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1.
Blood Adv ; 5(9): 2350-2361, 2021 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-33938941

RESUMEN

In an effort to identify acute myeloid leukemia (AML)-restricted targets for therapeutic development in AML, we analyzed the transcriptomes of 2051 children and young adults with AML and compared the expression profile with normal marrow specimens. This analysis identified a large cohort of AML-restricted genes with high expression in AML, but low to no expression in normal hematopoiesis. Mesothelin (MSLN), a known therapeutic target in solid tumors, was shown to be highly overexpressed in 36% of the AML cohort (range, 5-1077.6 transcripts per million [TPM]) and virtually absent in normal marrow (range, 0.1-10.7 TPM). We verified MSLN transcript expression by quantitative reverse transcription polymerase chain reaction, confirmed cell surface protein expression on leukemic blasts by multidimensional flow cytometry, and demonstrated that MSLN expression was associated with promoter hypomethylation. MSLN was highly expressed in patients with KMT2A rearrangements (P < .001), core-binding factor fusions [inv(16)/t(16;16), P < .001; t(8;21), P < .001], and extramedullary disease (P = .001). We also demonstrated the presence of soluble MSLN in diagnostic serum specimens using an MSLN-directed enzyme-linked immunosorbent assay. In vitro and in vivo preclinical efficacy of the MSLN-directed antibody-drug conjugates (ADCs) anetumab ravtansine and anti-MSLN-DGN462 were evaluated in MSLN+ leukemia cell lines in vitro and in vivo, as well as in patient-derived xenografts. Treatment with ADCs resulted in potent target-dependent cytotoxicity in MSLN+ AML. In this study, we demonstrate that MSLN is expressed in a significant proportion of patients with AML and holds significant promise as a diagnostic and therapeutic target in AML, and that MSLN-directed therapeutic strategies, including ADCs, warrant further clinical investigation.

2.
Clin Nutr ; 40(5): 2630-2639, 2021 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-33933729

RESUMEN

BACKGROUND & AIMS: A large number of clinical studies have shown that intravenous vitamin C supplementation is beneficial for critically ill patients, but current research conclusions are controversial. This meta-analysis included high-quality randomized controlled trials (RCTs) to evaluate the efficacy of intravenous vitamin C in critically ill patients. METHODS: We searched PubMed, EMBASE and the Cochrane Library from inception to August 15, 2020 to identify published reports of RCTs evaluating the role of intravenous vitamin C in critically ill patients. Risk ratios values (RRs) and 95% confidence intervals (CIs) were calculated by random-effects meta-analysis. Trial sequential analysis (TSA), meta-regression, subgroup analyses and sensitivity analyses were also performed. RESULTS: Our meta-analysis included 18 RCTs involving 2001 patients (1005 with vitamin C treatment and 996 control treatment). Intravenous vitamin C administration reduced the intensive care unit (ICU) length of stay (LOS) (MD = -0.36, 95% CI: -0.60 to -0.11, P = 0.004) and hospital LOS (MD = -1.50, 95% CI: -2.64 to -0.35, P = 0.01) but had no significant effect on the longest follow-up mortality, hospital or ICU mortality and change in Sequential Organ Failure Assessment (SOFA) score. TSAs for mortality, ICU and hospital LOS were inconclusive. CONCLUSIONS: Intravenous vitamin C administration may shorten ICU LOS and hospital LOS. It had no effect on mortality and organ failure. All TSAs were inconclusive, and the value of vitamin C for critically ill patients needs to be demonstrated in more high-quality RCTs.

3.
J Clin Invest ; 2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-33945512

RESUMEN

Down syndrome (DS), caused by trisomy of chromosome 21, occurs in 1 of every 800 live births. Early defects in cortical development likely account for the cognitive impairments in DS, although the underlying molecular mechanism remains elusive. Here, we performed histological assays and unbiased single-cell RNA sequencing (scRNA-seq) analysis on cerebral organoids derived from four euploid cell lines and from induced pluripotent stem cells (iPSCs) from three individuals with trisomy 21 to explore cell type-specific abnormalities associated with DS during early brain development. We found that neurogenesis was significantly affected based on diminished proliferation and decreased expression of layer II and IV markers in cortical neurons in the subcortical regions; this may be responsible for the reduced size of the organoids. Furthermore, suppression of the DSCAM-PAK1 pathway which showed enhanced activities in DS) via CRISPR/Cas9, CRISPRi or small-molecule inhibitor treatment reverses abnormal neurogenesis, thereby increasing the size of organoids derived from DS iPSCs. Our study demonstrated that 3D cortical organoids developed in vitro are a valuable model of DS and provided a direct link between dysregulation of the DSCAM-PAK1 pathway and developmental brain defects in DS.

4.
Korean J Parasitol ; 59(2): 167-171, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33951773

RESUMEN

Haemonchosis remains a significant problem in small ruminants. In this study, the assay of recombinase polymerase amplification (RPA) combined with the lateral flow strip (LFS-RPA) was established for the rapid detection of Haemonchus contortus in goat feces. The assay used primers and a probe targeting a specific sequence in the ITS-2 gene. We compared the performance of the LFS-RPA assay to a PCR assay. The LFS-RPA had a detection limit of 10 fg DNA, which was 10 times less compared to the lowest detection limit obtained by PCR. Out of 24 goat fecal samples, LFS-RPA assay detected H. contortus DNA with 95.8% sensitivity, compared to PCR, 79.1% sensitivity. LFS-RPA assay did not detect DNA from other related helminth species and demonstrated an adequate tolerance to inhibitors present in the goat feces. Taken together, our results suggest that LFS-RPA assay had a high diagnostic accuracy for the rapid detection of H. contortus and merits further evaluation.

5.
J Dermatol ; 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33932303

RESUMEN

With the accumulation of clinical practice, sirolimus is now widely viewed as an effective agent in kaposiform hemangioendothelioma (KHE) treatment using a dose based on experience. Therefore, this retrospective research aimed to provide evidence-based suggestions on the most appropriate dose and trough level of sirolimus. All unresectable KHE cases diagnosed at our center from January 2016 to December 2019 were included. Sirolimus monotherapy was initiated when there was no sign of Kasabach-Merritt phenomenon (KMP) at a dose of 0.8 mg/m2 twice a day in order to keep the trough level at 5-20 ng/mL. Patients' clinical information, tumor volume change, trough level fluctuation, and complication occurrence were all recorded. Efficacy represented by tumor shrinkage speed and safety manifested by complication grades were compared between different trough level groups (5-10 vs. 10-15 vs. >15 ng/mL). Twenty-one patients (10 girls and 11 boys) were enrolled. There were eight patients in the 5-10 ng/mL group, seven in the 10-15 ng/mL group, and six in the more than 15 ng/mL group. Trough level over 10 ng/mL manifested better efficacy in tumor shrinkage (t-test, p = 0.011) while a level over 15 ng/mL had no further benefit in efficacy (t-test, p = 0.65). In addition, tumors at a central location reacted better to sirolimus (t-test, p = 0.022). No significant differences were observed in complication occurrence among different concentrations, although boys seemed to be at higher risk of more severe complications (>grade II, χ2 -test, p = 0.009, odds ratio = 4.52, range = 1.20-17.24). It proved to be most efficacious in the management of KHE at a trough level between 10 and 15 ng/mL. Such concentration was safe and well tolerated.

6.
Opt Lett ; 46(9): 2047-2050, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33929415

RESUMEN

Phase measuring deflectometry is a powerful measuring method of complex optical surfaces that captures the reflected fringe images associated with a displaying screen and calculates the normal vectors of the surface under test (SUT) accordingly. The captured images are usually set conjugate to the SUT, which in turn makes the screen defocused. As a result, the blurring effect caused by the defocus and aberrations of the off-axis catadioptric imaging system can severely degrade the phases solved from the blurred images. In order to correct the phase errors, the space-variant point spread functions (PSFs) are modeled using a skew-normal function. The phase bias is estimated by forward convolution between the captured images and the PSF models. Demonstrated with a highly curved aspheric surface, the measurement accuracy can be improved by three times.

7.
J Food Sci ; 2021 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-33885160

RESUMEN

Grape varieties are directly related to the quality and sales price of table grapes and consumed products (raisin, wine, grape juice, etc.). To satisfy the identification requirements of rapid, accurate, and nondestructive detection, an improved denoising algorithm based on ensemble empirical mode decomposition (EEMD) and discrete wavelet transform (DWT) is proposed to couple with the hyperspectral image (HSI) of grape varieties in this study. First, the hyperspectral data of grape varieties are collected by using HSI instrument, and denoised by the proposed EEMD-DWT and other denoising algorithms. CARS-SPA (competitive adaptive reweighed sampling coupled with successive projections algorithm) is introduced to select the effective wavelengths and a discriminative model is constructed by using support vector machine (SVM). Finally, Monte Carlo experiments verified that EEMD-DWT was an effective and powerful spectra denoising method, and the SVM model constructed by combining with CARS-SPA had an excellent identification accuracy (99.3125%). The results suggested that the key wavelengths selected by using CARS-SPA and EEMD-DWT could be an alternative to the deal with HSI, and its potential to become a method for identifying grape varieties. PRACTICAL APPLICATION: Traditional grape varieties identification methods are destructive and time consuming. Therefore, HSI technology is applied to realize fast and nondestructive identification of grape varieties in this study. The research results indicate that it is feasible to combine HSI technology with machine learning algorithm to discriminate grape varieties. It is of great significance for grape grading and the promotion of excellent varieties, and also provides reference for grape industry producers to identify grape varieties quickly and accurately.

8.
J Int Med Res ; 49(4): 300060521995273, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33866841

RESUMEN

OBJECTIVE: To examine the clinical effects of revision endoscopic frontal sinus surgery (RESS) through modified agger nasi (MAN)-middle turbinate resection on refractory chronic rhinosinusitis (CRS). METHODS: We reviewed 156 patients who were treated for refractory CRS from February 2012 to August 2014. These patients had been diagnosed with refractory CRS by computed tomography and endoscopy and had received several surgical and medical treatments in the past, but their condition had not been cured. They were divided into the observation group (RESS through MAN-middle turbinate resection, n = 78) and the control group (endoscopic sinus surgery, n = 78). Complete or partial control of the patient's symptoms and signs suggested that the treatment was effective, and no improvement in the symptoms and signs indicated that the treatment was ineffective. RESULTS: The 6-month treatment efficacy rate was significantly higher in the observation group (91.03%) than in the control group (71.79%). The observation group had a significantly lower complication rate (7.69%) and recurrence rate (3.85%) than the control group (17.95% and 12.82%, respectively). CONCLUSION: RESS through MAN-middle turbinate resection together with adequate perioperative preparation has a significant effect on the outcome of refractory CRS and is worthy of clinical promotion.


Asunto(s)
Endoscopía/métodos , Seno Frontal/cirugía , Sinusitis Frontal/cirugía , Procedimientos Quírurgicos Nasales/métodos , Rinitis/cirugía , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Seno Frontal/diagnóstico por imagen , Sinusitis Frontal/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Reoperación , Estudios Retrospectivos , Rinitis/diagnóstico por imagen , Resultado del Tratamiento , Cornetes Nasales/diagnóstico por imagen , Cornetes Nasales/cirugía
9.
J Biol Chem ; 296: 100257, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33837735

RESUMEN

Mycobacterium tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase, was identified inhibiting Mtb PheRS at Ki ∼ 0.73 ± 0.06 µM. The inhibition mechanism was studied with enzyme kinetics, protein structural modeling, and crystallography, in comparison to a PheRS inhibitor of the noted phenyl-thiazolylurea-sulfonamide class. The 2.3-Å crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl-pyridinylphenyl group occupies the phenylalanine pocket, whereas a piperidine-piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bisubstrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the in vitro growth of Mtb H37Rv at ∼24 µM, and the potency of PF-3845 increased against an engineered strain Mtb pheS-FDAS, suggesting on target activity in mycobacterial whole cells. PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound.

10.
Pediatr Cardiol ; 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33856496

RESUMEN

Knowing the normal values of left ventricular (LV) systolic synchronicity in the early neonatal period is very important for understanding myocardial function. This retrospective study analyzed data of 105 newborns who were examined using real-time 3-dimensional echocardiography (RT3DE). The time to the point of minimal regional systolic volume (Tmsv) was measured from volume-time curves in each segment. Standard deviation (SD) and maximal difference (Dif) of Tmsv were calculated from 16 (6 basal/6 mid/4 apical), 12 (6 basal/6 mid), and 6 (basal) LV segments with the corresponding parameters adjusted for the R-R interval. Influences of age, sex, gestational age, birth weight, and heart rate on parameters were explored. Data showed no significant difference among Tmsv-16-SD, Tmsv-12-SD, and Tmsv-6-SD. A strong correlation was found between Tmsv-6-SD and Tmsv-6-Dif (r = 0.83, P < 0.001), Tmsv-12-SD and Tmsv-6-SD (r = 0.77, P < 0.001), and Tmsv-12-Dif and Tmsv-6-Dif (r = 0.76, P < 0.001) and a moderate correlation was found between Tmsv-16-SD and Tmsv-16-Dif (r = 0.66, P < 0.001), Tmsv-6-SD and Tmsv-12-Dif (r = 0.62, P < 0.001), and Tmsv-12-SD and Tmsv-6-Dif (r = 0.61, P < 0.001). Heart rate correlated negatively with Tmsv (r = - 0.03 to - 0.11, P < 0.004-0.000), but had no effect on parameters adjusted for %R-R. Age, sex, gestational age, and birth weight did not affect any of these parameters. Tmsv-Dif and Tmsv-SD measured from 16 segments using RT3DE are useful as possible parameters for evaluating LV systolic synchronicity in normal newborns.

11.
Artículo en Inglés | MEDLINE | ID: mdl-33808290

RESUMEN

Exploring spatio-temporal patterns of disease incidence can help to identify areas of significantly elevated or decreased risk, providing potential etiologic clues. The study uses the retrospective analysis of space-time scan statistic to detect the clusters of COVID-19 in mainland China with a different maximum clustering radius at the family-level based on case dates of onset. The results show that the detected clusters vary with the clustering radius. Forty-three space-time clusters were detected with a maximum clustering radius of 100 km and 88 clusters with a maximum clustering radius of 10 km from 2 December 2019 to 20 June 2020. Using a smaller clustering radius may identify finer clusters. Hubei has the most clusters regardless of scale. In addition, most of the clusters were generated in February. That indicates China's COVID-19 epidemic prevention and control strategy is effective, and they have successfully prevented the virus from spreading from Hubei to other provinces over time. Well-developed provinces or cities, which have larger populations and developed transportation networks, are more likely to generate space-time clusters. The analysis based on the data of cases from onset may detect the start times of clusters seven days earlier than similar research based on diagnosis dates. Our analysis of space-time clustering based on the data of cases on the family-level can be reproduced in other countries that are still seriously affected by the epidemic such as the USA, India, and Brazil, thus providing them with more precise signals of clustering.


Asunto(s)
Brasil , China/epidemiología , Ciudades , Análisis por Conglomerados , Humanos , India , Estudios Retrospectivos , Análisis Espacio-Temporal
12.
Nat Neurosci ; 24(5): 746-752, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33821000

RESUMEN

Serotonin (5-HT) is a phylogenetically conserved monoamine neurotransmitter modulating important processes in the brain. To directly visualize the release of 5-HT, we developed a genetically encoded G-protein-coupled receptor (GPCR)-activation-based 5-HT (GRAB5-HT) sensor with high sensitivity, high selectivity, subsecond kinetics and subcellular resolution. GRAB5-HT detects 5-HT release in multiple physiological and pathological conditions in both flies and mice and provides new insights into the dynamics and mechanisms of 5-HT signaling.

13.
Bioorg Med Chem Lett ; 42: 128057, 2021 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-33892105

RESUMEN

A pair of stereoisomers of new 4,5-dihydroxypiperine was isolated from P. retrofractum and showed profound activity on AlCl3-induced dementia. In order to determine their absolute configurations and biological activities, all four possible stereoisomers of 4,5-dihydroxypiperine were synthesized from piperidine by Sharpless asymmetric dihydroxylation and Mitsunobu reaction. Their absolute configurations were established as (4R,5R) (1), (4S,5S) (2), (4S,5R) (3) and (4R,5S) (4) by NMR, optical rotation and CD spectra. It is note that only compound 4 improved behavioral disorder in AlCl3-induced dementia. Accordingly, the pair of stereoisomers isolated from P. retrofractum was determined to be (4S,5S) and (4R,5S)-isomers (2 and 4). The ratio of the epimers was present as 1:0.7 (4:2).

14.
Metabolism ; 120: 154779, 2021 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-33895182

RESUMEN

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed and diagnosed based on modified criteria. However, evidence for the risks of developing subclinical atherosclerosis with MAFLD transitions according to its new definition has never been reported. METHODS: Using data from a community-based cohort, 6232 participants aged 40 years or older were included and were followed up for a median of 4.3 years during 2010-2015. Participants were categorized into four groups (stable non-MAFLD, MAFLD regressed to non-MAFLD, non-MAFLD progressed to MAFLD, and stable MAFLD). Subclinical atherosclerosis was defined as elevated carotid intima-media thickness (CIMT), elevated brachial-ankle pulse wave velocity (ba-PWV), or microalbuminuria. RESULTS: Compared with the stable non-MAFLD category, participants who progressed to MAFLD at follow-up visit had a 1.356-fold increased risk of developing elevated CIMT [odds ratio (OR) = 1.356; 95% confidence interval (CI) = 1.134-1.620], and a 1.458-fold increased risk of incident microalbuminuria (OR = 1.458; 95% CI = 1.034-2.056) after adjustment for confounders, respectively. In addition, participants with stable MAFLD showed 17.6%, 32.4%, and 35.4% increased risks of developing elevated CIMT, elevated ba-PWV and microalbuminuria, respectively. Compared with the stable MAFLD category, participants with MAFLD and low probability of fibrosis at baseline who regressed to non-MAFLD at follow-up visit had a 29.4% decreased risk of developing elevated CIMT (OR = 0.706; 95% CI = 0.507-0.984), a 43.1% decreased risk of developing elevated ba-PWV (OR = 0.569; 95% CI = 0.340-0.950), but was not significantly associated with incident microalbuminuria (OR = 0.709; 95% CI = 0.386-1.301). The decreased risks attributed to MAFLD regression were more evident in participants without diabetes or dyslipidemia, as well as in those with 0-1 metabolic risk abnormalities, respectively. CONCLUSIONS: MAFLD was significantly associated with higher risks of developing subclinical atherosclerosis. Moreover, the regression of MAFLD might modify the risks of developing subclinical atherosclerosis, especially among those with low probability of fibrosis or less metabolic risk abnormalities. Since 40% of baseline participants with missing data on MAFLD measurement at follow-up were excluded, the conclusions should be speculated with caution.

15.
Aging (Albany NY) ; 13(7): 10075-10086, 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33818417

RESUMEN

OBJECTIVE: To examine the association between stage 1 hypertension defined by the 2017 American College of Cardiology and American Heart Association (ACC/AHA) guideline and risk of developing arterial stiffness. METHODS: During 2010-2015, 4595 adults aged ≥40 years without cardiovascular disease were followed up for a median of 4.3 years. BP levels at baseline were categorized into normal, elevated, stage 1 hypertension, and stage 2 hypertension. The development of arterial stiffness was defined as a normal brachial-ankle pulse wave velocity (ba-PWV) at baseline and an increased ba-PWV at follow-up. RESULTS: Compared with participants with normal BP, participants with stage 1 hypertension had a 1.48-fold increased risk of developing arterial stiffness [odds ratio (OR) =2.48; 95% confidence interval (CI) =1.59-3.85] after adjustment for cardiovascular risk factors. The association was more evident in adults aged 40-59 years (OR =4.08; 95% CI =2.06-8.08) than that in those aged ≥60 years (OR =1.47; 95% CI =0.81-2.67). A systolic BP 130~139 mmHg was significantly associated with arterial stiffness independent of diastolic BP (OR =2.90; 95% CI =1.86-4.52). Stage 1 hypertension either at baseline or at follow-up was associated with increased risks compared with normal BP at both baseline and follow-up. CONCLUSIONS: The 2017 ACC/AHA stage 1 hypertension was significantly associated with higher risks of arterial stiffness.

17.
J Int Med Res ; 49(4): 3000605211004388, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33874775

RESUMEN

OBJECTIVE: Endometriosis is a common disease in women of childbearing age, leading to sexual dysfunction or loss of libido. We aimed to evaluated the effect of endometriosis on women's sexual function. METHODS: We performed a prospective case-control study to determine the effect of endometriosis on women's sexual function using a self-administered questionnaire from September 2017 to August 2018. The simplified Chinese version of the Female Sexual Function Index (FSFI) was used to assess sexual function. RESULTS: We found that sexual function of women in the endometriosis group (n=77) in all dimensions was significantly lower compared with that in the control group (n=63). The total FSFI score in patients was 25.5, which tended to be lower than that in the control group (26.7). Sexual arousal, sexual pain, and satisfaction were significantly different between the two groups. Sexual arousal and sexual pain scores were significantly lower in the endometriosis group than in the control group at the ages of 31 to 40 years. CONCLUSION: Women with endometriosis suffer from sexual dysfunction, especially those aged 31 to 40 years. Our findings suggest that the quality of sexual life in this subpopulation needs to be improved.

18.
J Bacteriol ; 2021 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-33875545

RESUMEN

Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in the biogenesis of Gram-negative bacterial lipoproteins which play crucial roles in bacterial growth and pathogenesis. We demonstrate that Lgt depletion in a clinical uropathogenic Escherichia coli strain leads to permeabilization of the outer membrane and increased sensitivity to serum killing and antibiotics. Importantly, we identify G2824 as the first described Lgt inhibitor that potently inhibits Lgt biochemical activity in vitro and is bactericidal against wild-type Acinetobacter baumannii and E. coli strains. While deletion of the major outer membrane lipoprotein, lpp, leads to rescue of bacterial growth after genetic depletion or pharmacologic inhibition of the downstream type II signal peptidase, LspA, no such rescue of growth is detected after Lgt depletion or treatment with G2824. Inhibition of Lgt does not lead to significant accumulation of peptidoglycan-linked Lpp in the inner membrane. Our data validate Lgt as a novel antibacterial target and suggest that, unlike downstream steps in lipoprotein biosynthesis and transport, inhibition of Lgt may not be sensitive to one of the most common resistance mechanisms that invalidate inhibitors of bacterial lipoprotein biosynthesis and transport.ImportanceAs the emerging threat of multidrug-resistant (MDR) bacteria continues to increase, no new classes of antibiotics have been discovered in the last fifty years. While previous attempts to inhibit the lipoprotein biosynthetic (LspA) or transport (LolCDE) pathways have been made, most efforts have been hindered by the emergence of a common mechanism leading to resistance; namely, the deletion of the major Gram-negative outer membrane lipoprotein, lpp Our unexpected finding that inhibition of Lgt is not susceptible to lpp deletion-mediated resistance uncovers the complexity of bacterial lipoprotein biogenesis and the corresponding enzymes involved in this essential outer membrane biogenesis pathway, and potentially points to new antibacterial targets in this pathway.

19.
Int J Nanomedicine ; 16: 2735-2749, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33859475

RESUMEN

Purpose: Nanocarriers, with a high drug loading content and good safety, to achieve desirable therapeutic effect are always the goals for industry and research. Methods and Results: In the present study, we developed a docetaxel loaded poly-2-oxazoline polymer micellar system which employed poly-2-butyl-2 oxazoline and poly-2-methyl-2 oxazoline as the hydrophobic chain and hydrophilic chain, respectively. This micellar system achieves a high load up to 25% against the docetaxel, and further demonstrates an IC50 as low as 40% of the commercialized docetaxel injection in vitro and a double maximum tolerated dose in MCF-7 cells in vivo. Conclusion: The high drug loading content, superior safety, and considerable anti-cancer activity make this newly developed docetaxel loaded poly(2-oxazoline) micelle go further in future clinical research.

20.
Mar Drugs ; 19(4)2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33806251

RESUMEN

The von Willebrand factor type D (VWD) domain in vitellogenin has recently been found to bind tetrodotoxin. The way in which this protein domain associates with tetrodotoxin and participates in transporting tetrodotoxin in vivo remains unclear. A cDNA fragment of the vitellogenin gene containing the VWD domain from pufferfish (Takifugu flavidus) (TfVWD) was cloned. Using in silico structural and docking analyses of the predicted protein, we determined that key amino acids (namely, Val115, ASP116, Val117, and Lys122) in TfVWD mediate its binding to tetrodotoxin, which was supported by in vitro surface plasmon resonance analysis. Moreover, incubating recombinant rTfVWD together with tetrodotoxin attenuated its toxicity in vivo, further supporting protein-toxin binding and indicating associated toxicity-neutralizing effects. Finally, the expression profiling of TfVWD across different tissues and developmental stages indicated that its distribution patterns mirrored those of tetrodotoxin, suggesting that TfVWD may be involved in tetrodotoxin transport in pufferfish. For the first time, this study reveals the amino acids that mediate the binding of TfVWD to tetrodotoxin and provides a basis for further exploration of the molecular mechanisms underlying the enrichment and transfer of tetrodotoxin in pufferfish.

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