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1.
Mar Drugs ; 19(6)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208540

RESUMO

Marine biomass is a treasure trove of materials. Marine polysaccharides have the characteristics of biocompatibility, biodegradability, non-toxicity, low cost, and abundance. An enormous variety of polysaccharides can be extracted from marine organisms such as algae, crustaceans, and microorganisms. The most studied marine polysaccharides include chitin, chitosan, alginates, hyaluronic acid, fucoidan, carrageenan, agarose, and Ulva. Marine polysaccharides have a wide range of applications in the field of biomedical materials, such as drug delivery, tissue engineering, wound dressings, and sensors. The drug delivery system (DDS) can comprehensively control the distribution of drugs in the organism in space, time, and dosage, thereby increasing the utilization efficiency of drugs, reducing costs, and reducing toxic side effects. The nano-drug delivery system (NDDS), due to its small size, can function at the subcellular level in vivo. The marine polysaccharide-based DDS combines the advantages of polysaccharide materials and nanotechnology, and is suitable as a carrier for different pharmaceutical preparations. This review summarizes the advantages and drawbacks of using marine polysaccharides to construct the NDDS and describes the preparation methods and modification strategies of marine polysaccharide-based nanocarriers.

2.
Talanta ; 233: 122578, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215070

RESUMO

Hydrogen peroxide (H2O2), one of the most important reactive oxygen species (ROS), can be generated endogenously in the liver and has been deemed as a biomarker for evaluating drug-induced liver injury (DILI). Therefore, it is highly crucial to construct an effective method for detecting H2O2 in the liver in order to evaluate DILI. Herein, a neoteric dual-signal colorimetric fluorescent probe XH-2 for sensing hydrogen peroxide was engineered and synthesized. Borate was grafted as a specific recognition group onto the fluorophore XH-1 (ΦF = 0.34) to establish a structurally unprecedented probe. The experimental results manifested that probe XH-2 (ΦF = 0.15) was able to detect hydrogen peroxide using a fluorescence method with an excellent linear range of 0-140 µM (R2 = 0.9974) and an especially low detection limit of 91 nM (λex/em = 570 nm/638 nm). In addition, the probe was capable of monitoring hydrogen peroxide in a colorimetric manner with the linear range of 0-110 µM (R2 = 0.9965). Furthermore, the specificity, applicability in serum (98.6-109.1%) and indirect detection of glucose make the probe XH-2 a superior probe. Based on its low cytotoxicity, the probe was successfully applied to monitor endogenous/exogenous hydrogen peroxide and quantitatively determine the concentration level of hydrogen peroxide at a range of 0-120 µM (R2 = 0.9859) in HepG2 cells. Ultimately, the probe could effectively monitor the level of hydrogen peroxide during DILI in HepG2 cells.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Preparações Farmacêuticas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colorimetria , Corantes Fluorescentes , Humanos , Peróxido de Hidrogênio
3.
Talanta ; 233: 122592, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34215081

RESUMO

Mitochondria, the main source of energy of cells, play a significant role in aerobic respiration process. Some stimulants can result in changes of mitochondrial microenvironments such as viscosity, pH and polarity. Abnormal changes of mitochondrial viscosity have been shown to relate to pathological activities and diseases. Therefore, it is critical to focus our attention on mitochondrial viscosity under different conditions. A novel organic water-soluble molecule called JLQL that could monitor viscosity was conveniently synthesized in two steps. The near-infrared sensor with maximum emission wavelength of 734.6 nm and the Stokes shift of 134.6 nm consisted of a fluorophore and a mitochondrial-targeting moiety as an acceptor group; the two were connected by a double bond. The fluorescence intensity of the sensor increased 175 times with the enhancement of viscosity of a PBS-glycerol system. The interference of other microenvironments such as pH and polarity and other interference analytes could be reduced. JLQL could sensitively and selectively differentiate different levels of mitochondrial viscosity induced by monensin or nystatin. Furthermore, the probe may provide an attractive way to monitor real-time changes of viscosity during mitophagy. Possessing the above properties, JLQL can potentially be employed as a powerful tool for the observation of mitochondrial viscosity.


Assuntos
Corantes Fluorescentes , Água , Células HeLa , Humanos , Mitocôndrias , Viscosidade
4.
Int J Biol Sci ; 17(9): 2338-2347, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239360

RESUMO

Rationale: Growth differentiation factor-8 (GDF-8), also known as myostatin, belongs to the transforming growth factor-beta (TGF-ß) superfamily. GDF-8 is expressed in the ovary and regulates various ovarian functions. Ovarian hyperstimulation syndrome (OHSS) is one of the most serious disorders during in vitro fertilization treatment. Aromatase, encoded by the CYP19A1 gene, is the enzyme that catalyzes the final step in estradiol (E2) biosynthesis. It has been demonstrated that high serum E2 levels are associated with the development of OHSS. However, the effects of GDF-8 on aromatase expression and its roles in the pathogenesis of OHSS remain unclear. Methods: The effect of GDF-8 on aromatase expression and the underlying mechanisms were explored by a series of in vitro experiments in primary human granulosa-lutein (hGL) and KGN cells. Rat OHSS model and human follicular fluid samples were used to examine the roles of the GDF-8 system in the pathogenesis of OHSS. Results: We demonstrate that GDF-8 stimulates aromatase expression and E2 production in hGL and KGN cells. In addition, TGF-ß type I receptor ALK5-mediated SMAD2/3 signaling is required for GDF-8-induced aromatase expression and E2 production. Using a rat OHSS model, we show that the aromatase and GDF-8 levels are upregulated in the ovaries of OHSS rats. Blocking the function of ALK5 by the administration of its inhibitor, SB431542, alleviates OHSS symptoms and the upregulation of aromatase. Clinical results reveal that the protein levels of GDF-8 are upregulated in the follicular fluid of OHSS patients. Moreover, the expression of GDF-8 is increased in hGL cells of OHSS patients. Conclusions: This study helps to elucidate the mechanisms mediating the expression of aromatase in human granulosa cells, which may lead to the development of alternative therapeutic approaches for OHSS.

5.
BMC Cancer ; 21(1): 860, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315423

RESUMO

BACKGROUND: The psychometric properties of the simplified Chinese version of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) have not been assessed. Therefore, we aimed to assess its validity, reliability, and responsiveness. PATIENTS AND METHODS: A Chinese version of the PRO-CTCAE and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30) were distributed to 1580 patients from four cancer hospitals in China. Validity assessments included construct validity, measured by Pearson's correlations and confirmatory factor analysis (CFA), and known-groups validity, measured by t-tests. The assessment of reliability included internal consistency, measured by Cronbach's ɑ, and test-retest reliability, measured by the intraclass correlation (ICC). Responsiveness was assessed by standardized response means (SRMs). RESULTS: Data from 1555 patients who completed the instruments were analyzed. The correlations were high between PRO-CTCAE items and parallel QLQ-C30 symptom scales (r > 0.60, p < 0.001), except for fatigue (severity: r = 0.49). Moreover, CFA showed the PRO-CTCAE structure was a good fit with the data (Root Mean Square Error of Approximation = 0.046). Known-groups validity was also confirmed. Cronbach's ɑ of all item clusters were greater than 0.9 and the median test-retest reliability coefficients of the 38 items were 0.85 (range = 0.71-0.91). In addition, the SRMs of PRO-CTCAE items were greater than 0.8, indicating strong responsiveness. CONCLUSION: The simplified Chinese version of the PRO-CTCAE showed good reliability, validity, and responsiveness.

6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(4): 598-604, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34323037

RESUMO

Objective: To investigate the in vitro eradicative effect of self-assembled azithromycin/rhamnolipid nanoparticles (AZI-RHL NPs) on P seudomonas aeruginosa ( P. aeruginosa) biofilm. Methods: AZI-RHL NPs were prepared and characterized. The minimum inhibitory concentration (MIC) of AZI-RHL NPs on planktonic P. aeruginosa was measured by the broth microdilution method. The eradicative effect of AZI-RHL NPs on P. aeruginosa biofilm was evaluated via crystal violet staining and SYTO 9/PI live/dead staining. Fluorescence labeling was used to measure the eradicative effect of NPs on extracellular polymeric substances (EPS). In addition, crystal violet staining was performed to evaluate the inhibitory effect of AZI-RHL NPs on the adhesion of P. aeruginosa on human bronchial epithelial BEAS-2B cells. To investigate the ability of AZI-RHL NPs to penetrate mucus, the interaction between NPs and mucin was measured via particle size changes after co-incubation with mucin solution. Results: The AZI-RHL NPs had a particle size of about 121 nm and were negatively charged on the surface, displaying a high encapsulation efficiency and a high drug loading capacity of 96.72% and 45.08% for AZI, respectively and 99.38% and 53.07% for RHL, respectively. The MIC of AZI-RHL NPs on planktonic P. aeruginosa was half of that of using AZI alone. AZI-RHL NPs displayed the capacity to effectively destroy the biofilm structure and remove the proteins and polysaccharides in EPS, eradicating biofilms in addition to reducing the survival rate of bacteria in the biofilm. AZI-RHL NPs were shown to have inhibited P. aeruginosa adhesion on BEAS-2B cells and prevented the residual bacteria from forming a new biofilm. There was no significant change in the particle size of NPs after co-incubation with mucin solution, indicating a weak interaction between NPs and mucin, and suggesting that NPs could penetrate the mucus and reach the P. aeruginosa infection sites. Conclusion: AZI-RHL NPs were able to effectively enhance the removal of P. aeruginosa biofilm through a four-step strategy of biofilm eradication, including penetrating the mucus, disintegrating the biofilm structure, killing the bacteria dispersed from biofilm, and preventing the adhesion of residual bacteria. We hope that this study will provide a replicable common strategy for the treatment of refractory infections caused by P. aeruginosa and other types of biofilms.


Assuntos
Nanopartículas , Pseudomonas aeruginosa , Antibacterianos/farmacologia , Azitromicina/farmacologia , Biofilmes , Glicolipídeos , Humanos , Testes de Sensibilidade Microbiana
8.
Placenta ; 112: 73-80, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34329970

RESUMO

INTRODUCTION: The human chorionic gonadotropin (hCG) is a dimer consisting of an α subunit and a ß subunit which is encoded by the CGB gene and is unique to hCG. hCG is a hormone mainly synthesized by syncytiotrophoblast cells in the placenta, plays a critical role in stimulating progesterone production that is necessary for maintaining normal pregnancy in the early stage. Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase family which has been shown to regulate various physiological and pathological events. In human chorionic villi and amniotic fluid, amphiregulin (AREG) is reported to be the most abundant EGFR ligand and can stimulate hCG expression. However, the underlying mechanism remains unknown. METHODS: We use BeWo cells, the commonly used cell model for the hCG production of trophoblast cells, as an in vitro model. The effects of AREG on CGB expression and hCG secretion as well as the underlying mechanisms were explored by a series of in vitro experiments. RESULTS: We show that treatment with AREG stimulates CGB expression and hCG secretion. Using pharmacological inhibitors, we show that the stimulatory effects of AREG on CGB expression and hCG secretion are mediated by the EGFR-activated ERK1/2 signaling pathways. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) is upregulated by AREG. Knockdown of ID3 attenuates the AREG-induced upregulation of CGB expression and hCG secretion. DISCUSSION: This study provides important insights into the molecular mechanisms that mediate AREG-induced upregulation of hCG production in human trophoblast cells which may lead to the development of alternative therapeutic approaches for the treatment of placental diseases.

9.
Artigo em Inglês | MEDLINE | ID: mdl-34255470

RESUMO

Durability is an important factor in evaluating the performance of a catalyst. In this work, the spatial protection of the carrier to nanoparticles was considered to improve the durability of the catalyst. It is found that a honeycombed graphene with a three-dimensional (3D)-hierarchical porous structure (3D HPG) can help to reduce the shedding of Pt-Co nanoparticles (Pt-Co NPs) because 3D HPG can form a protective layer to reduce the direct erosion of Pt-Co NPs on the interface by an electrolyte. Then, appropriate oxygen groups were introduced on the 3D reduced hierarchical porous graphene oxide (3D rHPGO) to improve the dispersion of Pt-Co NPs on the surface of the carrier. It was found that the Pt d-band of the catalyst was anchored by π sites of carbonyl of an oxygen group. After optimization, the catalyst (referred to as Pt-Co/3D rHPGO) achieved a 2-fold enhancement in mass activity than that of a commercial Pt/C catalyst. More importantly, after the accelerated durability test (ADT) of 20 000 cycles, the Pt-Co/3D rHPGO catalyst can almost sustain this level of performance, whereas other catalysts showed a comparatively large loss of activity. According to the results, the high durability of Pt-Co/3D rHPGO was attributed to spatial protection of Pt-Co NPs and the defects on the surface allowed the electrolyte to enter. In addition, oxygen groups provided an anchoring effect on nanoparticles. Thus, the Pt-Co/3D rHPGO electrocatalyst exhibited splendid durability, holding a potential to be applied in PEMFC for long-term work.

10.
Mol Brain ; 14(1): 118, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281570

RESUMO

Anxiety disorders are the most common psychiatric disorders, and the change in the activity of the prefrontal cortex (PFC) is considered as the underlying pathological mechanism. Parvalbumin-expressing (PV+) inhibition contributes to the overall activity of the PFC. However, the molecular mechanism underlying the excitation-inhibition imbalance of PV+ neurons in the PFC is unknown. Efnb2 is a membrane-bound molecule that plays an important role in the nervous system through binding the Eph receptor. To investigate whether the loss of Efnb2 in PV+ affects anxiety, we examined the behavior of wild type and Efnb2 in PV+ neurons knockout (KO) mice. We monitored the defensive responses to aversive stimuli of elevated plus maze (EPM) and found that KO mice exhibited obvious fearless and anxiolytic behaviors. To further investigate the underlying regulatory mechanism, we performed RNA sequencing, analyzed the differentially expressed genes (DEGs), and constructed the weighted gene co-expression network analysis (WGCNA). The WGCNA identified 12 characteristic modules. Among them, the MEgreen module showed the most significant correlation with KO mice of EPM stimuli. The Gene Ontology enrichment and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that this was related to the distal axon, Ras signaling pathway and insulin signaling pathway. Furthermore, the whole-cell voltage clamp recordings also proved that Efnb2 gene knock-out could affect synaptic function. Together with the transcriptomic analysis of mice with Efnb2 knockout on PV+ neurons, our findings suggest that Efnb2 gene in the PV+ neuron of PFC may be a crucial factor for fear and anxiety, which provide an insight into anxiety pathophysiology.

11.
BMC Vet Res ; 17(1): 249, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284781

RESUMO

BACKGROUND: Avian pathogenic Escherichia coli (APEC) strains cause infectious diseases in poultry. Resveratrol is extracted from Polygonum cuspidatum, Cassia tora Linn and Vitis vinifera, and displays good antimicrobial activity. The present study aimed to investigate the antibiofilm effect of resveratrol on APEC in vitro. The minimum inhibitory concentration (MIC) of resveratrol and the antibiotic florfenicol toward APEC were detected using the broth microdilution method. Then, the effect of resveratrol on swimming and swarming motility was investigated using a semisolid medium culture method. Subsequently, the minimum biofilm inhibitory concentration (MBIC) and the biofilm eradication rate were evaluated using crystal violet staining. Finally, the antibiofilm activity of resveratrol was observed using scanning electron microscopy (SEM). Meanwhile, the effects of florfenicol combined with resveratrol against biofilm formation by APEC were evaluated using optical microscopy (OM) and a confocal laser scanning microscopy (CLSM). RESULTS: The MICs of resveratrol and florfenicol toward APEC were 128 µg/mL and 64 µg/mL, respectively. The swimming and swarming motility abilities of APEC were inhibited in a resveratrol dose-dependent manner. Furthermore, resveratrol showed a significant inhibitory activity against APEC biofilm formation at concentrations above 1 µg/mL (p < 0.01). Meanwhile, the inhibitory effect of resveratrol at 32 µg/mL on biofilm formation was observed using SEM. The APEC biofilm was eradicated at 32 µg/mL of resveratrol combined with 64 µg/mL of florfenicol, which was observed using CLSM and OM. Florfenicol had a slight eradication effect of biofilm formation, whereas resveratrol had a strong biofilm eradication effect toward APEC. CONCLUSION: Resveratrol displayed good antibiofilm activity against APEC in vitro, including inhibition of swimming and swarming motility, biofilm formation, and could eradicate the biofilm.

12.
ACS Appl Mater Interfaces ; 13(28): 32763-32779, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34235912

RESUMO

Due to a special pathological type of triple-negative breast cancer (TNBC) and the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her 2), targeted therapies are not effective. The lack of effective treatment drugs and insensitivity to the current single-treatment methods are the biggest problems that we face with the TNBC treatment. Therefore, new strategies to achieve selective treatment and further visual efficacy evaluation will be powerful tools against TNBC. Herein, a novel tumor-targeted nanosized ultrasound contrast nanobubble loaded with chlorin e6 (Ce6), metformin (MET), and perfluorohexane (PFH) and covalently connected to the anti-PD-L1 peptide (DPPA-1) in the outer shell was fabricated. When accumulated in acidic tumor tissues, poly(ethylene glycol) (PEG) ligands detach, and DPPA-1 is exposed for programmed death-ligand 1 (PD-L1) targeting and blocking. The released metformin can relieve hypoxia by inhibiting mitochondrial complex I in the tumor microenvironment (TME) and enhance the therapeutic efficacy of Ce6 while synergizing with DPPA-1 by reducing PD-L1 expression. More significantly, photodynamic therapy (PDT) using multifunctional tumor-targeted nanosized ultrasound contrast agents (PD-L1-targeted pH-sensitive chlorin e6 (Ce6) and metformin (MET) drug-loaded phase transitional nanoparticles (Ce6/MET NPs-DPPA-1)) combined with PD-L1 checkpoint blocking can not only reduce tumor-mediated immunosuppression but also produce strong antitumor immunity. This finding provides a new idea for constructing multifunctional TNBC therapeutic nanoagents.

13.
J Cell Physiol ; 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34318927

RESUMO

Epigallocatechin-3-gallate (EGCG) is the most abundant and biologically active catechins extracted from green tea. The health benefits of EGCG have been extendedly studied. Ovarian steroidogenesis plays a pivotal role in maintaining normal reproductive function. Granulosa cells in the ovary are essential for steroid hormone production. To date, the effect of EGCG on steroidogenesis in human granulosa cells remains unclear. In the present study, we examine the physiological concentrations of EGCG on steroidogenesis in a steroidogenic human granulosa-like tumor cell line, KGN. Our results demonstrate that treatment with EGCG upregulates steroidogenic acute regulatory protein (StAR) expression and increases progesterone (P4) production. EGCG does not affect the expression levels of other steroidogenesis-related enzymes, such as P450 side-chain cleavage enzyme, 3ß-hydroxysteroid dehydrogenase, and aromatase. In addition, we identify the expression of 67-kDa laminin receptor (67LR) in KGN cells. Moreover, EGCG-induced StAR expression and P4 production require the 67LR-mediated activation of the PKA-CREB signaling pathway. These results provide a better understanding of the function of EGCG on ovarian steroidogenesis, which may lead to the development of alternative therapeutic approaches for reproductive disorders.

14.
Magn Reson Imaging ; 83: 68-76, 2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34314825

RESUMO

PURPOSE: To assess the MRI performance in differentiating pancreatic ductal adenocarcinomas (PDACs), from solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PNETs) using non-gaussian diffusion-weighted imaging models. METHODS: This was a retrospective study of patients diagnosed with PDACs (01/2015-06/2019) or with PNETs or SPNs diagnosed (01/2011-12/2019) at our hospital. The lesions were randomized 1:1 to the primary and validation cohorts. The regions of interest (ROIs) were manually drawn on each slice at DWI (b = 1500 s/mm2) from 3 T MRI. D (diffusion coefficient), D* (pseudodiffusion coefficient), f (perfusion fraction), distributed diffusion coefficient (DDC), α (diffusion heterogeneity index), mean diffusivity (MD) and mean kurtosis (MK) were obtained. The parameters with largest performance for differentiation were used to establish a diagnostic model. RESULTS: There were 148, 56, and 60 patients with PDAC, PNET, and SPN, respectively. For differentiating PDACs from SPNs, f and MK values were used to establish a diagnostic model with areas under the receiver operating characteristic curves (AUCs) of 0.92 and 0.89 in the primary and validation groups, respectively. For distinguishing PDACs from PNETs, α and MK values were used to establish a diagnostic model with AUCs of 0.87 and 0.86 in the primary and validation groups, respectively. The accuracy rate of the subjective evaluation with the assistance of non-gaussian DWI models for differentiating PDAC from SPNs and PNETs were higher than that of subjective diagnosis alone (P < 0.05). CONCLUSIONS: The non-gaussian DWI models could assist radiologists in accurately differentiating PDACs from PNETs and SPNs.

15.
Cell Signal ; 86: 110089, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34265413

RESUMO

Bone morphogenetic proteins (BMPs) are expressed in different cell types of the human ovarian follicle and play important roles in the regulation of ovarian function. BMP-9, also known as growth differentiation factor-2 (GDF-2), belongs to the transforming growth factor-beta (TGF-ß) superfamily. BMP-9 is mainly synthesized in the liver and secreted into the blood which allows it to regulate various physiological and pathological functions. To date, the expression of BMP-9 in the human ovary and its function in human granulosa cells remains unknown. In the present study, we detect the protein expression of BMP-9 in the human follicular fluid. Using the primary culture of human granulosa-lutein (hGL) cells obtained from patients undergoing in vitro fertilization as a cell model, we show that treatment with BMP-9 downregulates steroidogenic acute regulatory protein (StAR) expression and suppresses progesterone (P4) production. The expression levels of the P450 side-chain cleavage enzyme (P450scc) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) are not affected by BMP-9 treatment. Mechanistically, treatment of hGL cells with BMP-9 activates both SMAD1/5/8 and SMAD2/3 signaling pathways. Blocking the activations of SMAD1/5/8 and SMAD2/3 by pharmacological inhibitors or knockdown of SMAD4 attenuates the inhibitory effects of BMP-9 on StAR expression and P4 production. This study reveals a novel function of BMP-9 in the regulation of ovarian steroidogenesis.

16.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203270

RESUMO

Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell cycle signaling pathways, and is vital for cell proliferation, growth, and repair. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. Cell cycle regulation can be synergistic with chemotherapy in two aspects: inhibition or promotion. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulation strategies. This review presented the mechanism of the commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced. The current collaborative strategies of chemotherapy and cell cycle regulation are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of combination strategies for cancer therapy.

18.
Br J Nutr ; : 1-30, 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34250878

RESUMO

Iodine is an important element in thyroid hormone biosynthesis. Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis (HPT). Excessive iodine leads to elevated thyroid stimulating hormone (TSH) levels, but the mechanism is not yet clear. Type 2 deiodinase (Dio2) is a selenium-containing protease that plays a vital role in thyroid function. The purpose of this study was to explore the role of hypothalamus Dio2 in regulating TSH increase caused by excessive iodine and to determine the effects of iodine excess on thyrotropin-releasing hormone (TRH) levels. Male Wistar rats were randomized into five groups and administered different iodine dosages (folds of physiological dose): normal iodine (NI), 3-fold iodine (3HI), 6-fold iodine (6HI), 10-fold iodine (10HI), and 50-fold iodine (50HI). Rats were euthanized at 4, 8, 12, or 24 weeks after iodine administration. Serum TRH, TSH, total thyroxine (TT4), and total triiodothyronine (TT3) were determined. Hypothalamus tissues were frozen and sectioned to evaluate expression of Dio2, Dio2 activity, and monocarboxylate transporter 8 (MCT8). Prolonged high iodine intake significantly increased TSH expression (p < 0.05), but did not affect TT3 and TT4 levels. Prolonged high iodine intake decreased serum TRH levels in the hypothalamus (p < 0.05). Dio2 expression and activity in the hypothalamus exhibited an increasing trend compared at each time point with increasing iodine intake (p < 0.05). Hypothalamic MCT8 expression was increased in rats with prolonged high iodine intake(p < 0.05). These results indicate that iodine excess affects the levels of Dio2, TRH, and MCT8 in the hypothalamus.

19.
Arthritis Res Ther ; 23(1): 191, 2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34261522

RESUMO

BACKGROUND: We sought to examine the disease course of High Disease Activity Status (HDAS) patients and their different disease patterns in a real-world longitudinal cohort. Disease resolution till Lupus Low Disease Activity State (LLDAS) has been a general treatment goal, but there is limited information on this subset of patients who achieve this. METHODS: All consenting patients of the Monash Lupus Cohort who had at least 12 months of observation were included. HDAS was defined as SLEDAI-2K ≥ 10 ever, and HDAS episode as the period from the first HDAS clinic visit until attainment of LLDAS. We examined the associations of different HDAS patterns with the likelihood of damage accrual. RESULTS: Of 342 SLE patients, 151 experienced HDAS at least once, accounting for 298 HDAS episodes. The majority of HDAS patients (76.2%) experienced Recurrent HDAS (> 1 HDAS visit), and a smaller subset (47.7%) had Persistent HDAS (consecutive HDAS visits for longer than 2 months). Recurrent or Persistent HDAS patients were younger at diagnosis and more likely to experience renal or serositis manifestations; persistent HDAS patients were also more likely to experience neurological manifestations. Baseline SLEDAI greater than 10 was associated with longer HDAS episodes. Recurrent and Persistent HDAS were both associated with an increased likelihood of damage accrual. The total duration of HDAS episode greater than 2 years and experiencing multiple HDAS episodes (≥4) was also associated with an increased likelihood of damage accrual (OR 1.80, 95% CI 1.08-2.97, p = 0.02, and OR 3.31, 95% CI 1.66-13.26, p = 0.01, respectively). CONCLUSION: HDAS episodes have a highly variable course. Recurrent and Persistent HDAS, and longer duration of HDAS episodes, increased the risk of damage accrual. In addition to a major signifier of severity in SLE, its resolution to LLDAS can determine the subsequent outcome in SLE patients.

20.
J Biol Chem ; : 100958, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34274317

RESUMO

Nephrotic syndrome (NS) is a common kidney disorder caused by dysfunction of the glomerular filtration barrier. Some genetic mutations identified in NS patients cause amino acid substitutions of kidney ankyrin repeat-containing (KANK) proteins, which are scaffold proteins that regulate actin polymerization, microtubule targeting and cell adhesion via binding to various molecules, including the kinesin motor protein KIF21A. However, the mechanisms by which these mutations lead to NS are unclear. Here, we unexpectedly found that the eukaryotic translation initiation factor 4A1 (eIF4A1) interacts with an NS-associated KANK2 mutant (S684F) but not the wild-type protein. Biochemical and structural analyses revealed that the pathological mutation induces abnormal binding of eIF4A1 to KANK2 at the physiological KIF21A-binding site. Competitive binding assays further indicated that eIF4A1 can compete with KIF21A to interact with the S684F mutant of KANK2. In cultured mouse podocytes, this S684F mutant interfered with the KANK2/KIF21A interaction by binding to eIF4A1, and failed to rescue the focal adhesion or cell adhesion that had been reduced or morphologically changed by KANK2 knockout. These structural, biochemical, and cellular results not only provide mechanistic explanations for the podocyte defects caused by the S684F mutation, but also show how a gain-of-binding mutation can lead to a loss-of-function effect.

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