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1.
Cancer Discov ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627378

RESUMO

Mutations in IFN- and MHC-signaling genes endow immunotherapy resistance. Colorectal cancer patients infrequently exhibit IFN- and MHC-signaling gene mutations, and are generally resistant to immunotherapy. In exploring the integrity of the IFN- and MHC-signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways, and predicted colorectal cancer patient outcome. Loss of optineurin occurred in early stage human colorectal cancer. Immunologically, optineurin deficiency attenuated IFNGR1 and MHC-I expression, impaired T cell-immunity, and diminished immunotherapy efficacy in murine cancer models and cancer patients. Mechanistically, IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated-IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated-IFNGR1 lysosomal sorting and degradation - thereby maintaining IFNy- and MHC-I-signaling integrity. Furthermore, pharmacologically targeting IFNGR1-palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33533004

RESUMO

Ionizing radiation (IR) is a form of high energy. It poses a serious threat to organisms, but radiotherapy is a key therapeutic strategy for various cancers. It is significant to reduce radiation injury but maximize the effect of radiotherapy. MicroRNAs (miRNAs) are posttranscriptionally regulatory factors involved in cellular radioresponse. In this review, we show how miRNAs regulate important genes on cellular response to IR-induced damage and how miRNAs participate in IR-induced carcinogenesis. Additionally, we summarize the experimental and clinical evidence for miRNA involvement in radiotherapy and discuss their potential for improvement of radiotherapy. Finally, we highlight the role that miRNAs play in accident exposure to IR or radiotherapy as predictive biomarker. miRNA therapeutics have shown great perspective in radiobiology; miRNA may become a novel strategy for damage and protection against IR.

3.
Mol Neurobiol ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33411247

RESUMO

Somatostatin (SST) and its analogues like octreotide (OCT) have analgesic effect on a variety of pain through peripheral SST receptors (SSTRs). However, the precise molecular mechanisms have not yet been fully elucidated. This research aimed to identify possible antinociceptive mechanisms, showing functional links of the SSTR2 and acid-sensing ion channels (ASICs). Herein, we reported that OCT inhibited the electrophysiological activity of ASICs in rat dorsal root ganglia (DRG) neurons. OCT concentration-dependently decreased the peak amplitude of acid-evoked inward currents, which were mediated by ASICs. OCT shifted concentration-response curve to protons downwards, with a decrease of 36.53 ± 5.28% in the maximal current response to pH 4.5 in the presence of OCT. OCT inhibited ASIC-mediated currents through SSTR2, since the inhibition was blocked by Cyn 154806, a specific SSTR2 antagonist. The OCT inhibition of ASIC-mediated currents was mimicked by H-89, a membrane-permeable inhibitor of PKA, and reversed by internal treatment of an adenylyl cyclase activator forskolin or 8-Br-cAMP. OCT also decreased the number of action potentials induced by acid stimuli through SSTR2. Finally, peripheral administration of 20 µM OCT, but not 2 µM OCT, significantly relieved nociceptive responses to intraplantar injection of acetic acid in rats. This occurred through local activation of SSTR2 in the injected hindpaw and was reversed following co-application of Cyn 154806. Our results indicate that activation SSTR2 by OCT can inhibit the activity of ASICs via an intracellular cAMP and PKA signaling pathway in rat DRG neurons. These observations demonstrate a cross-talk between ASICs and SSTR2 in peripheral sensory neurons, which was a novel peripheral analgesic mechanism of SST and its analogues.

4.
Nat Med ; 27(1): 152-164, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398162

RESUMO

Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity.


Assuntos
Imunoterapia , Neoplasias Hepáticas Experimentais/secundário , Neoplasias Hepáticas Experimentais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Macrófagos/imunologia , Linfócitos T/imunologia , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Ativação Linfocitária , Masculino , Melanoma/imunologia , Melanoma/secundário , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Radioterapia Adjuvante , Linfócitos T/classificação , Linfócitos T/patologia , Falha de Tratamento , Resultado do Tratamento , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
5.
J Ethnopharmacol ; 271: 113818, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33465444

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ranunculus japonicus Thunb. (short for R. japonicus) is a topically applied herb with the activities of removing jaundice, nebula and edema, preventing malaria, stopping asthma, promoting diuresis and relieving pain. It was firstly recorded in Zhouhou Beiji Fang and has been used for the treatment of malaria, ulcers, carbuncle, jaundice, migraine, stomachache, toothache and arthritis for over 1800 years. AIM OF THE STUDY: This study aimed to uncover the potentially effective components of R. japonicus and the pharmacological mechanisms against rheumatoid arthritis (RA) by combing LC-MS and network pharmacology. MATERIALS AND METHODS: Firstly, the chemical constituents of R. japonicus were qualitatively identified by UPLC-ESI-LTQ-Orbitrap MS. Then we performed target prediction by PharmMapper, protein-protein interaction (PPI) analysis via String, GO and KEGG pathway enrichment analysis by DAVID and constructed the compound-target-pathway network using Cytoscape. Thirdly, crucial compounds in the network were quantitatively analyzed to achieve quality control of R. japonicus. Finally, the pharmacological activities of R. japonicus and two potentially bioactive ingredients were validated in RA-FLSs (Rheumatoid Arthritis Fibroblast-like Synoviocytes) in vitro. RESULTS: Overall fifty-four ingredients of R. japonicus were identified and forty-five components were firstly discovered in R. japonicus. Among them, twenty-seven validated compounds were predicted to act on twenty-five RA-related targets and they might exhibit therapeutic effects against RA via positive regulation of cell migration, etc. Nine potentially bioactive components of R. japonicus which played important roles in the compound-target-pathway network were simultaneously quantified by an optimized UPLC-ESI-Triple Quad method. In vitro, compared to control group, R. japonicus extract, berberine and yangonin significantly inhibited the migration capacity of RA-FLSs after 24 h treatment. CONCLUSION: This study clarified that R. japonicus and the bioactive ingredients berberine and yangonin might exert therapeutic actions for RA via suppressing the aggressive phenotypes of RA-FLSs through combined LC-MS technology and network pharmacology tools for the first time. The present research provided deeper understanding into the chemical profiling, pharmacological activities and quality control of R. japonicus and offered reference for further scientific research and clinical use of R. japonicus in treating RA.

6.
Cancer Cell ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33513345

RESUMO

Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an "eat-me" signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.

7.
Ann Palliat Med ; 9(6): 4179-4186, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33302679

RESUMO

BACKGROUND: Polyneuropathy caused by n-hexane in its occupational settings is diagnosed with bilaterally symmetrical sensory and motor abnormalities. However, no effective treatments are available. METHODS: We use the detailed physical, neurological examinations, rehabilitation assessment scale, and electrophysiological examinations at hospital admission and six months' follow up to assess the effect of a rehabilitation program on peripheral nerve injury caused by n-hexane nine patients. RESULTS: We found that all patients complained about sensory issues of numbness in the distal extremities and decreasing strength with a decreased locomotion speed and gait abnormalities on admission, which is following the result of electrophysiological examinations. After they underwent a hospitalized rehabilitation program for 6 months, all of them showed a significant improvement in muscle strength, balance, deep tendon reflex, walking speed, and Barthel index, which showed a significant improvement in their athletic ability, although some patients still had gait abnormalities. According to the electrophysiological test results, nine patients had increased motor conduction velocities and amplitudes and shortened distal latencies in the four limbs compared with the results upon admission or one month later. However, only some indexes of sensory nerve conduction showed significant differences. With the recovery of movement and sensory function, they could live entirely independently and even return to work. CONCLUSIONS: We suggest that early general physical evaluation with electrophysiological examinations and comprehensive rehabilitation, including different modalities, therapeutic exercise, nerve mobilization, gait training, occupational therapy, traditional Chinese medicine treatment, and patient education, are essential so that patients can perform activities of daily living independently and return to work early.

8.
Life Sci ; : 118789, 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33220291

RESUMO

AIMS: The objectives of this study were to explore physiological and pathological changes in the corneas of diabetic rats by intervening in the expression of silent information regulator 1 (Sirt1) and to investigate whether Sirt1 can regulate the activation of endoplasmic reticulum stress (ERS) while influencing corneal epithelial cell apoptosis under high glucose conditions. MATERIALS AND METHODS: Using 8-week old Sprague-Dawley rats, we established a model of type 1 diabetes, with or without Sirt1 intervention. Clinical evaluation was performed once per week. Primary rat corneal epithelial cells (RCECs) were cultured by combining Sirt1 intervention under high glucose conditions. Generation of reactive oxygen species (ROS), apoptosis, and the expression of Sirt1 and ERS-related proteins were evaluated in rat corneal tissues and RCECs. KEY FINDINGS: During the intervention, clinical evaluation of the ocular surface, ROS generation, apoptosis, and protein expression of ERS-related proteins in corneal tissue and cultured RCECs were altered with Sirt1expression levels. SIGNIFICANCE: Sirt1 expression influences the pathological progression of diabetic keratopathy, plays an important role in regulating the ERS pathway, and decreases corneal epithelial cell apoptosis.

9.
J Proteome Res ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33151695

RESUMO

Protection against low-dose ionizing radiation is of great significance. Uranium tailings are formed as a byproduct of uranium mining and a potential risk to organisms. In this study, we identified potential biomarkers associated with exposure to low-dose radiation from uranium tailings. We established a Wistar rat model of low dose rate irradiation by intratracheal instillation of a uranium tailing suspension. We observed pathological changes in the liver, lung, and kidney tissues of the rats. Using isobaric tags for relative and absolute quantification, we screened 17 common differentially expressed proteins in three dose groups. We chose alpha-1 antiproteinase (Serpina1), keratin 17 (Krt17), and aldehyde dehydrogenase (Aldh3a1) for further investigation. Our data showed that expression of Serpina1, Krt17, and Aldh3a1 had changed after the intratracheal instillation in rats, which may be potential biomarkers for uranium tailing low-dose irradiation. However, the underlying mechanisms require further investigation.

10.
Front Mol Biosci ; 7: 556481, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33134310

RESUMO

The outbreak of 2019 novel coronavirus (COVID-19) has caused serious threat to public health. Discovery of new anti-COVID-19 drugs is urgently needed. Fortunately, the crystal structure of COVID-19 3CL proteinase was recently resolved. The proteinase has been identified as a promising target for drug discovery in this crisis. Here, a dataset including 2030 natural compounds was screened and refined based on the machine learning and molecular docking. The performance of six machine learning (ML) methods of predicting active coronavirus inhibitors had achieved satisfactory accuracy, especially, the AUC (Area Under ROC Curve) scores with fivefold cross-validation of Logistic Regression (LR) reached up to 0.976. Comprehensive ML prediction and molecular docking results accounted for the compound Rutin, which was approved by NMPA (National Medical Products Administration), exhibited the best AUC and the most promising binding affinity compared to other compounds. Therefore, Rutin might be a promising agent in anti-COVID-19 drugs development.

12.
Lasers Med Sci ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33128166

RESUMO

Because of a large number of macrophages and its secreted pro-inflammatory factors in the synovial fluid of patients with rheumatoid arthritis, the present study aimed to investigate the effect and mechanism of 630-nm LED exposure on monocytes/macrophages and its anti-inflammatory effect. The THP-1 monocytes and PMA-induced THP-1 macrophages (THP-1 macrophages) were employed and irradiated by 630-nm LED for different time and times, and then measure the pro-inflammatory cytokines production by RT-qPCR and Milliplex MAP Multiplex assay, the proteins involved in inflammation pathway and reactive oxygen species (ROS) levels in the cells were detected by Western blot and DCFH-DA method. The exposure dose of red LED (15.3 J/cm2, 30.6 J/cm2) were determined as no-influence on the cell proliferation, the pro-inflammatory factors TNF-α and IL-1ß mRNAs, and secretions in supernatant of THP-1 macrophages were significantly decreased after LED exposure. The ROS production was blocked in THP-1 monocytes and THP-1 macrophages after treatment of LED. Finally, the phosphorylated NF-κB proteins which involved in inflammation pathway significantly decreased, and its inhibitors Nrf2 were slightly upregulated. The effects of LED anti-inflammation response are dependent on the mechanism of inhibiting ROS level and regulating NF-κB signaling pathways by increasing Nrf2 expression in the cells. It is suggested that 630-nm LED could decrease pro-inflammation in immune cells, and it may be a beneficial adjunct therapy in relieving inflammation of patients with rheumatoid arthritis.

13.
Neuropharmacology ; 181: 108356, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069757

RESUMO

Endothelin-1 (ET-1), an endogenous vasoconstrictor, has been known as a pro-nociceptive agent involved in multitude of pain. ET-1 acts on endothelin receptors on vascular endothelial cells, sensitizes release of ATP, which then acts on P2X3 receptors on nociceptors and results in mechanical hyperalgesia. Both endothelin receptors and P2X3 receptors are present in primary sensory neuron, where it remains unclear whether there is an interaction between them. Herein, we reported that ET-1 potentiated the electrophysiological activity of P2X3 receptors in rat dorsal root ganglia (DRG) neurons. ET-1 concentration-dependently increased α,ß-methylene-ATP (α,ß-meATP)-evoked inward currents, which were mediated by P2X3 receptors. ET-1 shifted the α,ß-meATP concentration-response curve upwards, with an increase of 34.38 ± 4.72% in the maximal current response to α,ß-meATP in the presence of ET-1. ET-1 potentiation of α,ß-meATP-evoked currents was voltage-independent. ET-1 potentiated P2X3 receptor-mediated currents through endothelin-A receptors (ETAR), but not endothelin-B receptors (ETBR). ET-1 potentiation was supressed by blockade of intracellular G-protein or protein kinase C (PKC) signaling. Moreover, there is a synergistic effect on mechanical allodynia induced by intraplantar injection of ET-1 and α,ß-meATP in rats. Pharmacological blockade of P2X3 receptors also alleviated ET-1-induced mechanical allodynia. These results suggested that ET-1 sensitized P2X3 receptors in primary sensory neurons via an ETAR and PKC signaling pathway. Our data provide evidence that cutaneous ET-1 induced mechanical allodynia not only by increasing the release of ATP from vascular endothelial cells, but also by sensitizing P2X3 receptors on nociceptive DRG neurons.

14.
Nature ; 585(7824): 277-282, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879489

RESUMO

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilação , Neoplasias/metabolismo , Sistema L de Transporte de Aminoácidos/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Histonas/química , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo
15.
Zhongguo Zhong Yao Za Zhi ; 45(16): 3883-3889, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893585

RESUMO

Shotgun based proteomics and peptidomics analysis were used to investigate the proteins and peptides in marine traditional Chinese medicine(TCM) Sepiae Endoconcha(cuttlebone). Peptides were extracted from cuttlebone by acidified methanol, and then strong cation exchange(SCX) resin was used to enrich those peptides. Also, proteins from cuttlebone were extracted and digested by trypsin. nano-LC Q Exactive Orbitrap mass spectrometry was used to analyze proteins and peptides from cuttlebone. As a result, a total of 16 proteins and 168 peptides were identified by protein database search, and 328 peptides were identified by De novo sequencing. The identified proteins were hemocyanin, enolase, myosin, actin, calmodulin, etc., and the identified peptides were derived from actin, histone, and tubulin. All these proteins and peptides were important components in cuttlebone, which would provide important theoretical and research basis for marine TCM cuttlebone investigations.


Assuntos
Peptídeos , Proteômica , Cátions , Bases de Dados de Proteínas , Espectrometria de Massas
16.
Plants (Basel) ; 9(9)2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32906664

RESUMO

High temperature is one of the major abiotic stresses that affect cucumber growth and development. Heat stress often leads to metabolic malfunction, dehydration, wilting and death, which has a great impact on the yield and fruit quality. In this study, genetic analysis and quantitative trait loci (QTL) mapping for thermotolerance in cucumber seedlings was investigated using a recombinant inbred line (RILs; HR) population and a doubled haploid (DH; HP) population derived from two parental lines '65G' (heat-sensitive) and '02245' (heat-tolerant). Inheritance analysis suggested that both short-term extreme and long-term mild thermotolerance in cucumber seedlings were determined by multiple genes. Six QTLs for heat tolerance including qHT3.1, qHT3.2, qHT3.3, qHT4.1, qHT4.2, and qHT6.1 were detected. Among them, the major QTL, qHT3.2, was repeatedly detected for three times in HR and HP at different environments, explained 28.3% of the phenotypic variability. The 481.2 kb region harbored 79 genes, nine of which might involve in heat stress response. This study provides a basis for further identifying thermotolerant genes and helps understanding the molecular mechanism underlying thermotolerance in cucumber seedlings.

17.
JCI Insight ; 5(18)2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32780724

RESUMO

Tumor-associated macrophages (TAMs) affect cancer progression and therapy. Ovarian carcinoma often metastasizes to the peritoneal cavity. Here, we found 2 peritoneal macrophage subsets in mice bearing ID8 ovarian cancer based on T cell immunoglobulin and mucin domain containing 4 (Tim-4) expression. Tim-4+ TAMs were embryonically originated and locally sustained while Tim-4- TAMs were replenished from circulating monocytes. Tim-4+ TAMs, but not Tim-4- TAMs, promoted tumor growth in vivo. Relative to Tim-4- TAMs, Tim-4+ TAMs manifested high oxidative phosphorylation and adapted mitophagy to alleviate oxidative stress. High levels of arginase-1 in Tim-4+ TAMs contributed to potent mitophagy activities via weakened mTORC1 activation due to low arginine resultant from arginase-1-mediated metabolism. Furthermore, genetic deficiency of autophagy element FAK family-interacting protein of 200 kDa resulted in Tim-4+ TAM loss via ROS-mediated apoptosis and elevated T cell immunity and ID8 tumor inhibition in vivo. Moreover, human ovarian cancer-associated macrophages positive for complement receptor of the immunoglobulin superfamily (CRIg) were transcriptionally, metabolically, and functionally similar to murine Tim-4+ TAMs. Thus, targeting CRIg+ (Tim-4+) TAMs may potentially treat patients with ovarian cancer with peritoneal metastasis.

18.
Front Chem ; 8: 543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695747

RESUMO

In recent years, gold compounds have gained more and more attentions in the design of new metal anticancer drugs. Numerous researches have reported that gold compounds, in addition to their widely studied cytotoxic antitumor effects, also reverse tumor immune escape and directly facilitate the functions of immune cells, leading to enhanced anticancer effects. This review mainly summarizes our current understandings of antitumor effects of gold drugs and their relationships with various aspects of antitumor immunity, including innate immunity, adaptive immunity, immunogenic cell death, and immune checkpoints, as well as their roles in adverse effects. Some recent examples of anticancer gold compounds are highlighted. The property of gold compounds is expected to combine with anticancer immunotherapy, such as immune checkpoint inhibitors, to develop new anticancer therapeutic strategies.

19.
Micromachines (Basel) ; 11(8)2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32717887

RESUMO

Piezoelectric composites are considered excellent core materials for fabricating various ultrasonic devices. For the traditional fabrication process, piezoelectric composite structures are mainly prepared by mold forming, mixing, and dicing-filing techniques. However, these techniques are limited on fabricating shapes with complex structures. With the rapid development of additive manufacturing (AM), many research fields have applied AM technology to produce functional materials with various geometric shapes. In this study, the Mask-Image-Projection-based Stereolithography (MIP-SL) process, one of the AM (3D-printing) methods, was used to build BaTiO3-based piezoelectric composite ceramics with honeycomb structure design. A sintered sample with denser body and higher density was achieved (i.e., density obtained 5.96 g/cm3), and the 3D-printed ceramic displayed the expected piezoelectric and ferroelectric properties using the complex structure (i.e., piezoelectric constant achieved 60 pC/N). After being integrated into an ultrasonic device, the 3D-printed component also presents promising material performance and output power properties for ultrasound sensing (i.e., output voltage reached 180 mVpp). Our study demonstrated the effectiveness of AM technology in fabricating piezoelectric composites with complex structures that cannot be fabricated by dicing-filling. The approach may bring more possibilities to the fabrication of micro-electromechanical system (MEMS)-based ultrasonic devices via 3D-printing methods in the future.

20.
J Neurochem ; 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32666510

RESUMO

Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after four and eight consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine.

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