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1.
Clin Exp Rheumatol ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34596022

RESUMO

In the past decade, an increasing number of studies have found a relationship between the occurrence and development of depression and autoimmune diseases, and the high prevalence of depression in patients with connective tissue diseases has also been confirmed. Primary Sjögren's syndrome (pSS) is a chronic autoimmune exocrinopathy characterised by lymphocytic infiltration and exocrine gland destruction. Depression in pSS patients is common, and the factors contributing to this condition are complicated. pSS patients with depression generally have a lower quality of life than pSS patients without depression. Several pathophysiological mechanisms involved in the condition have been proposed in recent years. Thus, in this review, we summarised recent progress on the impact of depression on pSS patients' quality of life, the possible pathogenesis underlying the development of depression in pSS patients and the management of such patients.

2.
Ann Palliat Med ; 10(9): 9792-9799, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34628905

RESUMO

BACKGROUND: To retrospectively analyze the effects of routine treatment and blood purification combined with antibiotics on the extravascular lung water index (EVLWI), inflammatory factors, and treatment outcomes in patients with severe acute pancreatitis (SAP) complicated with acute respiratory distress syndrome (ARDS). METHODS: A total of 131 SAP patients admitted to the intensive care unit of Suzhou Ninth Hospital Affiliated to Soochow University from January 2019 to December 2020 were retrospectively enrolled in this study. Patients were divided into two groups according to the treatment methods. In addition to conventional treatment, 60 patients in group A received continuous blood purification (CBP) treatment and 71 patients in group B did not. The EVLWI, inflammatory factors, remission time of clinical symptoms, curative effect, and patient outcomes were recorded at admission and after 1, 3, 5, and 7 days of treatment. RESULTS: There was a statistically significant difference in the clinical symptom relief time and the clinical efficacy between the two groups of patients (P<0.05). The mortality rate of patients in group A was 3.33%, which was significantly lower than the 14% mortality rate observed in patients in group B (P<0.05). The EVLWI, as well as the C-reactive protein (CRP), interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α levels were significantly lower in group A patients compared to group B patients on day 1, 3, and 7 post-treatment (P<0.05). There was also a significant difference in APACHE II scores between the two groups (P<0.05). The incidence of adverse reactions in group A was 6.7%, which was significantly lower than the 22.5% incidence observed in group B (P<0.05). CONCLUSIONS: Continuous blood purification combined with antibacterial drugs is safe and has a significant effect on the treatment of SAP patient complicated with ARDS, including effectively relieving clinical symptoms and signs, reducing the level of inflammatory factors, and promoting early disease outcomes.


Assuntos
Pancreatite , Síndrome do Desconforto Respiratório , Doença Aguda , Antibacterianos/uso terapêutico , Água Extravascular Pulmonar , Humanos , Pancreatite/tratamento farmacológico , Prognóstico , Síndrome do Desconforto Respiratório/tratamento farmacológico , Estudos Retrospectivos
3.
Mol Brain ; 14(1): 157, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641940

RESUMO

AIM: Growth hormone secretagogue receptor 1a (GHS-R1a) is widely distributed in brain including the hippocampus. Studies have demonstrated the critical role of hippocampal ghrelin/GHS-R1a signaling in synaptic physiology, memory and cognitive dysfunction associated with Alzheimer's disease (AD). However, current reports are inconsistent, and the mechanism underlying memory modulation of GHS-R1a signaling is uncertain. In this study, we aim to investigate the direct impact of selective increase of GHS-R1a expression in dCA1 excitatory/inhibitory neurons on learning and memory. METHODS: Endogenous GHS-R1a distribution in dCA1 excitatory/inhibitory neurons was assessed by fluorescence in situ hybridization. Cre-dependent GHS-R1a overexpression in excitatory or inhibitory neurons was done by stereotaxic injection of aav-hSyn-DIO-hGhsr1a-2A-eGFP virus in dCA1 region of vGlut1-Cre or Dlx5/6-Cre mice respectively. Virus-mediated GHS-R1a upregulation in dCA1 neurons was confirmed by quantitative RT-PCR. Different behavioral paradigms were used to evaluate long-term memory performance. RESULTS: GHS-R1a is distributed both in dCA1 excitatory pyramidal neurons (αCaMKII+) and in inhibitory interneurons (GAD67+). Selective increase of GHS-R1a expression in dCA1 pyramidal neurons impaired spatial memory and object-place recognition memory. In contrast, selective increase of GHS-R1a expression in dCA1 interneurons enhanced long-term memory performance. Our findings reveal, for the first time, a neuronal type-specific role that hippocampal GHS-R1a signaling plays in regulating memory. Therefore, manipulating GHS-R1a expression/activity in different subpopulation of neurons may help to clarify current contradictory findings and to elucidate mechanism of memory control by ghrelin/GHS-R1a signaling, under both physiological and pathological conditions such as AD.

5.
Bioorg Chem ; 116: 105384, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34601294

RESUMO

The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.

6.
J Clin Invest ; 131(17)2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34623332

RESUMO

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

7.
Asian J Surg ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34629266

RESUMO

Severe brainstem hemorrhage is the most intractable type of intracerebral hemorrhage. It is still a challenge for neurosurgeons. The surgical indications for brainstem hemorrhage are still controversial clinically, and there is no uniform standard. The death rate and disability rate of patients are very high, and the prognosis is very poor. A patient with severe brainstem hemorrhage was successfully treated by utilizing the trans-cerebellomedullary fissure approach with lateral ventricular drainage in combination with clinical experience at the hospital where the author worked. The case is being reported for the first time to provide a reference for improving the treatment of brainstem hemorrhage.

8.
Arch Insect Biochem Physiol ; : e21846, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632624

RESUMO

Gomphocerus sibiricus L., the dominant insect species in the alpine and subalpine grassland, overwinters with diapause at egg stage. In this study, cold tolerance and related cryoprotectants of G. sibiricus eggs were investigated. In particular, the supercooling point (SCP), water content, carbohydrates (trehalose, glucose, fructose, glycogen), polyols (glycerol, inositol, sorbitol), fat, and amino acids contents were evaluated at different developmental stages of G. sibiricus eggs collected under natural conditions. The SCPs of eggs were very low (-32.83 to -22.61°C) at mid-diapause. Water content gradually increased during development. The fructose, glycerol, and sorbitol contents were significantly higher in diapausing eggs than in early embryogenesis stage and post-diapause development stage. Glycogen content was high throughout the whole developmental period. The trehalose, glucose, and inositol contents were low during diapause compared to that in early embryogenesis stage and post-diapause development stage. There were no significant differences in the fat content of eggs among all development stages. The total amino acid contents in eggs in the early embryogenesis and at the start of diapause were higher than that in post-diapause eggs. The contents of Glu, Asp, Leu, Pro and Arg during diapause were significantly higher than those during post-diapause development. Results indicate that G. sibiricus eggs have a high supercooling capacity. Successful overwintering can be attributed to the accumulation of glycerol, fructose, sorbitol, and amino acids (Glu, Asp, Leu, Pro and Arg). These findings provide insight into the mechanisms underlying the adaptation of G. sibiricus to cold conditions.

9.
Tumori ; : 3008916211050687, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632867

RESUMO

OBJECTIVE: The expression of cytoskeleton-related protein γ-adducin (ADD3) was abnormally reduced in some tumors. Functional experiments demonstrated that it could inhibit the malignant progression of lung cancer and glioma, whereas the involvement of ADD3 in osteosarcoma was not clear. This study aimed to investigate the role of ADD3 in osteosarcoma and its upstream regulatory mechanisms. METHODS: ADD3 was knocked down by siRNA transfection and the expression level of ADD3 was determined using quantitative real-time PCR assay and Western blot. CCK-8 assay and colony formation were performed to detect the capacity of cell proliferation. Transwell assay and PI and Annexin V-FITC staining were used to determine cell migration and apoptosis, respectively. Luciferase reporter experiment was performed to investigate the interaction between ADD3 and miR-23b-3p. RESULTS: Based on gene silencing assays, we showed that knockdown of ADD3 suppressed apoptosis and promoted the proliferation and migration of osteosarcoma cells, revealing inhibitory effects of ADD3 in osteosarcoma. Luciferase reporter gene assays confirmed that miR-23b-3p could bind to the 3'-UTR of ADD3. Upregulation of miR-23b-3p not only inhibited the expression of ADD3, but also released the tumor suppressive role of ADD3 on the proliferation and migration of osteosarcoma cells. CONCLUSIONS: Our study found that ADD3 functioned as a tumor suppressor gene during osteosarcoma development. The abnormal upregulation of miR-23b-3p targeted the expression of ADD3 and resulted in accelerated osteosarcoma cell proliferation and migration. Thus, the miR-23b-3p/ADD3 axis contributes to the development of osteosarcoma and ADD3 is a key driver of malignancy.

10.
Radiat Oncol ; 16(1): 198, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635145

RESUMO

BACKGROUND: Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. METHODS: We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. RESULTS: All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. CONCLUSIONS: Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.

11.
Artigo em Inglês | MEDLINE | ID: mdl-34636339

RESUMO

In this work, we propose a ferromagnetic Bi2Se3 as a candidate to hold the coexistence of Weyland nodal-line semimetal phases, which breaks the time reversal symmetry. We demonstrate that the type-I Weyl semimetal phase, type-I-, type-II- and their hybrid nodal-line semimetal phases can arise by tuning the Zeeman exchange field strength and the Fermi velocity. Their topological responses under U(1) gauge field are also discussed. Our results raise a new way for realizing Weyl and nodal-line semimetals and will be helpful in understanding the topological transport phenomena in three-dimensional material systems.

12.
J Adv Res ; 33: 241-251, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34603793

RESUMO

Introduction: Arctigenin, derived from Arctium lappa L., has multiple pharmacological activities, including immunoregulatory, anti-diabetic, anti-tumor, and neuroprotective effects. Nevertheless, the potential therapeutic target of arctigenin in modulating inflammation remains undefined. Objectives: In the present study, we identified that arctigenin was a phosphodiesterase-4 (PDE4) selective inhibitor for the first time. Further investigations were performed to fully uncover the effects and mechanism of arctigenin on experimental murine psoriasis model. Methods: Crystal structure determination, PDEs enzyme assay, and isothermal titration calorimetry were included to illustrate the binding specialty, inhibitory effects, and selectivity of arctigenin on PDE4D. The anti-inflammatory effects were conducted in LPS-activated human peripheral blood mononuclear cells (PBMCs) and RAW264.7 cells. Imiquimod-induced murine psoriasis was performed to uncover the therapeutic effects and mechanism of arctigenin in vivo. Results: Arctigenin could bind to the catalytic domain of PDE4D via formation of hydrogen bonds as well as π-π stacking interactions between the dibenzyl butyrolactone of arctigenin and several residues of PDE4D. Accordingly, arctigenin showed prominent anti-inflammation in human PBMCs and murine RAW264.7 cells. PDE4 inhibition by arctigenin resulted in elevation of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylation of cAMP-response element binding protein (CREB), which were largely blocked through intervention of protein kinase A (PKA) activity by H89 treatment or reduction of protein expression by siRNA transfection. Moreover, we first identified that a topical application of arctigenin ameliorated experimental psoriatic manifestations in imiquimod-induced murine psoriasis model by decreasing adhesion and chemotaxis of several inflammatory cells. Further proteomics analysis revealed that arctigenin could rectify the immune dysfunction and hyperactivation of keratinocytes in the inflamed skin microenvironments, which might be largely related to the expression of Keratins. Conclusion: The research provided credible clew that inhibition of PDE4 by arctigenin might function as the potential therapeutic approach for the treatment of psoriasis.

13.
Front Immunol ; 12: 686439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616392

RESUMO

Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-ζ signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR+TCRdeficient human Tregs maintained both Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR+TCRdeficient Tregs did not impair the function of these HLA-A2+ islets, whereas similarly engineered A2-CAR+TCRdeficientCD4+ conventional T cells rejected the islets in less than 2 weeks. A2-CAR+TCRdeficient Tregs delayed graft-versus-host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.

14.
J Biol Chem ; : 101277, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619148

RESUMO

Nucleic acid-sensing pathways play critical roles in innate immune activation through the production of type I interferon (IFN-I) and proinflammatory cytokines. These factors are required for effective anti-tumor immune responses. Pharmacological modulators of the pre-mRNA spliceosome splicing factor 3b subunit 1 (SF3B1) are under clinical investigation as cancer cytotoxic agents. However, potential roles of these agents in aberrant RNA generation and subsequent RNA-sensing pathway activation have not been studied. In this study, we observed that SF3B1 pharmacological modulation using pladienolide B (Plad B) induces production of aberrant RNA species and robust IFN-I responses via engagement of the dsRNA sensor retinoic acid-inducible gene I (RIG-I) and downstream interferon regulatory factor 3 (IRF3). We found that Plad B synergized with canonical RIG-I agonism to induce the IFN-I response. In addition, Plad B induced NF-κB responses and secretion of proinflammatory cytokines and chemokines. Finally, we showed that cancer cells bearing the hotspot SF3B1K700E mutation, which leads to global aberrant splicing, had enhanced IFN-I response to canonical RIG-I agonism. Together, these results demonstrate that pharmacological modulation of SF3B1 in cancer cells can induce an enhanced IFN-I response dependent on RIG-I expression. The study suggests that spliceosome modulation may not only induce direct cancer cell cytotoxicity but also initiate an innate immune response via activation of RNA sensing pathways.

15.
Small ; : e2104459, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622561

RESUMO

With the rapid development of artificial intelligence and neural network computing, the requirement for information storage in computing is gradually increasing. Floating gate memories based on 2D materials has outstanding characteristics such as non-volatility, optical writing, and optical storage, suitable for application in photonic in-memory computing chips. Notably, the optoelectronic memory requires less optical writing energy, which means lower power consumption and greater storage levels. Here, the authors report an optoelectronic memory based on SnS2 /h-BN/graphene heterostructure with an extremely low photo-generated hole tunneling barrier of 0.23 eV. This non-volatile multibit floating gate memory shows a high switching ratio of 106 and a large memory window range of 64.8 V in the gate range ±40 V. And the memory device can achieve multilevel storage states of 50 under a low power light pulses of 0.32 nW and small light pulse width of 50 ms. Thanks to the Fowler-Nordheim tunneling of the photo-generated holes, the optical writing energy of the optoelectronic memory has been successfully reduced by one to three orders of magnitude compared to existing 2D materials-based systems.

16.
Anal Chem ; 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623153

RESUMO

Given the great harm of pesticide residues to the environment and public health, exploring ultrasensitive and low-cost methods for their quantitative analysis becomes intensely necessary. Herein, we proposed a double-functionalized gold nanoparticle (AuNP) probe as a signal amplification immunoassay for the detection of acetochlor (ATC), metolachlor, and propisochlor. The AuNP was modified with IgG and fluorophore-labeled duplex DNA by a polyadenine-based freezing method. The quenched fluorescence can be effectively recovered via duplex-specific nuclease (DSN) with excellent cleaving activity. This approach provided limits of detection (LODs) down to 0.03 ng/mL for ATC, 0.10 ng/mL for metolachlor, 0.14 ng/mL for propisochlor, and 0.08 ng/mL for their mixture. The average recoveries of ATC, metolachlor, and propisochlor were 93.0-106.6% from a corn sample, which are in good agreement with the commercial kit (R2 = 0.9995). This "turn-off" fluorescence immunoassay presents considerable potential in the analysis of chloroacetamide herbicide due to its simple process of probe preparing and ultrahigh sensitivity.

17.
J Org Chem ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34613739

RESUMO

A facile access to highly fused tetracyclic indeno-1,2-benzothiazines has been established via a Rh(III)-catalyzed C-H bond activation and intramolecular annulation cascade between sulfoximides and all-carbon diazo indandiones. This strategy is characterized by the fact that the diazo coupling partners do not require preactivation, along with its high efficiency, broad substrate generality, and facile transformation. Particularly, the highly conjugated tetracyclic products demonstrate good optical properties and can easily enter cells to emit bright fluorescence for live cell imaging.

18.
Circ Res ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34615369

RESUMO

Rationale: Plaque instability remains poorly understood and new therapeutic approaches to reduce plaque rupture and subsequent clinical events are of great interest. Recent studies revealed an important role of phenotypic switching of smooth muscle cells (SMC) in controlling plaque stability, including extracellular matrix (ECM) deposition. Objective: The aim of this study was to elucidate the role of hyaluronan (HA) derived from SMC-HA synthase 3 (Has3), in phenotypic switching and plaque stability in an animal model of atherosclerosis. Methods and Results: A mouse line with SMC-specific deletion of Has3 and simultaneous SMC lineage tracing (eYFP) on an Apoe-/- background was used. Lineage tracing of SMC with eYFP revealed that SMC-specific deletion of Has3 significantly increased the number of galectin-3 (LGALS3+) "transition-state" SMC and decreased alpha-smooth muscle actin (ACTA2+) SMC. Notably, SMC-Has3 deletion led to significantly increased collagen deposition and maturation within the fibrous cap (FC) and the whole lesion, as evidenced by Picrosirius red staining and LC-PolScope analysis. Single-cell RNA sequencing (scRNA-seq) of brachiocephalic artery (BCA) lesions demonstrated that the loss of SMC-Has3 enhanced the transition of SMC to an Lgals3+, ECM-producing phenotype with elevated acute-phase response gene expression. Experiments using cultured murine aortic SMC revealed that blocking cluster of differentiation-44 (CD44), an important HA binding receptor, recapitulated the enhanced acute-phase response and synthesis of fibrous ECM. Conclusions: These studies provide evidence that the deletion of SMC-Has3 results in an ECM-producing "transition state" SMC phenotype (characterized by LGALS3+ expression), likely via reduced CD44 signaling, resulting in increased collagen formation and maturation, an index consistent with increased plaque stability.

19.
Oncol Rep ; 46(6)2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34617574

RESUMO

Propofol is a commonly used anesthetic with controversial effects on cancer cells. A growing number of studies have demonstrated that low concentrations of propofol are associated with tumor suppression and when used as an intravenous anesthesia improved recurrence­free survival rates for many cancers, but deeper insights into its underlying mechanism are needed. The study detailed herein focused upon the effect of propofol on pancreatic cancer cells and the mechanism by which propofol reduces A disintegrin and metalloproteinase 8 (ADAM8) expression. The ability of propofol to impact the proliferation, migration and cell cycle of pancreatic cancer cell lines was assessed in vitro. This was mechanistically explored following the identification of SP1 binding sites within ADAM8, which enabled the regulatory effects of specificity protein 1 (SP1) on ADAM8 following propofol treatment to be further explored. Ultimately, this study was able to show that propofol significantly inhibited the proliferation, migration and invasion of pancreatic cancer cells and decreased the percentage of cells in S­phase. Propofol treatment was also shown to repress ADAM8 and SP1 expression, but was unable to affect ADAM8 expression following knockdown of SP1. Moreover, a direct physical interaction between SP1 and ADAM8 was verified using co­immunoprecipitation and dual­luciferase reporter assays. Cumulatively, these results suggest that propofol represses pathological biological behaviors associated with pancreatic cancer cells through the suppression of SP1, which in turn results in lower ADAM8 mRNA expression and protein levels.

20.
Nucl Med Biol ; 102-103: 56-86, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34624831

RESUMO

Hydrogen cyanide (HCN) is a versatile synthon for generating carbon­carbon and carbon-heteroatom bonds. Unlike other one-carbon synthons (i.e., CO, CO2), HCN can function as a nucleophile (as in potassium cyanide, KCN) and an electrophile (as in cyanogen bromide, (CN)Br). The incorporation of the CN motif into organic molecules generates nitriles, hydantoins and (thio)cyanates, which can be converted to carboxylic acids, aldehydes, amides and amines. Such versatile chemistry is particularly attractive in PET radiochemistry where diverse bioactive small molecules incorporating carbon-11 in different positions need to be produced. The first examples of making [11C]HCN for radiolabeling date back to the 1960s. During the ensuing decades, [11C]cyanide labeling was popular for producing biologically important molecules including 11C-labeled α-amino acids, sugars and neurotransmitters. [11C]cyanation is now reemerging in many PET centers due to its versatility for making novel tracers. Here, we summarize the chemistry of [11C]HCN, review the methods to make [11C]HCN past and present, describe methods for labeling different types of molecules with [11C]HCN, and provide an overview of the reactions available to convert nitriles into other functional groups. Finally, we discuss some of the challenges and opportunities in [11C]HCN labeling such as developing more robust methods to produce [11C]HCN and developing rapid and selective methods to convert nitriles into other functional groups in complex molecules.

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