 microglobulin (ß2-MG), and cystatin C (CysC) levels were significantly lower in the HD + HP group than in the HD group (p < 0.05), iPTH levels were significantly higher than at the first day after treatment (p < 0.05), and iPTH level was significantly higher (p < 0.05). CONCLUSION: The clearance effects of HD + HP on iPTH, ß2-MG, and CysC are better than HD alone. Treatment with HD + HP every 2 weeks is recommended for maintenance HD patients.
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Hemoperfusão/métodos , Hiperparatireoidismo Secundário/terapia , Diálise Renal/métodos , Adulto , Idoso , Cistatina C/sangue , Feminino , Hemoperfusão/normas , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Diálise Renal/normas , Resultado do Tratamento , Microglobulina beta-2/sangueRESUMO
The antimicrobial peptide PaDef was isolated from Mexican avocado fruit and was reported to inhibit the growth of Escherichia coli and Staphylococcus aureus in 2013. In this study, an N-terminal 6 × His tagged recombinant PaDef (rPaDef) with a molecular weight of 7.5 KDa, for the first time, was expressed as a secreted peptide in Pichia pastoris. The optimal culture condition for rPaDef expression was determined to be incubation with 1.5% methanol for 72 h at 28 °C under pH 6.0. Under this condition, the amount of the rPaDef accumulation reached as high as 79.6 µg per 1 ml of culture medium. Once the rPaDef peptide was purified to reach a 95.7% purity using one-step nickel affinity chromatography, its strong and concentration-dependent antimicrobial activity was detected to be against a broad-spectrum of bacteria of both Gram-negative and Gram-positive. The growth of these bacterial pathogens was almost completely inhibited when the rPaDef peptide was at a concentration of as low as 90 µg/ml. In summary, our data showed that rPaDef derived from Mexican avocado fruit can be expressed and secreted efficiently when P. pastoris was used as a cell factory. This is the first report on heterologous expression of PaDef in P. pastoris and the approach described holds great promise for antibacterial drug development.
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Peptídeos Catiônicos Antimicrobianos , Escherichia coli/crescimento & desenvolvimento , Persea/genética , Pichia/metabolismo , Proteínas de Plantas , Staphylococcus aureus/crescimento & desenvolvimento , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Peptídeos Catiônicos Antimicrobianos/farmacologia , Persea/química , Pichia/genética , Proteínas de Plantas/biossíntese , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/farmacologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologiaRESUMO
BACKGROUND: The ability of Yersinia pestis to form a biofilm is an important characteristic in flea transmission of this pathogen. Y. pestis laterally acquired two plasmids (pPCP1and pMT1) and the ability to form biofilms when it evolved from Yersinia pseudotuberculosis. Small regulatory RNAs (sRNAs) are thought to play a crucial role in the processes of biofilm formation and pathogenesis. RESULTS: A pPCP1-derived sRNA HmsA (also known as sR084) was found to contribute to the enhanced biofilm formation phenotype of Y. pestis. The concentration of c-di-GMP was significantly reduced upon deletion of the hmsA gene in Y. pestis. The abundance of mRNA transcripts determining exopolysaccharide production, crucial for biofilm formation, was measured by primer extension, RT-PCR and lacZ transcriptional fusion assays in the wild-type and hmsA mutant strains. HmsA positively regulated biofilm synthesis-associated genes (hmsHFRS, hmsT and hmsCDE), but had no regulatory effect on the biofilm degradation-associated gene hmsP. Interestingly, the recently identified biofilm activator sRNA, HmsB, was rapidly degraded in the hmsA deletion mutant. Two genes (rovM and rovA) functioning as biofilm regulators were also found to be regulated by HmsA, whose regulatory effects were consistent with the HmsA-mediated biofilm phenotype. CONCLUSION: HmsA potentially functions as an activator of biofilm formation in Y. pestis, implying that sRNAs encoded on the laterally acquired plasmids might be involved in the chromosome-based regulatory networks implicated in Y. pestis-specific physiological processes.
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Proteínas de Bactérias/genética , Biofilmes/crescimento & desenvolvimento , Yersinia pestis/fisiologia , Proteínas de Bactérias/metabolismo , GMP Cíclico/análogos & derivados , GMP Cíclico/genética , GMP Cíclico/metabolismo , Fenótipo , Plasmídeos/genética , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Fatores de Transcrição/genética , Yersinia pestis/enzimologia , Yersinia pestis/genética , beta-Galactosidase/metabolismoRESUMO
Mytichitin-A is an antimicrobial peptide isolated from the serum of Mytilus coruscus and is reported to inhibit bacterial growth as tested on several Gram-positive bacteria. To produce large quantity of Mytichitin-A to further investigate its biological activity, nucleotide sequence encoding a recombinant 6 × His-Mytichitin-A (rMytichitin-A) peptide was synthesized and inserted into the inducible yeast expression vector pPICZαA. With the availability of such an expression vector called pPICZαA-Mytichitin-A, we transformed Pichia pastoris GS115 cells with a SacI-linearized pPICZαA-Mytichitin-A by electroporation. Transgenic strains secreting rMytichitin-A with a molecular weight of approximate 10 KDa as expected were obtained. The optimal culture condition for rMytichitin-A expression was determined to be 1.0% methanol induction, 96 h incubation at 28 °C and the amount of rMytichitin-A reached 45.5 µg/ml. The percentage of rMytichitin-A was estimated to be 73.6% of the total protein. After rMytichitin-A was purified using nickel ions affinity chromatography, approximate 9.1 mg pure rMytichitin-A was obtained from 500 ml of cell culture medium with 97.8% purity. More importantly, both the culture supernatant and purified rMytichitin-A inhibited the growth of Gram-positive bacteria, especially Staphylococcus aureus and Bacillus subtilis with a minimum inhibition concentration of as low as 31 and 48 µg/ml, respectively. Differently from the native protein, however, the rMytichitin-A is not active against Gram-negative bacteria. Taken together, this is the first report on the heterologous expression of Mytichitin-A in P. pastoris. Our study showed that P. pastoris is an effective expression system for producing large quantities of biologically active Mytichitin-A for both research and application purposes.
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Peptídeos Catiônicos Antimicrobianos , Bacillus subtilis/crescimento & desenvolvimento , Bactérias Gram-Negativas/crescimento & desenvolvimento , Mytilus/genética , Pichia/metabolismo , Staphylococcus aureus/crescimento & desenvolvimento , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Peptídeos Catiônicos Antimicrobianos/farmacologia , Mytilus/metabolismo , Pichia/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacocinéticaRESUMO
Primary thymic adenocarcinoma of enteric type is a very rare subtype of thymic carcinoma. Choosing appropriate systemic chemotherapy for patients with unresectable or recurrent disease remain a big challenge. We present a case of 38-year-old man with primary thymic adenocarcinoma of enteric type. The patient received multiline chemotherapy. Metastatic lesions were effectively controlled by FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) chemotherapy. According to the present case and the literature review, FOLFOX and XELOX (capecitabine/oxaliplatin) regimens are reasonable treatment choice for unresectable or recurrent primary thymic adenocarcinoma of enteric type, even in the first-line chemotherapy.
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OBJECTIVE: Computed tomography (CT)-guided percutaneous lung biopsy is an effective diagnostic procedure for patients with solitary pulmonary nodules (SPN). The aim of this study is to evaluate the safety of this procedure for elderly patients with SPN. METHODS: A total of 125 patients with SPN who received a CT-guided percutaneous lung biopsy were retrospectively analyzed. Patients were divided into elderly (age 65 and above) and non-elderly groups. The patients' characteristics and procedure-related complications were compared between the two groups. RESULTS: The elderly and non-elderly groups included 74 and 51 patients, respectively. The success rate of a CT-guided percutaneous lung biopsy was 100%. The diagnosis rate of lung cancer in the elderly group was significantly higher than that in the non-elderly group (83.78% vs. 64.70%, p = 0.014). The incidence of pulmonary hemorrhage after lung biopsy in the elderly group (44, 59.45%) was significantly higher than that in the non-elderly group (21, 41.17%, p = 0.044), and moderate hemorrhage was the main contributor. The incidence rate of pneumothorax in the elderly group numerically increased, but the difference did not reach statistical significance. CONCLUSION: Computed tomography-guided percutaneous lung biopsy was an efficient procedure for diagnosing SPN in elderly patients. Although complication rates were relatively higher in elderly patients, the safety of this procedure was acceptable.
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The rapid growth of industrial digitalization and financial support are the main driving forces for the green transformation of China's economy. Aiming to explore how digitalization and financial development impact ecological efficiency (eco-efficiency), this study proposes a unified research framework by integrating multiple technologies using the panel data that covered 30 China's provinces from 2006 to 2018. First, China's provincial digital development index is constructed to measure the level of digitalization, and regional eco-efficiency is estimated by a non-radial data envelope analysis (DEA) model. Based on that, the panel data regression model and panel vector autoregression (PVAR) model are used to explore the direct effects and dynamic effect of digitalization and financial development on eco-efficiency, respectively. Then, the threshold regression model is employed to check the threshold effect of the two variables on eco-efficiency. The following conclusions are drawn: (1) Both digitalization and financial development have a significantly positive correlation with regional eco-efficiency, indicating that China's digitalization and financial development in recent years have both improved regional eco-efficiency. (2) Eco-efficiency has positive and longer responses to the impulse coming from digitalization and financial development, and the response of ecological efficiency to financial development is greater than its response to digitalization. (3) Threshold effects exist in the impact mechanism of digitalization on regional eco-efficiency. This indicates that the level of financial support is too low to promote the improvement in ecological efficiency. Eco-efficiency can be improved only to a certain extent. The research conclusions provide a policy reference for improving eco-efficiency and promoting China's green development.
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Eficiência , Tecnologia , China , Desenvolvimento Econômico , IndústriasRESUMO
To combat bacteria and even biofilm infections, developing alternative antibacterial wound dressings independent of antibiotics is imperative. Herein, this study developed a series of bioactive chitin/Mn3O4 composite hydrogels under mild conditions for infected wound healing application. The in situ synthesized Mn3O4 NPs homogeneously distribute throughout chitin networks and strongly interact with chitin matrix, and as well as endow the chitin/Mn3O4 hydrogels with NIR-assisted outstanding photothermal antibacterial and antibiofilm activities. Meantime, the chitin/Mn3O4 hydrogels exhibit favorable biocompatibility and antioxidant property. Furthermore, the chitin/Mn3O4 hydrogels with the assist of NIR show an excellent skin wound healing performance in a mouse full-thickness S. aureus biofilms-infected wound model, by accelerating the phase transition from inflammation to remodeling. This study broadens the scope for the fabrication of chitin hydrogels with antibacterial property, and offers an excellent alternative for the bacterial-associated wound infection therapy.
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Quitina , Infecção dos Ferimentos , Animais , Camundongos , Quitina/farmacologia , Staphylococcus aureus , Antibacterianos/farmacologia , Modelos Animais de Doenças , Hidrogéis/farmacologia , Cicatrização , Infecção dos Ferimentos/tratamento farmacológicoRESUMO
Background: It is now understood that APOBEC3 family proteins (A3s) are essential in tumor progression, yet their involvement in tumor immunity and stemness across diverse cancer types remains poorly understood. Methods: In the present study, comprehensive genome-wide statistical and bioinformatic analyses were conducted to elucidate A3 family expression patterns, establishing clinically relevant correlations with prognosis, the tumor microenvironment(TME), immune infiltration, checkpoint blockade, and stemness across cancers. Different experimental techniques were applied, including RT-qPCR, immunohistochemistry, sphere formation assays, Transwell migration assays, and wound-healing assays, to investigate the impact of A3C on low-grade glioma (LGG) and glioblastoma multiforme (GBM), as well as its function in glioma stem cells(GSCs). Results: Dysregulated expression of A3s was observed in various human cancer tissues. The prognostic value of A3 expression differed across cancer types, with a link to particularly unfavorable outcomes in gliomas. A3s are associated with the the TME and stemness in multiple cancers. Additionally, we developed an independent prognostic model based on A3s expression, which may be an independent prognostic factor for OS in patients with glioma. Subsequent validation underscored a strong association between elevated A3C expression and adverse prognostic outcomes, higher tumor grades, and unfavorable histology in glioma. A potential connection between A3C and glioma progression was established. Notably, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses implicated A3C in immune system-related diseases, with heightened A3C levels contributing to an immunosuppressive tumor microenvironment (TME) in glioma. Furthermore, in vitro experiments substantiated the role of A3C in sustaining and renewing glioma stem cells, as A3C deletion led to diminished proliferation, invasion, and migration of glioma cells. Conclusion: The A3 family exhibits heterogeneous expression across various cancer types, with its expression profile serving as a predictive marker for overall survival in glioma patients. A3C emerges as a regulator of glioma progression, exerting its influence through modulation of the tumor microenvironment and regulation of stemness.
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Glioblastoma , Glioma , Humanos , Microambiente Tumoral/genética , Glioma/genética , Bioensaio , Biologia Computacional , Citidina DesaminaseRESUMO
Summary.-This study was designed to examine negative pragmatic transfer of the speech act of English compliments by Chinese who learn English as a foreign language and to estimate the correlation between the amount of negative pragmatic transfer and English proficiency of the Chinese learners. Frequencies of students' performance showed that both in the favored compliments and the response strategies, differences were evident between Chinese English learners and native English speakers. This indicated that Chinese learners had trouble with the "slang" or "idioms" of the target language and tended to transfer negatively their L1 pragmatic norms to their L2 communication. Moreover, the favored compliment response strategies used by two groups of Chinese learners--who had different levels of English proficiency--differed, and negative pragmatic transfer decreased as proficiency in English increased.
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Idioma , Fala , Estudantes/psicologia , Transferência de Experiência , Adolescente , Adulto , China , Comparação Transcultural , Feminino , Humanos , Masculino , Multilinguismo , Inquéritos e Questionários , Análise e Desempenho de Tarefas , Vocabulário , Adulto JovemRESUMO
The trend of economic decline for coal cities is a serious threat to the high-quality development of China's economy, and how to improve the environmental total factor productivity (ETFP) has become an urgent issue. Based on the framework of data envelopment analysis (DEA), this paper estimates ETFP using the global Malmquist-Luenberger productivity index (GMLPI). We decompose GMLPI into environmental technical efficiency change (ETEC) and the best practice gap change (BPGC). Then, the difference-in-difference (DID) model combining propensity score matching (PSM) method is used to investigate the effect of the Sustainable Development Plan of National Resource-based Cities (2013-2020) (SDP) aiming to improve ETFP. The results indicate that (1) On average, the GMLPI and BPGC are rising, while the ETEC is decreasing in the observed sample period; the western regions have the biggest BPGC, while the eastern regions have the biggest ETEC; (2) The SDP significantly improves the GMLPI and BPGC but has little effect on the ETEC; Coal cities located in eastern and central regions have policy effect, while the western regions do not have. (3) The SDP affects ETFP through slowing down the economic growth rate and reducing population agglomeration, but promoting the optimization of industrial structure. Those findings have policy implications for improving ETFP and promoting the industrial upgrade of coal cities.
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Carvão Mineral , Eficiência , China , Cidades , Desenvolvimento Econômico , Política Ambiental , Desenvolvimento SustentávelRESUMO
In this study, a series of N-benzyl-2-(5-phenylpyridin-2-yl) acetamide-based derivatives were successfully designed and synthesized as anti-cancer agents. KC-180-2 was screened as a potentially leading compound with dual mechanisms of action: Src signaling and tubulin polymerization inhibition. It efficiently suppressed the proliferation of five cancer cell lines (MDA-MB-231, H446, SKOV-3, HepG2, and HT29), with IC50 values ranging from 5 to 188 nM, especially small-cell lung cancer (SCLC) cells (IC50, 5 nM). Correspondingly, it exerted a significant therapeutic effect on the H446 small-cell lung cancer xenograft model, significantly reducing the volume of tumors without obvious toxicity. Mechanistically, this compound significantly inhibited the polymerization of purified tubulin in vitro, inducing G2/M cell cycle arrest and binding to the kinase catalytic domain of the Src protein, which reduced the phosphorylation of Src. Thus, KC-180-2 is a potential lead compound for the further development of a new anti-tumor drug against SCLC.
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OBJECTIVE: To investigate the predictive role of dynamic changes of plasma biomarkers in patients with viral and mycoplasma community-acquired pneumonia (CAP). METHODS: From January 2020 to June 2020, 141 patients with viral and mycoplasma CAP in People's Hospital of Ningxia Hui Autonomous Region were enrolled. Pneumonia severity index (PSI) scores [grade I-II (PSI score ≤ 70), grade III (PSI score 71-90) and grade IV-V (PSI score ≥ 91)], serum amyloid A (SAA), hypersensitive C-reactive protein (hs-CRP), procalcitonin (PCT), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) on the 1 day after admission were compared between the different pathogens (viral and mycoplasma) or different disease severity. The change in level of SAA, hs-CRP on the third day (Δ3 d = 1 d-3 d) were compared among different disease outcome groups (patients were divided into improved group, stable group and exacerbation group based on PSI scores or lung CT images on the third day). The change in the level of SAA, hs-CRP on the seventh day (Δ7 d = 1 d-7 d) were compared among different disease prognosis groups (patients were divided into survival group and death group based on 28-day survival data). The receiver operating characteristic curve (ROC) were drawn to evaluate the value of SAA in the evaluation of disease and prediction prognosis. RESULTS: The level of SAA in mycoplasma group (43 cases) was significantly higher than that in virus group (98 cases) on the 1 day after admission. There were no significant differences in other plasma biomarkers between the two groups. The more severe the illness, the higher the SAA level on the 1 day after admission. The trends of other plasma biomarkers in the two groups were consistent with SAA. The levels of SAA in the patients with exacerbation of the virus group and mycoplasma group (12 cases, 9 cases) were significantly higher than those of the improved group (57 cases, 26 cases) and the stable group (29 cases, 8 cases). SAA increased gradually in the exacerbation group, decreased gradually in the improved group, and slightly increased in the stable group. ΔSAA3 d were differences among three groups. The change trend of hs-CPR was consistent with SAA. The level of SAA in the death group was higher than that in the survival group on the seventh day. SAA increased in the death group and decreased in survival group with time from hospital admission. There were differences according to ΔSAA7 d between death group and survival group. The change trend of hs-CPR was consistent with SAA. ROC curve showed that the value of SAA was better than hs-CRP in assessing the severity of patients on admission day, and the area under ROC curve (AUC) was respectively 0.777 [95% confidence interval (95%CI) was 0.669-0.886], 0.729 (95%CI was 0.628-0.830). The value of ΔSAA3 d was better than SAA on the third day predicting disease trends, and AUC was respectively 0.979 (95%CI was 0.921-1.000), 0.850 (95%CI was 0.660-1.000). hs-CRP on the third day and Δhs-CRP3 d had no predictive value. Both SAA on the seventh day and ΔSAA7 d have predictive value for prognosis. AUC was respectively 0.954 (95%CI was 0.898-0.993) and 0.890 (95%CI was 0.689-1.000). SAA on the seventh day and ΔSAA7 d were better than hs-CRP on the seventh day. Δhs-CRP7 d have no predictive value. CONCLUSIONS: SAA is a sensitive and valuable indicator for CAP patients with viruses and mycoplasma. Dynamic monitoring of SAA can evaluate the patient's progression, prognosis, and assist diagnosis and treatment.
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Infecções Comunitárias Adquiridas , Mycoplasma , Pneumonia , Proteínas Amiloidogênicas , Biomarcadores , Proteína C-Reativa/análise , Infecções Comunitárias Adquiridas/diagnóstico , Humanos , Mycoplasma/metabolismo , Pneumonia/diagnóstico , Prognóstico , Curva ROC , Estudos RetrospectivosRESUMO
As a key mediator of cell death and inflammation, receptor-interacting protein kinase 1 (RIPK1) responds to a broad set of inflammatory and pro-death stimuli in human diseases. Inhibitors targeting RIPK1 are being investigated for the treatment of a wide range of human diseases, including ulcerative colitis. In the present study, we designed, synthesized, and investigated the anti-necroptosis and RIPK1-inhibition effects of SZ-15-a symmetrical high-molecular-weight (>500 Da) compound. SZ-15 effectively inhibited necroptosis in U937 and HT-29 cells at concentrations of 1 nM and 10 nM, respectively, and SZ-15 at a concentration of 10 nM almost completely blocked RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) protein phosphorylation induced by necrosis inducers. SZ-15 suppressed the pro-necroptosis function of RIPK1 by downregulating the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. The activities of SZ-15 were effectively restricted to the gut: The percent recovery of the parent form of SZ-15 in mouse feces was 85.75%. Nevertheless, SZ-15 was effectively absorbed and detected in colon tissues after 1 h at a concentration of 3335 ± 868 ng/g, indicating that membrane permeability was maintained. SZ-15 alleviated dextran sulfate sodium (DSS)-induced ulcerative colitis in vivo by decreasing TNF-α, IL-1ß, IL-22, and IL-6 mRNA expression in colonic tissues. Our preclinical study describes a novel gut-restricted RIPK1 inhibitor that shows great potential for use in the clinical treatment of ulcerative colitis.