Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 966
Filtrar
1.
Biotechnol Lett ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34308525

RESUMO

OBJECTIVES: γ-amino butyric acid (GABA) is a non-protein amino acid, considered a potent bioactive compound. This study focused on biosynthesis of food-grade GABA by immobilized glutamate decarboxylase (GAD) from Lactobacillus plantarum in the rice vinegar and monosodium glutamate (MSG) reaction system. RESULTS: The gene encoding glutamate decarboxylase (GadB) from L. plantarum has been heterologously expressed in Lactococcus lactis and biochemically characterized. Recombinant GadB existed as a homodimer, and displayed maximal activity at 40 °C and pH 5.0. The Km value and catalytic efficiency (kcat/Km) of GadB for L-Glu was 22.33 mM and 62.4 mM-1 min-1, respectively, with a specific activity of 24.97 U/mg protein. Then, purified GadB was encapsulated in gellan gum beads. Compared to the free enzyme, immobilized GadB showed higher operational and storage stability. Finally, 9.82 to 21.48 g/L of GABA have been acquired by regulating the amounts of catalyst microspheres ranging from 0.5 to 0.8 g (wet weight) in 0.8 mL of the designed rice vinegar and MSG reaction system. CONCLUSIONS: The method of production GABA by immobilized GadB microspheres mixed in the rice vinegar and MSG reaction system is introduced herein for the first time. Especially, the results obtained here meet the increased interest in the harnessing of biocatalyst to synthesize food-grade GABA.

2.
Ann Palliat Med ; 10(6): 6367-6378, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34237959

RESUMO

BACKGROUND: Patients in the intensive care unit (ICU) often have serious infections, and anti-infection treatment is vital for these patients. Procalcitonin (PCT) is often used to identify bacterial infections and monitor the effectiveness of anti-infection treatments. This study aims to analyze the current research hotspots of the application of PCT in ICU patients, and to suggest future research directions. METHODS: The Science Citation Index Expanded (SCI-EXPANDED) database in the Web of Science Core Collection (WOSCC) was used as the data source to search literature from 1995 to February 6, 2021. The search strategy was subject term = procalcitonin AND Web of Science categories = Critical Care Medicine. Using CiteSpace software, literature on the application of PCT in ICU patients was analyzed. RESULTS: A total of 1,243 papers, including 665 (53.5%) original articles, 87 (7.0%) reviews, 93 (7.5%) letters, 297 (23.9%) conference abstracts, and 101 (8.1%) other articles, were analyzed. The citation frequency was 40,442, the h-index was 96, and the average number of citations per item was 32.54. Research was mainly from the United States, Germany, France, and Spain, amongst others. The research institutions were mainly Univ Basel Hosp, Univ Pittsburgh, and Univ Hosp Geneva. Authors including Schuetz P made more contributions. Critical Care Medicine, Intensive Care Medicine, and Critical Care were important journals in this field of research. The keywords with the highest frequency were PCT, sepsis, and infection, and the more central ones were PCT, inflammation, septic shock, and C-reactive protein. The keywords with the strongest citation bursts were PCT, cytokine, and serum. CONCLUSIONS: Papers are mainly published in critical care medical journals. The countries, institutions, and authors that carry out research are relatively limited. The current hot spots are still inflammation, infection, and shock, especially the management and prognosis prediction of critically ill patients.


Assuntos
Unidades de Terapia Intensiva , Pró-Calcitonina , Bibliometria , França , Alemanha , Humanos , Espanha , Estados Unidos
3.
Mol Med Rep ; 24(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34278469

RESUMO

Diabetic nephropathy (DN) is a predominant cause of end­stage renal disease. The impairment of the autophagy of human renal tubular epithelial cells (HK­2 cells) is involved in the pathogenic mechanisms of DN. Sirtuin (Sirt)3 regulates the scavenging of damaged organelles and maintains energy balance. The present study aimed to examine the protective effects of Sirt3 on HK­2 cells stimulated by high glucose (HG). HK­2 cells were cultured in normal glucose (NG), HG or hyperosmotic medium. The viability of the HK­2 cells was detected using a Cell Counting Kit­8 assay. The expression and localization of Sirt3 were detected via immunofluorescence. Following transfection with an overexpression plasmid, the expression levels of key components in the Notch homolog 1 (Notch­1)/hairy and enhancer of split­1 (Hes­1) pathway and those of the autophagy­related proteins, Beclin­1, LC­3II and p62, were measured by western blot analysis and reverse transcription­quantitative PCR (RT­qPCR). As the Notch­1/Hes­1 pathway was inhibited, the expression levels of Beclin­1, LC­3II and p62 were also examined at transcriptional and translational level. It was found that prolonged culture in HG medium markedly reduced cell viability compared with the cells cultured in NG or in NG + mannitol, an effect that was aggravated with the increasing duration of culture. HG was capable of inhibiting the expression levels of Beclin­1, LC­3II and Sirt3, and upregulating p62 and the Notch­1/Hes­1 pathway, as verified by western blot analysis and RT­qPCR. The results of immunofluorescence staining revealed that HG decreased Sirt3 expression. Sirt3 reversed the HG­induced inhibition of the expression of Beclin­1 and LC­3II and the upregulation of p62. Moreover, Sirt3 reversed the HG­induced inhibition of the Notch­1/Hes­1 signaling pathway. However, this autophagy­promoting effect of Sirt3 was counteracted by the Notch­1/Hes­1 pathway activator. On the whole, the present study demonstrated that Sirt3 promoted the autophagy of HK­2 cells, at least partly, via the downregulation of Notch­1/Hes­1.

4.
Phys Rev Lett ; 127(2): 020401, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34296907

RESUMO

We investigate whether paradigmatic measurements for quantum state tomography, namely mutually unbiased bases and symmetric informationally complete measurements, can be employed to certify quantum correlations. For this purpose, we identify a simple and noise-robust correlation witness for entanglement detection, steering, and nonlocality that can be evaluated based on the outcome statistics obtained in the tomography experiment. This allows us to perform state tomography on entangled qutrits, a test of Einstein-Podolsky-Rosen steering and a Bell inequality test, all within a single experiment. We also investigate the trade-off between quantum correlations and subsets of tomographically complete measurements as well as the quantification of entanglement in the different scenarios. Finally, we perform a photonics experiment in which we demonstrate quantum correlations under these flexible assumptions, namely with both parties trusted, one party untrusted and both parties untrusted.

5.
Cancer Lett ; 518: 140-151, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34274452

RESUMO

The activating transcription factor 1 (ATF1) has been identified as a vital pathogenic factor in the progression of colorectal cancer (CRC), whiles, the precise regulatory mechanisms remain elusive. Here, we comprehensively characterized the ATF1 cistrome by RNA-seq and ChIP-seq assays in CRC cell lines. As the results, we identified 358 genes differentially regulated and 15,029 ATF1 binding sites and demonstrated that ATF1 was widely involved in major signaling pathways in CRC, such as Wnt, TNF, Jak-STAT. Subsequently, by the expression quantitative trait loci (eQTL) analyses, we found that rs7017386 was associated with the expression of CCAT1 and PVT1 in the Wnt pathway. By a two-stage population study with 6,131 CRC cases and 10,022 healthy controls, we identified the variant was associated with CRC risk. Mechanistically, we found rs7017386 allele-specifically enhanced the binding affinity of ATF1 and promoted the expressions of PVT1 and CCAT1, via forming a long-range chromatin loop. Moreover, those two lncRNAs could synergistically facilitate c-Myc expression to activate the Wnt pathway in CRC progression. Our findings not only demonstrated the transcriptomic profiling of ATF1 in CRC, but also provided important clues for the etiology of CRC.

6.
IEEE Trans Cybern ; PP2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097633

RESUMO

This article investigates the dynamic consensus problem for the discrete-time second-order integrator networked multiagent system with time-varying delay and switching topology, in which the speed of each agent is not required to be synchronized to zero value. Novel consensus protocols using only relative state information are proposed, and sufficient conditions for dynamic consensus are derived. The results show that consensus can be reached for both the case with delay and the case without delay, if the gain is sufficiently small and the union of interaction graphs is scrambling or contains a spanning tree frequently enough as the system evolves. Numerical examples demonstrate the effectiveness of the theoretical results.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34089241

RESUMO

Multidrug-resistant Salmonella Enteritidis (S. Enteritidis) isolates have become a significant threat to public health, and fosfomycin has been proposed as one of the therapeutic antibiotics for serious infections by resistant pathogens. In this study, a total of 501 clinical S. Enteritidis isolates were screened and 14 (2.8%) isolates exhibited resistance to fosfomycin (MIC ≥ 1,024 µg/mL) as well as ceftriaxone (MIC ≥ 128 µg/mL). The fosA3 gene was identified in these 14 isolates. The fosA3 gene that co-transferred with blaCTX-M-55 was observed on the IncFII plasmids with sizes of ~ 78 (n = 7) or ~ 111 (n = 2) kbp in 9 transconjugants. The fosA3-bearing plasmid p12367A is 111,764 bp in length and possessed a typical IncFII backbone. A 7.6-kbp multidrug resistance region (MRR) was identified in p12367A, which was comprised of fosA3 and blaCTX-M-55 genes interspersed with ΔISEcp1 and three copies of IS26. Two typical antibiotic resistance determinants (IS26-orf3-orf2-orf1-fosA3-IS26 and IS26-orf477-blaCTX-M-55 -ΔISEcp1-IS26) shared one IS26 in the MRR. The genetic arrangement of the MRR may have resulted from the stepwise integration of IS26 mobile elements via homologous recombination. Horizontal transfer of IncFII plasmids might contribute to the dissemination of fosA3 and blaCTX-M-55 resistance genes in S. Enteritidis interspecies. These findings underline further challenges for the prevention and treatment of Enterobacteriaceae infections posed by epidemic IncFII plasmids bearing fosA3-blaCTX-M-55 .

8.
J Med Genet ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-34085947

RESUMO

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified. METHODS: An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN. RESULTS: We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45×10-7 for rs2517611 at 6p22.1, p=1.76×10-9 for rs2524182 at 6p21.33 and p=2.17×10-10 for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify TCF19 expression by regulating the binding affinity of the transcription factor SREBF1 to the promoter of TCF19. In addition, experiments revealed that the inhibition of TCF19 may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN. CONCLUSION: These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that TCF19 may function as a putative susceptibility gene for SCCHN.

9.
Environ Pollut ; 287: 117630, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34182385

RESUMO

Bisphenol A (BPA) may induce oxidative stress as well as the toxicity of colon cancer cells. We hypothesized that BPA exposure and interactions with genetic variants might be associated with colorectal cancer (CRC) risk, and the association might be partly mediated by oxidative stress. We measured urinary BPA and three oxidative stress markers [8-iso-prostaglandinF2α (8-isoPGF2α), 8-hydroxydeoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in 275 new CRC cases and 538 healthy controls. A set of 25 genetic variations in 12 candidate DNA repair genes and 5 metabolic enzyme genes were genotyped by Sequenom MassARRAY approach. In multivariable logistic regression, significant positive associations of CRC risk with BPA, 8-OHdG and HNE-MA were observed. Additionally, 8-OHdG, HNE-MA and 8-isoPGF2α were significantly positively associated with BPA (P < 0.05). The mediation analysis showed BPA-associated HNE-MA significantly mediated 11.81% of the effect of BPA on CRC risk. Moreover, BPA was found to interact with ERCC5 rs17655 and rs2296147 (both Pmultiplicative < 0.05) to increase CRC risk. In brief, our results suggested BPA was associated with CRC risk and the positive association of BPA with CRC risk might be partly mediated by the oxidative stress HNE-MA. BPA might interact with ERCC5 rs17655 and rs2296147 to increase CRC risk.

10.
Clin Transl Med ; 11(6): e485, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34185429

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the common gastrointestinal malignancy with an inferior prognosis outcome. DNA replication licensing aberration induced by dysregulation of minichromosome maintenance proteins (MCMs) causes genomic instability and cancer metastasis. SUMOylation modification plays a pivotal role in regulation of genomic integrity, while its dysregulation fueled by preexisting germline variants in cancers remains poorly understood. METHODS: Firstly, we conducted two-stage survival analysis consisting of an exome-wide association study in 904 ESCC samples and another independent 503 ESCC samples. Then, multipronged functional experiments were performed to illuminate the potential biological mechanisms underlying the promising variants, and MCM10 influences the ESCC progression. Finally, we tested the effects of MCM10 inhibitors on ESCC cells. RESULTS: A germline variant rs2274110 located at the exon 15 of MCM10 was identified to be significantly associated with the prognosis of ESCC patients. Individuals carrying rs2274110-AA genotypes confer a poor survival (hazard ratio = 1.61, 95% confidence interval = 1.35-1.93, p = 1.35 × 10-7 ), compared with subjects carrying rs2274110-AG/GG genotypes. Furthermore, we interestingly found that the variant can increase SUMOylation levels at K669 site (Lys[K]699Arg[R]) of MCM10 protein mediated by SUMO2/3 enzymes, which resulted in an aberrant overexpression of MCM10. Mechanistically, aberrant overexpression of MCM10 facilitated the proliferation and metastasis abilities of ESCC cells in vitro and in vivo by inducing DNA over-replication and genomic instability, providing functional evidence to support our population finding that high expression of MCM10 is extensively presented in tumor tissues of ESCC and correlated with inferior survival outcomes of multiple cancer types, including ESCC. Finally, MCM10 inhibitors Suramin and its analogues were revealed to effectively block the metastasis of ESCC cells. CONCLUSIONS: These findings not only demonstrate a potential biological mechanism between aberrant SUMOylation, genomic instability and cancer metastasis, but also provide a promising biomarker aiding in stratifying ESCC individuals with different prognosis, as well as a potential therapeutic target MCM10.

11.
Ann Palliat Med ; 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34154343

RESUMO

BACKGROUND: Patients in the intensive care unit (ICU) often have serious infections, and anti-infection treatment is vital for these patients. Procalcitonin (PCT) is often used to identify bacterial infections and monitor the effectiveness of anti-infection treatments. This study aims to analyze the current research hotspots of the application of PCT in ICU patients, and to suggest future research directions. METHODS: The Science Citation Index Expanded (SCI-EXPANDED) database in the Web of Science Core Collection (WOSCC) was used as the data source to search literature from 1995 to February 6, 2021. The search strategy was subject term = procalcitonin AND Web of Science categories = Critical Care Medicine. Using CiteSpace software, literature on the application of PCT in ICU patients was analyzed. RESULTS: A total of 1,243 papers, including 665 (53.5%) original articles, 87 (7.0%) reviews, 93 (7.5%) letters, 297 (23.9%) conference abstracts, and 101 (8.1%) other articles, were analyzed. The citation frequency was 40,442, the h-index was 96, and the average number of citations per item was 32.54. Research was mainly from the United States, Germany, France, and Spain, amongst others. The research institutions were mainly Univ Basel Hosp, Univ Pittsburgh, and Univ Hosp Geneva. Authors including Schuetz P made more contributions. Critical Care Medicine, Intensive Care Medicine, and Critical Care were important journals in this field of research. The keywords with the highest frequency were PCT, sepsis, and infection, and the more central ones were PCT, inflammation, septic shock, and C-reactive protein. The keywords with the strongest citation bursts were PCT, cytokine, and serum. CONCLUSIONS: Papers are mainly published in critical care medical journals. The countries, institutions, and authors that carry out research are relatively limited. The current hot spots are still inflammation, infection, and shock, especially the management and prognosis prediction of critically ill patients.

12.
Eur J Cancer ; 151: 94-105, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33975060

RESUMO

AIM: This study aimed to identify the functional genes and genetic variants associated with the prognosis of pancreatic ductal adenocarcinoma (PDAC) and reveal the mechanism underlying their prognostic roles. METHODS: First, we implement a two-stage exome-wide association study in a total of 1070 patients to identify the genetic variant correlated with PDAC prognosis. Then we performed fine mapping through bioinformatics analysis and dual-luciferase reporter assays to reveal the causal functional variant and prognostic gene. Next, we established the gene knockdown, knockout, and overexpression cell lines with small interfering RNA, CRISPR/Cas9, and lentivirus, respectively, and investigated the gene function on cell proliferation and migration in vivo and in vitro. Finally, we performed the RNA-seq to elucidate downstream genes and mechanisms altering PDAC prognosis. RESULTS: We identified the CAV1-CAV2 locus tagged by rs8940 was significantly associated with PDAC prognosis, and rs10249656 in the 3'untranslated region of CAV2 was the real functional variant, which upregulated CAV2 expression through abolishing miR-548s binding. We observed upregulated CAV2 in PDAC and the higher expression correlated with worse prognosis. Transient knockdown of CAV2 inhibited PDAC migration without affecting proliferation rate. Knockout of CAV2 suppressed PDAC progression and metastasis, whereas stable overexpression of CAV2 promoted. Overexpressed CAV2 promoted the PDAC progression and metastasis via perturbing genes in the focal adhesion (CCND1, IGTA1, and ZYX) and extracellular matrix organisation (PLOD2, CAST, and ITGA1) pathways mechanically. CONCLUSION: These findings shed light on an important role of CAV2 on PDAC progression and the prognostic impact of its genetic variation.

14.
J Am Soc Nephrol ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952630

RESUMO

BACKGROUND: Identification of target antigens PLA2R, THSD7A, NELL1, or Semaphorin-3B can explain the majority of cases of primary membranous nephropathy (MN). However, target antigens remain unidentified in 15%-20% of patients. METHODS: A multipronged approach, using traditional and modern technologies, converged on a novel target antigen, and capitalized on the temporal variation in autoantibody titer for biomarker discovery. Immunoblotting of human glomerular proteins followed by differential immunoprecipitation and mass spectrometric analysis was complemented by laser-capture microdissection followed by mass spectrometry, elution of immune complexes from renal biopsy specimen tissue, and autoimmune profiling on a protein fragment microarray. RESULTS: These approaches identified serine protease HTRA1 as a novel podocyte antigen in a subset of patients with primary MN. Sera from two patients reacted by immunoblotting with a 51-kD protein within glomerular extract and with recombinant human HTRA1, under reducing and nonreducing conditions. Longitudinal serum samples from these patients seemed to correlate with clinical disease activity. As in PLA2R- and THSD7A- associated MN, anti-HTRA1 antibodies were predominantly IgG4, suggesting a primary etiology. Analysis of sera collected during active disease versus remission on protein fragment microarrays detected significantly higher titers of anti-HTRA1 antibody in active disease. HTRA1 was specifically detected within immune deposits of HTRA1-associated MN in 14 patients identified among three cohorts. Screening of 118 "quadruple-negative" (PLA2R-, THSD7A-, NELL1-, EXT2-negative) patients in a large repository of MN biopsy specimens revealed a prevalence of 4.2%. CONCLUSIONS: Conventional and more modern techniques converged to identify serine protease HTRA1 as a target antigen in MN.

15.
Adv Healthc Mater ; : e2100523, 2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-33963672

RESUMO

The reconstruction of dermal blood vessels is essential for skin regeneration process. However, the lack of vascular structure, insufficient angiogenesis induction, and ineffective graft-host anastomosis of the existing skin substitutes are major bottle-necks for permanent skin replacement in tissue engineering. In this study, the uniform strontium silicate (SS) microcylinders are successfully synthesized and integrated into the biomaterial ink to serve as stable cell-induced factors for angiogenesis, and then a functional skin substitute based on a vascularization-induced biomimetic multicellular system is prepared via a "cell-writing" bioprinting technology. With an unprecedented combination of vascularized skin-mimicking structure and vascularization-induced function, the SS-containing multicellular system exhibits outstanding angiogenic activity both in vitro and in vivo. As a result, the bioprinted skin substitutes significantly accelerate the healing of both acute and chronic wounds by promoting the graft-host integration and vascularized skin regeneration in three animal models. Therefore, the study provides a referable strategy to fabricate biomimetic multicellular constructs with angiogenesis-induced function for regeneration of vascularized complex and hierarchical tissues.

16.
Foodborne Pathog Dis ; 18(7): 489-496, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34037429

RESUMO

Antimicrobial resistance (AMR) is a major public health challenge and spreads through humans, animals, and the environment. Many reports show that AMR genes (ARGs) or phenotypes can be transferred from food animals to humans. However, the level and correlation of AMR in different nodes of the poultry meat supply chain are still poorly understood. Herein, 225 Escherichia coli isolates were recovered from chilled chicken samples from markets (123) and chicken fecal samples from farms (102) in Zhejiang Province, China. The dominant sequence types (STs) were ST155 (8.89%), ST48 (7.56%), and ST10 (7.11%), which are common in chicken and fecal samples. Antimicrobial susceptibility testing (AST) analysis showed that the E. coli isolates from fecal samples and retail chickens were resistant to ampicillin (61.77% and 63.42%, respectively) and trimethoprim (56.87% and 52.85%). Moreover, 36.59% of the E. coli isolates from chilled chickens and 39.22% of the isolates from fecal samples were resistant to three or more antimicrobial agents. A total of 59 ARGs were identified in sequenced E. coli genomes, including the mcr-1 gene involved in colistin resistance. The E. coli from farms and markets could be clustered in the same branch according to core single nucleotide polymorphisms. In addition, toxin genes astA and hlyE were also predicted in 86.5% (32/37) and 13.5% (5/37) of the above genomes, respectively. Taken together, these findings demonstrated that E. coli isolates from markets and farms showed similar AMR patterns, suggesting that E. coli strains in markets may originate from farms.

17.
FASEB J ; 35(6): e21555, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34046947

RESUMO

Preeclampsia (PE) is a life-threatening disease of pregnant women associated with severe hypertension, proteinuria, or multi-organ injuries. Mitochondrial-mediated placental oxidative stress plays a key role in the pathogenesis of PE. However, the underlying mechanism remains to be revealed. Here, we identify Rnd3, a small Rho GTPase, regulating placental mitochondrial reactive oxygen species (ROS). We showed that Rnd3 is down-regulated in primary trophoblasts isolated from PE patients. Loss of Rnd3 in trophoblasts resulted in excessive ROS generation, cell apoptosis, mitochondrial injury, and proton leakage from the respiratory chain. Moreover, Rnd3 overexpression partially rescues the mitochondrial defects and oxidative stress in human PE primary trophoblasts. Rnd3 physically interacts with the peroxisome proliferators-activated receptor γ (PPARγ) and promotes the PPARγ-mitochondrial uncoupling protein 2 (UCP2) cascade. Forced expression of PPARγ rescues deficiency of Rnd3-mediated mitochondrial dysfunction. We conclude that Rnd3 acts as a novel protective factor in placental mitochondria through PPARγ-UCP2 signaling and highlight that downregulation of Rnd3 is a potential factor involved in PE pathogenesis.


Assuntos
Mitocôndrias/patologia , PPAR gama/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Trofoblastos/patologia , Proteína Desacopladora 2/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Feminino , Humanos , Mitocôndrias/metabolismo , Estresse Oxidativo , PPAR gama/genética , Placenta/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Gravidez , Trofoblastos/metabolismo , Proteína Desacopladora 2/genética , Proteínas rho de Ligação ao GTP/genética
18.
Mol Pharm ; 18(6): 2285-2297, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33998814

RESUMO

Cholecystokinin-2 receptor (CCK2R) has been proven to be a specific biomarker for colorectal malignancies. Immunotoxins are a valuable class of immunotherapy agents consisting of a targeting element and a bacterial or plant toxin. Previous work demonstrated that targeting CCK2R is a good therapeutic strategy for the treatment of colorectal cancer (CRC). In the present study, we developed a new version of CCK2R-targeting immunotoxin GD9P using a targeted peptide, GD9, as the binding motif and a truncated Pseudomonas exotoxin A (PE38) as the cytokiller. BALB/c nude mice were treated with different doses of GD9P, and pharmacodynamics, pharmacokinetic, and toxicological data were obtained throughout this study. Compared to the parental immunotoxin rCCK8PE38, GD9P exhibited about 1.5-fold yield, higher fluorescence intensity, and increased antitumor activity against human CRC in vitro and in vivo. The IC50 values of GD9P in vitro ranged from 1.61 to 4.55 nM. Pharmacokinetic studies were conducted in mice with a T1/2 of 69.315 min. When tumor-bearing nude mice were treated with GD9P at doses ≥2 mg/kg for five doses, a rapid shrinkage in tumor volume and, in some cases, complete remission was observed. A preliminary safety evaluation demonstrated a good safety profile of GD9P as a Pseudomonas exotoxin A-based immunotherapy. The therapy in combination with oxaliplatin can increase the antitumor efficacy and reduce the toxic side effects caused by chemotherapy. In conclusion, the data support the use of GD9P as a promising immunotherapy targeting CCK2R-expressing colorectal malignancies.

19.
J Ethnopharmacol ; 277: 114216, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34044076

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii Debeaux, a famous traditional medicinal herb for collapse, rheumatic fever, and painful joints, always raises global concerns about its fatal toxicity from toxic alkaloids when improperly processed. Therefore, it is urgent to clarify the internal molecular mechanism of processing detoxification on Aconitum and develop simple and reliable approaches for clinical application, which is also of great significance to the rational medicinal use of Aconitum. AIM OF THE STUDY: The study aimed at developing a complete molecular mechanism exploration strategy in complex medicinal herb decocting system, clarifying the internal molecular mechanism of processing detoxification on Aconitum, and exploring valid approaches for detoxification. MATERIALS AND METHODS: Aconiti Lateralis Radix Praeparata (Fuzi) was selected as the model for exploring the complex Aconitum detoxification mechanism using an advanced online real-time platform based on extractive electrospray ionization mass spectrometry. The methods realized the sensitive capture of dynamic trace intermediates, accurate qualitative and quantitative analysis, and real-time and long-term monitoring of multi-components with satisfactory accuracy and resistance to complex matrices. RESULTS: Components in the complex Aconitum decocting system were real-timely characterized and fat meat was discovered and verified to directionally detoxify Aconitum while reserving the therapy effect. More importantly, the dynamic detoxification mechanism in the chemically complex Aconitum decoction was molecularly profiled. A novel reaction pathway based on nucleophilic substitution reaction mechanism was proposed. As confirmed by the theoretic calculations at DFT B3LYP/6-31G (d) levels, fatty acids (e.g., palmitic acid) acted as a green, cheap, and high-performance catalyst and promote the decomposition of toxic diester alkaloids to non-toxic and active benzoyl-monoester alkaloids through the discovered mechanism. CONCLUSION: The study exposed a novel detoxification molecular mechanism of Aconitum and provided an effective method for the safe use of Aconitum, which could effectively guide the development of traditional processing technology and compatibility regulation of the toxic herb and had great value to the modernization and standardization development of traditional medicine.

20.
J Ethnopharmacol ; 277: 114233, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34044077

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Viscum comprises approximately 100 species that are mainly distributed across Africa, Asia and Europe. The extracts and preparations of Viscum species are widely used as common complementary and alternative medicines in the treatment of rheumatism and cancer. AIM OF THE REVIEW: This review aims to explore the medicinal properties of twelve species belonging to the genus Viscum for potential therapeutic applications. MATERIALS AND METHODS: We collected online information (including PubMed, CNKI, Google Scholar, and Web of Science) from January 1915 to April 2021 and knowledge from classical books on Chinese herbal medicines available for 12 species of the genus Viscum, including Viscum coloratum (Kom.) Nakai, Viscum album L., Viscum articulatum Burm. f., Viscum liquidambaricola Hayata, Viscum ovalifolium DC., Viscum capitellatum Sm., Viscum cruciatum Sieber ex Boiss., Viscum nudum Danser, Viscum angulatum B.Heyne ex DC., Viscum tuberculatum A.Rich., Viscum multinerve Hayata, and Viscum diospyrosicola Hayata. RESULTS: At least 250 different compounds have been reported across twelve Viscum species, including amino acid and peptides, alkaloids, phenolic acids, flavonoids, terpenoids, carbohydrates, fatty acids, lipids, and other types of compounds. In particular, for Viscum coloratum (Kom.) Nakai and Viscum album L., the plants, preparations, and bioactive components have been thoroughly reviewed. This has allowed to elucidate the role of active components, including lectins, viscotoxins, flavonoids, terpenoids, phenolic acids, and polysaccharides, in multiple bioactivities, such as anti-cancer, anti-rheumatism arthralgia, anti-inflammation, anti-cardiovascular diseases, enhancing immunity, and anti-chemotherapy side effects. We also evaluated quality control methods based on active compounds, in vivo exposure compounds, and discriminated chemical markers. CONCLUSIONS: This is the first report to systematically review the pharmaceutical development history, chemical composition, clinical evidence, pharmacological activity, discriminated chemical markers, in vivo exposure, and quality control on twelve distinct species of Viscum plants with medicinal properties. The significant safety and efficacy, along with the minor side effects are constantly confirmed in clinics. The genus Viscum is thus an important medicinal resource that is worth exploring and developing in future pharmacological and chemical studies.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...