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1.
Brain Inform ; 8(1): 23, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34725741

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative brain pathology formed due to piling up of amyloid proteins, development of plaques and disappearance of neurons. Another common subtype of dementia like AD, Parkinson's disease (PD) is determined by the disappearance of dopaminergic neurons in the region known as substantia nigra pars compacta located in the midbrain. Both AD and PD target aged population worldwide forming a major chunk of healthcare costs. Hence, there is a need for methods that help in the early diagnosis of these diseases. PD subjects especially those who have confirmed postmortem plaque are a strong candidate for a second AD diagnosis. Modalities such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) can be combined with deep learning methods to diagnose these two diseases for the benefit of clinicians. RESULT: In this work, we deployed a 3D Convolutional Neural Network (CNN) to extract features for multiclass classification of both AD and PD in the frequency and spatial domains using PET and SPECT neuroimaging modalities to differentiate between AD, PD and Normal Control (NC) classes. Discrete Cosine Transform has been deployed as a frequency domain learning method along with random weak Gaussian blurring and random zooming in/out augmentation methods in both frequency and spatial domains. To select the hyperparameters of the 3D-CNN model, we deployed both 5- and 10-fold cross-validation (CV) approaches. The best performing model was found to be AD/NC(SPECT)/PD classification with random weak Gaussian blurred augmentation in the spatial domain using fivefold CV approach while the worst performing model happens to be AD/NC(PET)/PD classification without augmentation in the frequency domain using tenfold CV approach. We also found that spatial domain methods tend to perform better than their frequency domain counterparts. CONCLUSION: The proposed model provides a good performance in discriminating AD and PD subjects due to minimal correlation between these two dementia types on the clinicopathological continuum between AD and PD subjects from a neuroimaging perspective.

2.
IUCrJ ; 8(Pt 6): 973-979, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34804549

RESUMO

SARS-CoV-2 emerged at the end of 2019 to cause an unprecedented pandemic of the deadly respiratory disease COVID-19 that continues to date. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and is therefore an important drug target. Understanding the catalytic mechanism of Mpro, a cysteine protease with a catalytic site comprising the noncanonical Cys145-His41 dyad, can help in guiding drug design. Here, a 2.0 Šresolution room-temperature X-ray crystal structure is reported of a Michaelis-like complex of Mpro harboring a single inactivating mutation C145A bound to the octapeptide Ac-SAVLQSGF-CONH2 corresponding to the nsp4/nsp5 autocleavage site. The peptide substrate is unambiguously defined in subsites S5 to S3' by strong electron density. Superposition of the Michaelis-like complex with the neutron structure of substrate-free Mpro demonstrates that the catalytic site is inherently pre-organized for catalysis prior to substrate binding. Induced fit to the substrate is driven by P1 Gln binding in the predetermined subsite S1 and rearrangement of subsite S2 to accommodate P2 Leu. The Michaelis-like complex structure is ideal for in silico modeling of the SARS-CoV-2 Mpro catalytic mechanism.

3.
Chin Med J (Engl) ; 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732662

RESUMO

BACKGROUND: Microglia plays an indispensable role in the pathological process of sleep deprivation (SD). Here, the potential role of microglial CX3C-chemokine receptor 1 (CX3CR1) in modulating the cognition decline during SD was evaluated in terms of microglial neuroinflammation and synaptic pruning. In this study, we aimed to investigat whether the interference in the microglial function by the CX3CR1 knockout affects the CNS's response to SD. METHODS: Middle-aged wild-type (WT) C57BL/6 and CX3CR1-/- mice were either subjected to SD or allowed normal sleep (S) for 8 h to mimic the pathophysiological changes of middle-aged people after staying up all night. After which, behavioral and histological tests were used to explore their different changes. RESULTS: CX3CR1 deficiency prevented SD-induced cognitive impairments, unlike WT groups. Compared with the CX3CR1-/- S group, the CX3CR1-/- SD mice reported a markedly decreased microglia and cellular oncogene fos density in the dentate gyrus (DG), decreased expression of pro-inflammatory cytokines, and decreased microglial phagocytosis-related factors, whereas increased levels of anti-inflammatory cytokines in the hippocampus and a significant increase in the density of spines of the DG were also noted. CONCLUSIONS: These findings suggest that CX3CR1 deficiency leads to different cerebral behaviors and responses to SD. The inflammation-attenuating activity and the related modification of synaptic pruning are possible mechanism candidates, which indicate CX3CR1 as a candidate therapeutic target for the prevention of the sleep loss-induced cognitive impairments.

4.
Front Physiol ; 12: 691867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34744757

RESUMO

Aims: The underlying mechanism of diabetic enteropathy, a common complication of type 1 diabetes, remains unclear. Store-operated Ca2+ entry (SOCE) is a ubiquitous type of Ca2+ influx involved in various cellular functions. Here, we show that SOCE-related stromal interaction molecule 1 (STIM1) and Orai1 participate in inappropriate cellular Ca2+ homeostasis, augmenting agonist-induced small intestinal smooth muscle contraction and small bowel transit speed in a mouse model of type 1 diabetes. Methods and Results: We used small interfering (si)RNA to suppress STIM1 and Orai1 proteins, and employed intracellular Ca2+, small intestinal contraction and intestinal transit speed measurement to investigate the functional change. We found that SOCE activity and Orai1 and STIM1 expression levels of small intestinal smooth muscle were significantly increased in cells cultured in high glucose medium or in diabetic mice. Gastrointestinal transit speed and SOCE-mediated contractions were markedly increased in diabetic mice; Knocking down Orai1 or STIM1 with siRNA rescued both alterations in diabetic mice. However, the Orai1-large conductance Ca2+-activated K+ (BKCa) channel interaction was decreased in diabetic mice, and suppressing Orai1 expression or inhibiting the BKCa channel increased agonist-induced small intestinal contractions in normal mice. Conclusion: We concluded that the increased SOCE caused by excessive STIM1 and Orai1 expression and decreased Orai1-BKCa interaction augmented small intestinal smooth muscle contraction and accelerated small bowel transit speed in diabetic mice. This finding demonstrates a pathological role for SOCE in diabetic enteropathy and provides a potential therapeutic target for diabetic enteropathy.

5.
Methods Enzymol ; 659: 219-240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34752287

RESUMO

Neutron scattering is a powerful technique for determining the structure and dynamics of biological materials in a variety of environmental conditions. A distinguishing property of the neutron is its sensitivity to detecting hydrogen and distinguishing it from its isotope deuterium. This enables unique types of experiments that take advantage of this differential sensitivity called isotopic contrast variation. Using this approach, the chemistry of the system is not changed, but the visibility of individual sample components can be tuned by varying the deuterium content of the system under investigation. Deuterated proteins are commonly produced in bacterial systems that are adapted to growth in D2O minimal media. To maximize the yield of deuterium-labeled protein and efficiently utilize D2O and occasionally the deuterated substrate, fed-batch processes are routinely used to maximize biomass production without compromising cell viability. A step-by-step procedure will be described along with a case study of the production of deuterated green fluorescent protein. Limitations of the process will also be discussed.

6.
Front Endocrinol (Lausanne) ; 12: 712200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659110

RESUMO

Objectives: This study investigated the clinical efficacy and safety of metformin hydrochloride sustained-release (SR) tablet (II) produced by Dulening and the original metformin hydrochloride tablet produced by Glucophage in the treatment of type 2 diabetes mellitus (T2DM). Methods: This randomized, open and parallel controlled clinical trial consecutively recruited a total of 886 patients with T2DM in 40 clinical centers between May 2016 and December 2018. These patients were randomly assigned to the Dulening group (n=446), in which patients were treated with Dulening metformin SR tablets, and the Glucophage group (n=440), in which patients were treated with Glucophage metformin tablets, for 16 weeks. The changes in the levels of glycated hemoglobin (HbAc1) and fasting blood glucose (FBG) as well as weight loss were compared between these two groups. Also, the overall incidence of adverse drug reactions (ADRs) and the incidence of ADR of the gastrointestinal system observed in patients of these two groups were also compared. Results: There were no significant differences in demographic and basal clinical characteristics between these two groups. The Dulening and Glucophage groups showed comparable levels of decrease in HbA1c levels, FBG and weight loss after 12-week treatment (all p>0.05). The Dulening group had a significantly lower overall incidence of ADRs as well as gastrointestinal ADR than the Glucophage group. Conclusions: Metformin SR tablets (II) and the original metformin tablets exhibit similar therapeutic efficacy in the treatment of T2DM, but metformin SR tablets (II) has the significantly lower incidence of ADRs than the original metformin tablets.

7.
Ying Yong Sheng Tai Xue Bao ; 32(10): 3415-3427, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34676702

RESUMO

Daxing'an Mountains is one of regions in China with the most significant climate change. Larix gmelinii and Pinus sylvestris var. mongolica are the most important species in this area. The study of their radial growth response to climate change would provide a scientific basis for predicting the dynamics of boreal forests under climate change. A total of 451 tree-ring cores of L. gmelinii and P. sylvestris var. mongolica were collected from six sites in the Daxing'an region, and 12 standard chronologies were established. We compared the tree growth trend since 1900, and analyzed their response to the climate factor in each site using Pearson correlation analysis. Effects of temperature and precipitation on the annual radial growth of L. gmelinii and P. sylvestris var. mongolica were investigated by linear mixed models. The time stability of the relationship between two species growth-climate was compared by moving correlation. The results showed that the radial growth of L. gmelinii was negatively correlated with mean temperature in March and positively correlated with precipitation in the previous winter and July of current year. The radial growth of P. sylvestris var. mongolica was positively correlated with temperature in August and precipitation in the growing season (from May to September) of current year. Snow in winter played an important role in promoting the radial growth of L. gmelinii, whereas precipitation in summer limited the radial growth of P. sylvestris var. mongolica. The responses of L. gmelinii and P. sylvestris var. mongolica to climate change were significantly different, which affected tree growth, species composition, and spatial distribution in the boreal forests.


Assuntos
Larix , Pinus sylvestris , China , Mudança Climática , Árvores
8.
Res Sq ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34642689

RESUMO

Direct-acting antivirals for the treatment of COVID-19, which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), are needed to complement vaccination efforts. The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral proliferation. In addition, PLpro dysregulates the host immune response by cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host proteins. As a result, PLpro is a promising target for inhibition by small-molecule therapeutics. Here we have designed a series of covalent inhibitors by introducing a peptidomimetic linker and reactive electrophilic "warheads" onto analogs of the noncovalent PLpro inhibitor GRL0617. We show that the most promising PLpro inhibitor is potent and selective, with activity in cell-based antiviral assays rivaling that of the RNA-dependent RNA polymerase inhibitor remdesivir. An X-ray crystal structure of the most promising lead compound bound covalently to PLpro establishes the molecular basis for protease inhibition and selectivity against structurally similar human deubiquitinases. These findings present an opportunity for further development of potent and selective covalent PLpro inhibitors.

9.
ACS Appl Mater Interfaces ; 13(42): 50005-50016, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34637269

RESUMO

Practical applications of carbon anodes in high-power potassium-ion batteries (PIBs) were hampered by their limited rate properties, due to the sluggish K+ transport kinetics in the bulk. Constructing convenient ion/electron transfer channels in the electrode is of great importance to realize fast charge/discharge rates. Here, cross-linked porous carbon nanofibers (inner porous carbon nanotubes and outer soft carbon layer) modified with oxygen-containing functional groups were well designed as anodes to realize robust de-/potassiation kinetics. The novel anode delivered excellent rate capabilities (107 mAh g-1 at 20 A g-1 and 78 mAh g-1 at 40 A g-1) and superior cycling stability (76% capacity retention after 14,000 cycles at 2 A g-1). In situ XRD measurement, in situ Raman spectra, and galvanostatic intermittent titration verified its surface-dominated potassium storage behavior with fast de-/potassiation kinetics, excellent reversibility, and rapid ion/electron transport. Moreover, theoretical investigation revealed that the carboxyl groups in the carbon offered additional capacitive adsorption sites for K+, thus significantly enhancing the reversible capacity. Surprisingly, a full cell using the anode and perylene-3,4,9,10-tetracarboxylic dianhydride cathode achieved an outstanding power density of 23,750 W kg-1 and superior fast charge/slow discharge performance.

10.
Adv Mater ; : e2104150, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617334

RESUMO

Organic carbonyl electrode materials have shown great prospects for rechargeable batteries in view of their high capacity, flexible designability, and sustainable production. However, organic carbonyl electrode materials still suffer from unsatisfactory electrochemical performance, which is highly relevant to their redox processes. Herein, an in-depth understanding on redox processes and the correlated electrochemical performance of organic carbonyl electrode materials is provided. The redox processes discussed mainly involve molecular structure evolution (intermediates), crystal structure evolution (phase transition), and charge storage mechanisms. The properties of intermediates can affect voltage, cycling stability, reversible capacity, and rate performance of batteries. Moreover, the reversible capacity/cycling stability and rate performance would be also influenced by phase transition and charge storage mechanisms (diffusion- or surface-controlled), respectively. To accelerate the practical applications of organic carbonyl electrode materials, future work should focus on developing more in situ or operando characterization techniques and further understanding the intrinsic relationships between redox processes and performance. It is hoped that the work discussed herein will stimulate more attention to the detailed redox processes and their correlations with the performance of organic carbonyl electrode materials in rechargeable batteries.

11.
Neurol Sci ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34709479

RESUMO

OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disorder whose main symptoms are muscle weakness and fatigue. Irisin is a novel skeletal muscle-derived myokine participating in several physiological and pathological processes. The initial objective of the project was to explore serum levels of irisin in patients with MG, as well as its correlation with disease severity. METHODS: We retrospectively evaluated serum levels of irisin in 77 MG patients and 57 healthy controls (HCs) by enzyme-linked immunosorbent assay. Further, clinical parameters were measured properly. RESULTS: Serum irisin levels were significantly elevated in MG patients compared with HCs (p < 0.001). Furthermore, serum irisin levels were associated with the myasthenia gravis activities of daily living score in ocular myasthenia gravis (OMG) patients (r = 0.476, p = 0.004), but there was no relationship to be considered of any relevant value in generalized myasthenia gravis (GMG) patients. Acetylcholine receptor antibody-positive MG patients had higher serum irisin levels compared with HCs. Thymoma, endotracheal intubation, or intensive care unit treatments subsequently were not found to have effect on serum levels of irisin, but tendencies of increase were observed in negative ones. CONCLUSIONS: Serum irisin levels were elevated in patients with MG, suggesting its possible involvement in MG. And irisin is expected to be a signal to evaluate the activities of daily living of OMG patients, while its effect needs further study.

12.
Artigo em Inglês | MEDLINE | ID: mdl-34699184

RESUMO

Zn anodes have gained intensive attention for their environmental-friendliness and high volumetric capacity but are limited by their severe dendrite formation. Understanding the initial nucleation behavior is critical for manipulating the uniform deposition of Zn. Herein, the allometric growth and dissolution of Zn in the initial nucleation and early stages are visualized with in situ atomic force microscopy in aqueous ZnCl2 electrolytes. Zn nuclei grow via a horizontal radial direction and dissolve reversibly in a top-down process. The critical nucleation radius and density are dependent on the electrolyte concentration of ZnCl2, namely, the initial nucleus size is proportional to the ratio of surface free energy between deposited Zn and the electrolyte and overpotentials for Zn electrodeposition, and the density is inversely proportional to the cube of this ratio. This investigation provides guidelines for regulating uniform metal electrodeposition and yields benefits for the development of anode-free batteries.

13.
J Med Chem ; 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34705466

RESUMO

Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (Mpro) is an established drug target for the design of protease inhibitors. We performed a structure-activity relationship (SAR) study of noncovalent compounds that bind in the enzyme's substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of Mpro complexed with Mcule-5948770040 (compound 1), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of 1. In vitro enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on Mpro inhibition, showing that (1) maintaining correct geometry of an inhibitor's P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups.

14.
Can J Physiol Pharmacol ; 99(11): 1184-1190, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34612711

RESUMO

Genistein, an isoflavonoid that can inhibit protein tyrosine kinase (PTK) phosphorylation, has been shown to play pivotal roles in the signal transduction pathways of hypoxic disorders. In this study, we established a rat model of isolated beating atrium and investigated the regulator role of genistein and its downstream signaling pathways in acute hypoxia-induced atrial natriuretic peptide (ANP) secretion. Radioimmunoassay was used to detect the ANP content in the atrial perfusates. Western blot analysis was used to determine the protein level of hypoxia-inducible factor 1α (HIF-1α), and GATA4 in the atrial tissue. The results showed that acute hypoxia substantially promoted ANP secretion, whereas this effect was partly attenuated by the PTKs inhibitor genistein (3 µM). By Western blotting analysis, we found that hypoxia-induced increase in phosphorylation of Akt and transcriptional factors, including HIF-1α, were also reversed by genistein. The perfused HIF-1α inhibitors rotenone (0.5 µM) or CAY10585 (10 µM) plus genistein significantly abolished the enhanced ANP section induced by hypoxia. Additionally, the perfused PI3K/Akt agonist insulin-like growth factor 1 (30 µM) also abolished ANP secretion induced by genistein and inhibited expression of HIF-1α. In summary, our data suggested that acute hypoxia markedly increased ANP secretion by PTKs through the phosphoinositide-3 kinase (PI3K)/HIF-1α dependent pathway.

15.
Signal Transduct Target Ther ; 6(1): 369, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697295

RESUMO

The lung is the prophylaxis target against SARS-CoV-2 infection, and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen. In this study, we develop a safe and cost-effective platform to express neutralizing antibody in the lung with replicating mRNA basing on alphavirus replicon particle (VRP) delivery system, to prevent SARS-CoV-2 infections. First, a modified VEEV replicon with two subgenomic (sg) promoters was engineered to translate the light and heavy chains of antibody simultaneously, for expression and assembly of neutralizing anti-SARS-CoV-2 antibody CB6. Second, the feasibility and protective efficacy of replicating mRNA against SARS-CoV-2 infection were demonstrated through both in vitro and in vivo assays. The lung target delivery with the help of VRP system resulted in efficiently block SARS-CoV-2 infection with reducing viral titer and less tissue damage in the lung of mice. Overall, our data suggests that expressing neutralizing antibodies in the lungs with the help of self-replicating mRNA could potentially be a promising prophylaxis approach against SARS-CoV-2 infection.


Assuntos
Alphavirus , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/terapia , Replicon , SARS-CoV-2/metabolismo , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/genética , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/genética , COVID-19/genética , COVID-19/metabolismo , Chlorocebus aethiops , Cricetinae , Feminino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , SARS-CoV-2/genética , Células Vero
16.
Eur J Med Chem ; 226: 113896, 2021 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624825

RESUMO

Targeting neddylation pathway has been recognized as an attractive anticancer therapeutic strategy, thus discovering potent and selective neddylation inhibitors is highly desirable. Our work reported the discovery of novel cinnamyl piperidine compounds and their antitumor activity in vitro and in vivo. Among these compounds, compound 4g was identified as a novel neddylation inhibitor and decreased the neddylation levels of cullin 1, cullin 3 and cullin 5. Mechanistic studies demonstrated that compound 4g could inhibit the migration ability of gastric cancer cells and induce apoptosis partly mediated by the Nrf2-Keap1 pathway. Furthermore, in vivo anti-tumor studies showed that 4g effectively inhibited tumor growth without obvious toxicity. Collectively, the cinnamyl piperidine derivatives could serve as new lead compounds for developing highly effective neddylation inhibitors for gastric cancer therapy.

17.
J Int Med Res ; 49(10): 3000605211051225, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34670424

RESUMO

OBJECTIVE: To evaluate the prevalence of type 2 diabetes mellitus (T2DM) with chronic kidney disease (DM-CKD) and identify the associated factors in patients attending primary hospitals in Anhui Province, China. METHODS: A multi-stage sampling method was used to collect the demographic information, general clinical data, and details of the kidney disease of patients in 2019 through a questionnaire survey, physical examination, and laboratory examination. RESULTS: A total of 1067 patients with T2DM were studied, of whom 345 had chronic kidney disease (CKD; 32.33%); 18.8%, 12.2%, 58.0%, 9.9% and 1.2% of the participants had stages 1 to 5 CKD. Fifty-point-three percent of the participants were female and they were 59 ± 11.3 years old. Multivariate regression analysis revealed that age, systolic blood pressure, the duration of diabetes, hyperlipidaemia, and smoking were associated with DM-CKD. The duration of diabetes was positively associated with body mass index, 2-hour postprandial glucose, fasting blood glucose concentration, glycosylated haemoglobin, total cholesterol concentration and triglyceride concentration. CONCLUSIONS: The incidence of DM-CKD is relatively high in primary hospitals in Anhui Province. Appropriate preventive and therapeutic measures should be instituted according to the age, the duration of diabetes, sex, hypertension, smoking habits, and lipidaemia of patients.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Idoso , China/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Feminino , Hospitais , Humanos , Pessoa de Meia-Idade , Prevalência
18.
Bioorg Med Chem ; 47: 116358, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34479103

RESUMO

Bruton tyrosine kinase (BTK) is a key kinase in the B cell antigen receptor signal transduction pathway, which is involved in the regulation of the proliferation, differentiation and apoptosis of B cells. BTK has become a significant target for the treatment of hematological malignancies and autoimmune diseases. Ibrutinib, the first-generation BTK inhibitor, has made a great contribution to the treatment of B cell malignant tumors, but there are still some problems such as resistance or miss target of site mutation. Therefore, there is an imperative need to develop novel BTK inhibitors to overcome these problems. Besides, proteolysis targeting chimera (PROTAC) technology has been successfully applied to the development of BTK degradation agents, which has opened a fresh way for the BTK targeted treatment. This paper reviews the biological function of BTK, the discovery and development of BTK targeted drugs as a promising cancer therapy. It mainly reviews the binding sites and structural characteristics of BTK, structure-activity relationships, activity and drug resistance of BTK inhibitors, as well as potential treatment strategies to overcome the resistance of BTK, which provides a reference for the rational design and development of new powerful BTK inhibitors.

19.
Biochem Biophys Res Commun ; 578: 7-14, 2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34520980

RESUMO

Ubiquitin-conjugating enzyme E2S (UBE2S), an important E2 enzyme in the process of ubiquitination, has exhibited oncogenic activities in various malignant tumors. However, it remains unknown whether UBE2S plays a role in urinary bladder cancer (UBC) development. In the current study, our data confirmed UBE2S upregulation in UBC. In vitro and in vivo experiments demonstrated that UBE2S knockdown resulted in attenuated proliferation and enhanced apoptosis, which was inverse to the phenotypes with UBE2S overexpression. Gain and loss of function assays confirmed that UBE2S exerts oncogenic activities in UBC by mediating the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we discovered that this UBE2S-modulated carcinogenic mechanism was in the consequence of directly targeting tuberous sclerosis 1 (TSC1), which is the upstream inhibitor of mTOR signaling for ubiquitous degradation. Taken together, this study demonstrated that UBE2S is a carcinogen in UBC and promotes UBC progression by ubiquitously degrading TSC1. This consequently mediates the activation of the mTOR pathway, suggesting a potential therapeutic regimen for UBC by targeting the newly identified UBE2S/TSC1/mTOR axis.

20.
Artigo em Inglês | MEDLINE | ID: mdl-34491893

RESUMO

Cells of bacterial strains G9T and 7MK23T, isolated from forest soil samples collected from the Dinghushan Biosphere Reserve, Guangdong Province, PR China, were Gram-stain-negative, aerobic and rod-shaped. Strain G9T was motile with single polar flagellum and grew at 12-37 °C (optimum, 28 °C), pH 4.5-8.0 (optimum, pH 6.0-7.5) and in the presence of 0-3.5 % NaCl (optimum, 1.5%, w/v); while strain 7MK23T was non-motile and grew at 12-42 °C (optimum, 28-33 °C), pH 2.5-8.5 (optimum, pH 4.5-6.5) and NaCl levels of 0-1.0 % (optimum, 0-0.5 %, w/v). Phylogenetic analysis based on 16S rRNA gene sequences revealed that both isolates fell within the cluster of the genus Dyella. The closely related species (with a 16S rRNA gene sequence similarity >98.65%) of strain G9T were Dyella terrae JS14-6T (99.0 %), D. kyungheensis THG-B117T (98.8 %) and D. amyloliquefaciens DHC06T (98.7 %) while that of strain 7MK23T were D. mobilis DHON07T (99.2 %) and D. flava DHOC52T (99.1 %), but the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strains G9T, 7MK23T and the closely related Dyella species listed above were in the ranges of 77.5-83.8 % and 22.0-27.0 %, much lower than the species demarcation lines of 95.5 and 70 %, respectively. Phylogenomic analyses using UBCG and Phylophlan also supported that these two strains represent two novel species of Dyella. The major fatty acids of strain G9T were iso-C15 : 0, iso-C17 : 1 ω9c and iso-C17 : 0 while that of strain 7MK23T were iso-C15 : 0 and anteiso-C15 : 0. Ubiquinone-8 was the only respiratory quinone detected in both strains. The polar lipids of strain G9T consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, and several unknown phospholipids, aminophospholipids, aminolipids and lipid while strain 7MK23T contained phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine and several unknown phospholipids and aminophospholipids. The DNA G+C contents of strains G9T and 7MK23T were 64.7 and 63.4 mol%, respectively. On the basis of 16S rRNA gene sequence phylogenetic and phylogenomic analyses as well as phenotypic data obtained, we propose that strains G9T and 7MK23T represent two novel species of the genus Dyella, for which the names Dyella telluris sp. nov. (type strain G9T=KACC 21725T=GDMCC 1.2132T) and Dyella acidiphila sp. nov. (type strain 7MK23T=KCTC 62739T=GDMCC 1.1446T) are proposed.


Assuntos
Florestas , Gammaproteobacteria/classificação , Filogenia , Microbiologia do Solo , Técnicas de Tipagem Bacteriana , Composição de Bases , China , DNA Bacteriano/genética , Ácidos Graxos/química , Gammaproteobacteria/isolamento & purificação , Hibridização de Ácido Nucleico , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
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