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1.
Artigo em Inglês | MEDLINE | ID: mdl-36670545

RESUMO

Hydrophobic tagging (HyT) is a potential therapeutic strategy for targeted protein degradation (TPD). Norbornene was discovered as an unprecedented hydrophobic tag in this study and was used to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors. The most promising degrader, Hyt-9, potently reduced ALK levels through Hsp70 and the ubiquitin-proteasome system (UPS) in vitro without compensatory upregulation of ALK. Furthermore, Hyt-9 exhibited a significant tumor-inhibiting effect in vivo with moderate oral bioavailability. More importantly, norbornene can also be used to degrade the intractable enhancer of zeste homolog 2 (EZH2) when tagged with the EZH2 inhibitor tazemetostat. Thus, the discovery of novel hydrophobic norbornene tags shows promise for the future development of TPD technology.

2.
Sci Total Environ ; : 161615, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36681331

RESUMO

Dissolved Organic Matter (DOM), an important part of the carbon cycle in reservoir ecosystems, has a great impact on aquatic environment to recognize the conversion process of different media DOM. The distribution, spectral characteristics, and sources of DOM in Gangnan Reservoir during thermal stratification were analyzed using ultraviolet-visible absorption spectroscopy and excitation-emission matrix spectroscopy. Three humic-like components (C2, C3, and C4) and two protein-like components (C1 and C5) were identified. The proportions of the humic-like components increased with the progression of thermal stratification (C2 and C3 were dominant), whereas the protein-like components decreased in proportion, and the trend in the interstitial water was constant (C3 and C4 were dominant). The proportion of the humic-like components in the sediments was highest during the stationary period of thermal stratification (C2 and C3 were dominant). C2 and C3 were significantly correlated in the water body and interstitial water (P < 0.001), while C1 and C5 were correlated in the sediment (P < 0.05). In the water body, C2 and C3 were negatively correlated during the formative period of thermal stratification (slope = -1.85; R2 = 0.52), strongly positively correlated during the stationary period (slope = 0.76; R2 = 0.94), and positively correlated during the weakening period of thermal stratification (slope = 0.46; R2 = 0.30). With the progression of thermal stratification, the relative contribution of endogenous substances decreased gradually, whereas the humification degree increased in the water body and interstitial water. The protein-like components and key physicochemical factors (Fe, Mn, TN, TP, and CODMn) were significantly correlated during the formative period (P < 0.05), and humic-like components and key physicochemical factors (NO2--N and TN) were significantly correlated during the stationary and weakening periods (P < 0.05). C1, C4, and C5 indicated NO3--N during the formative period; C2 and C3 indicated NO3--N during the stationary period; and C2 and C4 indicated NO3--N during the weakening period in the water body. These findings enhance the understanding the mutual transformation processes of DOM in reservoir ecosystems and could guide water quality management.

3.
J Appl Clin Med Phys ; : e13907, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36660774

RESUMO

PURPOSE: The Akesis Galaxy RTi (AK) is a novel rotational 60 Co-based cranial stereotactic radiosurgery (SRS) system. While similar systems have been compared against the fixed-source Leksell Gamma Knife (GK) system using stylized phantoms, dosimetric plan quality with realistic anatomy has yet to be characterized for this or any other rotating system versus GK. This study aims to benchmark AK dosimetric performance against GK by retrospectively replanning previously-treated GK patients at our institution. METHODS: Thirteen patients, previously treated on a GK Icon, were re-planned on the AK treatment planning system using the same prescription doses and isodoses as the original GK plans. The cohort includes patients treated for brain metastases, schwannomas, pituitary adenomas, trigeminal neuralgias, and arteriovenous malformations. Plans are evaluated with target coverage metrics (Dmin , Dmean , D95% , V150% ) and dose conformality indices: Radiation Therapy Oncology Group conformity index (CI), selectivity, Paddick CI (PCI), gradient index (GI). RESULTS: AK plans use fewer shots and larger collimation compared to GK plans, resulting in statistically significant reductions in treatment time (p = 0.047) by as much as 88.4 minutes while maintaining comparable target V100% . For most metastatic cases, GK produces higher Dmin (16.0-25.9 vs. 12.5-24.3 Gy, p = 0.008) while AK produces higher V150% (0.03-14.92 vs. 0.02-11.59 cc, p = 0.028). For non-metastatic cases, GK provides superior CI (p = 0.025) and GI (p = 0.044). No statistically significant differences were found in the remaining metrics. CONCLUSION: This cohort demonstrates that the AK system is able to achieve largely comparable dosimetric results to GK, typically with shorter treatment times. Further investigation with a larger cohort is underway.

4.
Adv Healthc Mater ; : e2202737, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36603134

RESUMO

The topographic cues of wound dressings play important roles in regulating cellular behaviors, such as cellular migration and morphology, and are capable of providing a prolonged stimulus for promoting wound healing. However, 3D porous dressings that can guide wound healing from the periphery to the center are poorly studied. Herein, radial sponges with adjustable lamellar spacing and microridge spacing by ice templating are developed to facilitate wound healing. With denser lamellae and microridges, fibroblasts achieve a more orderly arrangement, a larger elongation, and a greater migration rate. Meanwhile, the elongated state enables human umbilical vein endothelial cells to vascularization. The faster healing rate and a higher degree of vascularization based on radial sponges are further demonstrated in full-thickness skin defects in rats. Taken together, radial sponges with the densest lamellae and microridges perform the best in guiding the wound from the periphery to the center of the repair environment. It is believed that the proposed structure here can be combined with various biochemical factors to provide dressings with functions.

5.
Mol Brain ; 16(1): 3, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604739

RESUMO

Pain is known to have sensory and affective components. The sensory pain component is encoded by neurons in the primary somatosensory cortex (S1), whereas the emotional or affective pain experience is in large part processed by neural activities in the anterior cingulate cortex (ACC). The timing of how a mechanical or thermal noxious stimulus triggers activation of peripheral pain fibers is well-known. However, the temporal processing of nociceptive inputs in the cortex remains little studied. Here, we took two approaches to examine how nociceptive inputs are processed by the S1 and ACC. We simultaneously recorded local field potentials in both regions, during the application of a brain-computer interface (BCI). First, we compared event related potentials in the S1 and ACC. Next, we used an algorithmic pain decoder enabled by machine-learning to detect the onset of pain which was used during the implementation of the BCI to automatically treat pain. We found that whereas mechanical pain triggered neural activity changes first in the S1, the S1 and ACC processed thermal pain with a reasonably similar time course. These results indicate that the temporal processing of nociceptive information in different regions of the cortex is likely important for the overall pain experience.


Assuntos
Giro do Cíngulo , Percepção do Tempo , Humanos , Giro do Cíngulo/fisiologia , Córtex Somatossensorial , Dor , Córtex Cerebral/fisiologia
6.
Clin Rheumatol ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598587

RESUMO

OBJECTIVES: This healthy volunteer control-based study was conducted to explore alterations of compositions and function of gut microbiota in Chinese pSS patients. METHOD: The high-throughput Illumina Miseq sequencing method, targeting the V3-V4 region of the 16S ribosomal RNA (rRNA) gene, was used to compare the microbiota communities between 30 pSS patients and 30 age-matched healthy volunteers. The intestinal dysbiosis of pSS patients was evaluated and its correlation with some disease phenotypes was analyzed. Furthermore, we performed the amino acid sequence alignment analysis to illustrate the molecular mimicry patterns of new microbial peptides. RESULTS: Compared with that in healthy controls, the composition and function of the gut microbiota significantly differed in pSS patients. Certain genera and species, including genera: Escherichia-Shigella, Sardovia, Veillonella, Insteinimonas, and Lactobacillales; species: Escherichia coli, Lactobacillus phage Sal3, Lactobacillus reuteri, Lactobacillus gasseri, Streptococcus lutetiensis, Streptococcus mutans, Scardovia wiggsiae, and Fusobacterrium ulcerans were found to be enriched in the feces of pSS patients, while butyrate-producing bacteria were less abundant in pSS patients. Certain genera (including Lactobacillales) and species (including Lactobacillus gasseri) were associated with disease severity and therapy resistance parameters. Autoantigen epitopes of "WPSALPT, NPARSFG, MNPARSFG, and AFGLAIGT" from aquaporin-5 were aligned perfectly with one enriched microbiota of patients with pSS, namely Escherichia coli. CONCLUSIONS: The composition and function of the gut microbiota significantly differed in pSS patients compared with that in healthy controls. Our study would facilitate the possible research on the role of gut microbiota in the pathogenesis of pSS.

7.
Mol Cancer ; 22(1): 10, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635761

RESUMO

Skin cancer has emerged as the fifth most commonly reported cancer in the world, causing a burden on global health and the economy. The enormously rising environmental changes, industrialization, and genetic modification have further exacerbated skin cancer statistics. Current treatment modalities such as surgery, radiotherapy, conventional chemotherapy, targeted therapy, and immunotherapy are facing several issues related to cost, toxicity, and bioavailability thereby leading to declined anti-skin cancer therapeutic efficacy and poor patient compliance. In the context of overcoming this limitation, several nanotechnological advancements have been witnessed so far. Among various nanomaterials, nanoparticles have endowed exorbitant advantages by acting as both therapeutic agents and drug carriers for the remarkable treatment of skin cancer. The small size and large surface area to volume ratio of nanoparticles escalate the skin tumor uptake through their leaky vasculature resulting in enhanced therapeutic efficacy. In this context, the present review provides up to date information about different types and pathology of skin cancer, followed by their current treatment modalities and associated drawbacks. Furthermore, it meticulously discusses the role of numerous inorganic, polymer, and lipid-based nanoparticles in skin cancer therapy with subsequent descriptions of their patents and clinical trials.


Assuntos
Nanopartículas , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Nanotecnologia
8.
J Food Sci Technol ; 60(2): 562-571, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36712221

RESUMO

This study aimed to develop nutritious and healthy Sichuan hotpot oil. Four blended oil formulas were formulated using MATLAB based on the fatty acid composition of four base constituents (beef tallow, mutton tallow, peanut oil, and palm oil). The sensory characteristics, physicochemical properties, nutritional composition, harmful substances, and antioxidant capacity of the oils were analyzed during the boiling process. A blend of 60% beef tallow + 10% mutton tallow + 10% peanut oil + 20% palm oil exhibited a low level of peroxide (0.03 g/100 g) and malondialdehyde (0.04 mg/kg), and high phytosterol content (1028.33 mg/kg), which was the suitable hotpot blending oil. Furthermore, the changes in the physicochemical properties during boring were low, with a high retention rate of phytosterol (94.85%), and the levels of 3,4-benzopyrene (1.12 µg/kg) and 3-monochloropropane-1,2-diol ester (0.67 mg/kg) were both lower than the recommended limits. This study will provide a theoretical basis for the advancement of the hotpot oil industry.

10.
Elife ; 122023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36692269

RESUMO

Epifluorescence miniature microscopes ('miniscopes') are widely used for in vivo calcium imaging of neural population activity. Imaging data is typically collected during a behavioral task and stored for later offline analysis, but emerging techniques for online imaging can support novel closed-loop experiments in which neural population activity is decoded in real time to trigger neurostimulation or sensory feedback. To achieve short feedback latencies, online imaging systems must be optimally designed to maximize computational speed and efficiency while minimizing errors in population decoding. Here we introduce DeCalciOn, an open-source device for real-time imaging and population decoding of in vivo calcium signals that is hardware compatible with all miniscopes that use the UCLA Data Acquisition (DAQ) interface. DeCalciOn performs online motion stabilization, neural enhancement, calcium trace extraction, and decoding of up to 1024 traces per frame at latencies of <50 ms after fluorescence photons arrive at the miniscope image sensor. We show that DeCalciOn can accurately decode the position of rats (n=12) running on a linear track from calcium fluorescence in the hippocampal CA1 layer, and can categorically classify behaviors performed by rats (n=2) during an instrumental task from calcium fluorescence in orbitofrontal cortex (OFC). DeCalciOn achieves high decoding accuracy at short latencies using innovations such as field-programmable gate array (FPGA) hardware for real time image processing and contour-free methods to efficiently extract calcium traces from sensor images. In summary, our system offers an affordable plug-and-play solution for real-time calcium imaging experiments in behaving animals.

11.
Sci Total Environ ; : 161754, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36709888

RESUMO

Microorganisms exist throughout the soil profile and those microorganisms living in deeper soil horizons likely play key roles in regulating biogeochemical processes. However, the vertical differentiations of microbes along soil depth and their global biogeographical patterns remain poorly understood. Herein, we conducted a global meta-analysis to clarify the vertical changes of microbial biomass, diversity, and microbial relative abundance across the soil profiles. Data was collected from 43 peer-reviewed articles of 110 soil profiles (467 observations in total) from around the world. We found soil microbial biomass and bacterial diversity decreased with depth in soils. Among examined edaphic factors, the depth variation in soil pH exhibited significant negative associations with the depth change in microbial biomass and bacterial Shannon index, while soil total organic carbon (TOC) and total nitrogen (TN) exhibited significant positive associations. For the major bacteria phyla, the relative abundances of Proteobacteria and Bacteroidetes decreased with soil depth, while Chloroflexi, Gemmatimonadetes, and Nitrospirae increased. We found both parallels and differences in the biogeographical patterns of microbial attribute of topsoil vs. subsoil. Microbial biomass was significantly controlled by the soil nutrient concentrations in both topsoil and subsoil compared with climatic factors, while bacterial Shannon index was significantly controlled by the edaphic factors and across latitudes or climatic factors. Moreover, mean annual precipitation can also be used as a predictor of microbial biomass in subsoil which is different from topsoil. Collectively, our results provide a novel integrative view of how microbial biomass and bacterial community response to soil depth change and clarify the controlling factors of the global distribution patterns of microbial biomass and diversity, which are critical to enhance ecosystem simulation models and for formulating sustainable ecosystem management and conservation policies.

12.
J Environ Sci (China) ; 127: 320-327, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36522064

RESUMO

The high NO3- concentration in fine particulate matters (PM2.5) during heavy haze events has attracted much attention, but the formation mechanism of nitrates remains largely uncertain, especially concerning heterogeneous uptake of NOX by aqueous phase. In this work, the heterogeneous uptake of NO2 by sodium acetate (NaAc) droplets with different NO2 concentrations and relative humidity (RH) conditions is investigated by microscopic Fourier transform infrared spectrometer (micro-FTIR). The IR feature changes of aqueous droplets indicate the acetate depletion and nitrite formation in humid environment. This implies that acetate droplets can provide the alkaline aqueous circumstances caused by acetate hydrolysis and acetic acid (HAc) volatilization for nitrite formation during the NO2 heterogeneous uptake. Meanwhile, the nitrite formation will exhibit a pH neutralizing effect on acetate hydrolysis, further facilitating HAc volatilization and acetate depletion. The heterogeneous uptake coefficient increases from 5.2 × 10-6 to 1.27 × 10-5 as RH decreases from 90% to 60% due to the enhanced HAc volatilization. Furthermore, no obvious change in uptake coefficient with different NO2 concentrations is observed. This work may provide a new pathway for atmospheric nitrogen cycling and secondary nitrite aerosol formation.


Assuntos
Nitritos , Dióxido de Nitrogênio , Acetato de Sódio , Aerossóis/análise , Material Particulado , Água
13.
Leg Med (Tokyo) ; 60: 102184, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36502647

RESUMO

Postmortem diagnosis of acute myocardial infarction (AMI), especially early AMI, is a challenge for forensic scientists. Circular RNAs (circRNA) are a unique type of RNA with a closed loop structure and more stability, compared with linear RNA. We aimed at evaluating whether circRNAs are ideal postmortem diagnostic markers for AMI. We employed bioinformatics methods to screen for target circRNAs. Divergent and convergent primers were used to confirm the loop structure. Ribonuclease R (RNaseR) digestion and artificial simulated room temperature test were performed to evaluate the stability of circRNAs. Furthermore, RT-PCR analysis was performed to assess the expressions of target circRNAs in a mouse model of AMI and in autopsy cases, while the diagnostic significance of circRNAs was evaluated by the receiver-operator characteristic (ROC) curve. The bioinformatics analysis screened out circSMARCC1 and circLRBA as target circRNAs. Agarose gel electrophoresis revealed the loop structure of target circRNAs. RNaseR digestion and the artificial simulated room temperature test showed that the stability of circRNAs was good. In mouse AMI model, circSMARCC1 levels were elevated while circLRBA levels were suppressed. Finally, in forensic autopsy cases, circSMARCC1 levels were significantly elevated, while circLRBA levels were significantly suppressed in the MI and early-MI group, relative to the normal control group. The ROC curve analysis showed that both circSMARCC1 and circLRBA can distinguish between AMI and normal control cases. Futher, a combination of the two circRNAs can increase the diagnostic efficacy of AMI. Thus, circSMARCC1 and circLRBA are potential biomarkers for postmortem diagnosis of AMI.


Assuntos
Infarto do Miocárdio , RNA Circular , Animais , Camundongos , Autopsia , RNA Circular/genética , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , RNA/genética , Biomarcadores/metabolismo
14.
Drug Resist Updat ; 66: 100906, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36565657

RESUMO

It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.


Assuntos
Antineoplásicos , Neoplasias , Animais , Humanos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/patologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/farmacologia
15.
iScience ; 26(1): 105707, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36570771

RESUMO

Pain is driven by sensation and emotion, and in turn, it motivates decisions and actions. To fully appreciate the multidimensional nature of pain, we formulate the study of pain within a closed-loop framework of sensory-motor prediction. In this closed-loop cycle, prediction plays an important role, as the interaction between prediction and actual sensory experience shapes pain perception and subsequently, action. In this Perspective, we describe the roles of two prominent computational theories-Bayesian inference and reinforcement learning-in modeling adaptive pain behaviors. We show that prediction serves as a common theme between these two theories, and that each of these theories can explain unique aspects of the pain perception-action cycle. We discuss how these computational theories and models can improve our mechanistic understandings of pain-centered processes such as anticipation, attention, placebo hypoalgesia, and pain chronification.

16.
J Surg Res ; 281: 245-255, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36209683

RESUMO

INTRODUCTION: Heme oxygenase-1 (HO-1) is a protective protein in oxidative stress response. LXA4 is an "inflammatory braking signal" that is widely studied at present. The purpose of this study was to elucidate that LXA4 can protect cells by inducing HO-1 in human pulmonary microvascular endothelial cells (HPMECs) as in vitro model to explain acute lung injury after severe acute pancreatitis. METHODS: This study was performed in two parts: (1) To investigate the mechanisms of lipoxin A4-induced HO-1 expression in vitro, the study subjects were divided into four groups: a control group, LXA4 group (50 ng/mL LXA4), inhibitor group (50 ng/mL LXA4 + 20 µM LY294002 or 50 ng/mL LXA4 + 2 nmol/mL Bis II), and agonist group (50 ng/mL insulin-like growth factor 1, PMA). Western blotting was used to detect the expression of p-Akt, Akt, protein kinase C (PKC), p-Nrf2, Nrf2, and Keap1, and the location of Nrf2 was detected using immunofluorescence. The activation of antioxidant responsive element induced by Nrf2 was detected using Electrophoretic Mobility Shift Assay and (2) to investigate the cytoprotection of HO-1 induced by LXA4 in vitro, the subjects were divided into four groups: a control group, tumor necrosis factor α (TNF-α) group (50 ng/mL), LXA4 group (50 ng/mL TNF-α + 50 ng/mL LXA4), and Zinc protoporphyrin IX group (pretreated with 0.5 µM Zinc protoporphyrin IXfor 12 h, followed by 50 ng/mL TNF-α + 50 ng/mL LXA4). BCECF/AM-labeled THP-1 cells were used to analyze the adhesion of HPMECs, and a mitochondrial membrane potential assay kit with JC-1 was used to analyze the apoptosis of HPMECs. RESULTS: In part one, (1) LXA4 upregulated the expression of HO-1 in a dose-dependent manner and (2) LXA4 activated the PI3K/Akt and PKC pathways and modulated the phosphorylation and subsequent depolymerization of Nrf2 from Keap1, promoting the translocation of Nrf2 to the nucleus. In part two, (1) LXA4 reversed the changes in mitochondrial membrane potential to alleviate apoptosis in HPMECs and (2) LXA4 attenuated the adhesion of HPMECs induced by TNF-α. CONCLUSIONS: LXA4 can activate the PI3K/Akt and PKC pathways and induce the phosphorylation of Nrf2, resulting in the upregulation of HO-1. In addition, LXA4 alleviates adhesion and protects mitochondrial function by upregulating the expression of HO-1, which exerts cytoprotection in severe acute pancreatitis-induced lung injury.


Assuntos
Lesão Pulmonar Aguda , Pancreatite , Humanos , Heme Oxigenase-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Citoproteção , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença Aguda , Células Endoteliais/metabolismo , Estresse Oxidativo , Lesão Pulmonar Aguda/prevenção & controle
17.
Drug Resist Updat ; 66: 100907, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36527888

RESUMO

The binding of programmed death-1 (PD-1) on the surface of T cells and PD-1 ligand 1 (PD-L1) on tumor cells can prevent the immune-killing effect of T cells on tumor cells and promote the immune escape of tumor cells. Therefore, immune checkpoint blockade targeting PD-1/PD-L1 is a reliable tumor therapy with remarkable efficacy. However, the main challenges of this therapy are low response rate and acquired resistance, so that the outcomes of this therapy are usually unsatisfactory. This review begins with the description of biological structure of the PD-1/PD-L1 immune checkpoint and its role in a variety of cells. Subsequently, the therapeutic effects of immune checkpoint blockers (PD-1 / PD-L1 inhibitors) in various tumors were introduced and analyzed, and the reasons affecting the function of PD-1/PD-L1 were systematically analyzed. Then, we focused on analyzing, sorting out and introducing the possible underlying mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade including abnormal expression of PD-1/PD-L1 and some factors, immune-related pathways, tumor immune microenvironment, and T cell dysfunction and others. Finally, promising therapeutic strategies to sensitize the resistant patients with PD-1/PD-L1 blockade treatment were described. This review is aimed at providing guidance for the treatment of various tumors, and highlighting the drug resistance mechanisms to offer directions for future tumor treatment and improvement of patient prognosis.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias , Receptor de Morte Celular Programada 1 , Humanos , Antígeno B7-H1 , Resistência a Medicamentos , Imunoterapia , Microambiente Tumoral
18.
Drug Resist Updat ; 66: 100905, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36463807

RESUMO

Multidrug resistance (MDR) is the phenomenon in which cancer cells simultaneously develop resistance to a broad spectrum of structurally and mechanistically unrelated drugs. MDR severely hinders the effective treatment of cancer and is the major cause of chemotherapy failure. ATP-binding cassette (ABC) transporters are extensively expressed in various body tissues, and actively transport endogenous and exogenous substrates through biological membranes. Overexpression of ABC transporters is frequently observed in MDR cancer cells, which promotes efflux of chemotherapeutic drugs and reduces their intracellular accumulation. Increasing evidence suggests that ABC transporters regulate tumor immune microenvironment (TIME) by transporting various cytokines, thus controlling anti-tumor immunity and sensitivity to anticancer drugs. On the other hand, the expression of various ABC transporters is regulated by cytokines and other immune signaling molecules. Targeted inhibition of ABC transporter expression or function can enhance the efficacy of immune checkpoint inhibitors by promoting anticancer immune microenvironment. This review provides an update on the recent research progress in this field.

19.
Phytochemistry ; 206: 113522, 2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36471552

RESUMO

The fungus Pseudopestalotiopsis theae isolated from the fresh leaves of Illigera celebica, has been reported to be a pathogenic fungus that can cause gray blight on tea leaves, a disease characterized by the appearance of necrotic lesions on tea leaves. The pathogenic substances in this fungus have not been clearly identified. Considering the possible involvement of specialized metabolites in symptom appearance, a chemical investigation of specialized metabolites on P. theae was conducted, resulting in the isolation of eight meroterpenoids, including six undescribed biscognienynes G-L and two known ones (biscognienynes B and D). The structures of these new compounds were characterized by extensive NMR spectroscopic and HR-ESI-MS data, and their absolute configurations were elucidated by ECD calculations. Except for biscogniyne L, all the isolated biscognienynes showed different degrees of phytotoxicity to tea in vivo, thereby revealing for the first time the substances in P. theae that cause tea gray blight. Inspired by the fact that phytotoxins produced by pathogenic fungus are an effective resource for designing natural and safe bioherbicides, when assayed the herbicidal activity through Petri dish bioassays, biscognienynes G-J showed phytotoxic effects against seed germination and seedling growth of Setaria viridis, strongly inhibiting seed germination percentage and radicle and germ lengths of seedlings. The results of this study demonstrated the great potential of biscognienynes G-J to be proposed and developed as ecofriendly herbicides.

20.
Artigo em Inglês | MEDLINE | ID: mdl-36472882

RESUMO

The overwhelmingly competitive hydrogen evolution reaction (HER) is a bottleneck challenge in the electrocatalytic nitrogen reduction reaction (eNRR) process. Herein, we develop a general and effective strategy to suppress the HER via covalent surface functionalization to modulate the local microenvironment of the electrocatalyst. A hydrophobic molecular layer with tunable coverage density was coated on the surface of Ti3C2Tx MXene, and the one with appropriate coverage density significantly improved the eNRR efficiency with an excellent faradaic efficiency (FE) of 38.01% at -0.35 V and a high NH3 yield rate of 17.81 µg h-1mgcat-1 at -0.55 V (vs RHE) in a Na2SO4 solution, which were 3.5-fold in FE and 6.5-fold in NH3 yield rate higher than those of the pristine Ti3C2Tx. Experimental results combined with molecular dynamics (MD) simulations reveal that the hydrophobic molecular layer on the surface greatly limits the proton transfer and benefits higher exposure of active sites with enhanced N2 chemisorption ability, which cumulatively contribute to the boosted eNRR efficiency.

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