ABSTRACT
Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs. Recently, the Cingulin (CGN) protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant nonsyndromic hearing loss. Here, we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death. Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice, resembling the auditory phenotype in human patients. Interestingly, a human-specific residue (V1112) in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN. Moreover, the expression of heat shock factor 1 (HSF1) decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death. In summary, these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN, which can be targeted by the expression of the cell chaperone response regulator HSF1.
ABSTRACT
The purpose of this study was to reveal the spatial and temporal evolution patterns of habitat quality in karst counties of Guizhou plateau and its driving factors and to provide scientific basis for balanced ecological conservation and sustainable development of karst regions. Using DEM data, meteorological data, socio-economic data, and four periods of land use data in 1989, 2003, 2010, and 2020, the InVEST model was used to analyze the spatial and temporal evolution characteristics of habitat quality in Puding County from 1989 to 2020 and to quantitatively detect the driving forces of its spatial divergence. The results were as follows:â Arable land and forest land were the main land use types in Puding County, which constituted the surface cover landscape matrix. Land use changes from 2003-2010 were the most significant, among which forest land had the largest increase of 86.42%; arable land was the most severely lost land use type, with an area decrease of 157.57 km2, mainly flowing to forest land and construction land. â¡ From 1989 to 2020, the average value of habitat quality index in Puding County increased from 0.60 to 0.73. Spatially, the distribution pattern of "high-low-high" was generally from northeast to southwest, with the high value areas of habitat quality mainly distributed in the woodland and grassland areas in the northeast and the low value areas concentrated in the construction land in the central and south areas. ⢠Land use type was the primary factor affecting the spatial and temporal distribution of habitat quality, with an explanation of 91.00%. In the interaction detection, the interaction of any two influencing factors was greater than that of individual factors alone, and the interaction between land use type and average annual precipitation was the strongest, reaching 96.00%; the interaction with lithological factors reached 94.00%, with natural and human factors jointly dominating the spatial and temporal changes in habitat quality. From the results of this study, we concluded that the habitat quality of Puding County was generally good from 1989 to 2020, and the relationship between land use type changes and habitat quality was close. Optimizing the land use structure and reducing the influence of human activities are important to improve the habitat quality of Puding County.
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AIMS: The vascular aging process accelerated by type 2 diabetes mellitus (T2DM) is responsible for the elevated risk of associated cardiovascular diseases (CVDs). Metabolic disorder-induced immune senescence has been implicated in multi-organ/tissue damage. Herein, we sought to determine the role of immunosenescence in diabetic vascular aging and to investigate the underlying mechanisms. METHODS AND RESULTS: Aging hallmarks of the immune system appear prior to the vasculature in streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM mice or db/db mice. Transplantation of aged splenocytes or diabetic splenocytes into young mice triggered vascular senescence and injury compared to normal control splenocyte transfer. RNA-seq profile and validation in immune tissues revealed that the Toll-like receptor 4 (TLR4)- Nuclear factor-kappa B (NF-κB) -NLRP3 axis might be the mediator of diabetic premature immunosenescence. The absence of Nlrp3 attenuated immune senescence and vascular aging during T2DM. Importantly, senescent immune cells, particularly T cells, provoked perivascular adipose tissue (PVAT) dysfunction and alternations in its secretome, which in turn impair vascular biology. In addition, senescent immune cells may uniquely affect vasoconstriction via influencing PVAT. Lastly, rapamycin alleviated diabetic immune senescence and vascular aging, which may be partly due to NLRP3 signaling inhibition. CONCLUSION: These results indicated that NLRP3 inflammasome-mediated immunosenescence precedes and drives diabetic vascular aging. The contribution of senescent immune cells to vascular aging is a combined effect of their direct effects and induction of PVAT dysfunction, the latter of which can uniquely affect vasoconstriction. We further demonstrated that infiltration of senescent T cells in PVAT was increased and associated with PVAT secretome alterations. Our findings suggest that blocking the NLRP3 pathway may prevent early immunosenescence and thus mitigate diabetic vascular aging and damage, and targeting senescent T cells or PVAT might also be the potential therapeutic approach.
ABSTRACT
Borophenes have sparked considerable interest owing to their fascinating physical characteristics and diverse polymorphism. However, borophene nanoribbons (BNRs) with widths less than 2â nm have not been achieved. Herein, we report the experimental realization of supernarrow BNRs. Combining scanning tunneling microscopy imaging with density functional theory modeling and ab initio molecular dynamics simulations, we demonstrate that, under the applied growth conditions, boron atoms can penetrate the outermost layer of Au(111) and form BNRs composed of a pair of zigzag (2,2) boron rows. The BNRs have a width self-contained to â¼1â nm and dipoles at the edges to keep them separated. They are embedded in the outermost Au layer and shielded on top by the evacuated Au atoms, free of the need for post-passivation. Scanning tunneling spectroscopy reveals distinct edge states, primarily attributed to the localized spin at the BNRs' zigzag edges. This work adds a new member to the boron material family and introduces a new physical feature to borophenes.
ABSTRACT
Xanthoceras sorbifolium Bunge, also known as Tu-Mu-Gua and Wen-Dan-Ge-Zi, has several applications. Clinical data and experimental studies have shown anti-tumor, anti-inflammatory, anti-bacterial, and anti-oxidant properties of Xanthoceras sorbifolium Bunge that inhibits prostate hyperplasia, lowers blood pressure and lipid level, and treats enuresis and urinary incontinence. It also has neuroprotective effects and can treat Alzheimer's disease and Parkinson's syndrome. The research on the chemical composition and pharmacological effects of Xanthoceras sorbifolium Bunge has been increasing. Triterpenoid and triterpenoid saponins are the main constituents in Xanthoceras sorbifolium Bunge and exhibit biological activities. In this review, we summarized the research progress on triterpenoids and their glycosides in Xanthoceras sorbifolia, including the chemical constituents, pharmacological activities, and biogenic pathways of triterpenoid mother nucleus. The results would provide a reference for further research and development of triterpenoids and their glycosides in Xanthoceras sorbifolia.
Subject(s)
Saponins , Triterpenes , Saponins/chemistry , Saponins/pharmacology , Saponins/isolation & purification , Triterpenes/chemistry , Triterpenes/pharmacology , Triterpenes/isolation & purification , Humans , Sapindaceae/chemistry , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/isolation & purificationABSTRACT
The wide application of benzophenones (BPs), such as benzophenone-3 (BP3), as an ingredient in sunscreens, cosmetics, coatings, and plastics, has led to their global contamination in aquatic environments. Using the marine diatom Chaetoceros neogracilis as a model, this study assessed the toxic effects and mechanisms of BP3 and its two major metabolites (BP8 and BP1). The results showed that BP3 exhibited higher toxicity on C. neogracilis than BP8 and BP1, with their 72-h median effective concentrations being 0.4, 0.8 and 4 mg/L, respectively. Photosynthesis efficiencies were significantly reduced after exposure to environmentally relevant concentrations of the three benzophenones, while cell viability, membrane integrity, membrane potential, and metabolic activities could be further impaired at their higher concentrations. Comparative transcriptomic analysis, followed by gene ontology and KEGG pathway enrichment analyses unraveled that all the three tested benzophenones disrupted photosynthesis and nitrogen metabolism of the diatom through alteration of similar pathways. The toxic effect of BP3 was also attributable to its unique inhibitory effects on eukaryotic ribosome biosynthesis and DNA replication. Taken together, our findings underscore that benzophenones may pose a significant threat to photosynthesis, oxygen production, primary productivity, carbon fixation, and the nitrogen cycle of diatom in coastal waters worldwide.
Subject(s)
Cosmetics , Diatoms , Diatoms/metabolism , Sunscreening Agents/toxicity , Sunscreening Agents/metabolism , Cosmetics/metabolism , Benzophenones/toxicity , Benzophenones/metabolismABSTRACT
OBJECTIVE: This research aims to explore the efficiency and safety of endoscopic combined intrarenal surgery (Micro-ECIRS) composed of micro-percutaneous nephrolithotomy (Micro-perc) and retrograde intrarenal surgery (RIRS) in the Galdakao-modified supine Valdivia (GMSV) position for a single session for the treatment of complex nephrolithiasis in children. MATERIALS AND METHODS: This study retrospectively reviewed patients aged < 18 years who underwent Micro-ECIRS in the GMSV position for renal stones larger than 2 cm under ultrasound guidance between August 2020 to May 2022 at our institution. RESULTS: A total of 13 patients (8 males and 5 females) received Micro-ECIRS for renal stones under ultrasound guidancewhile adopting the GMSV position. The average stone size was 2.7 cm (range: 2.1-3.7 cm). Among them, 6 patients had left kidney stones, 5 patients had right kidney stones, and 2 patients had bilateral kidney stones. The mean operative time was 70.5 min (range: 54-93 min). The mean hospital stay was 6.4 days (range: 4-9 days). The mean hemoglobin decrease was 8.2 g/L (range: 5.1-12.4 g/L). The total number of kidneys that had complete stone clearance was 8 kidneys at 48 h postoperatively, 11 kidneys at 2 weeks postoperatively, and 14 kidneys at 1 month postoperatively. CONCLUSION: Our results demonstrate that Micro-ECIRS while patients are in the GMSV position is a safe and effective method for the treatment of complex children nephrolithiasis. However, all children made three hospital visits and received anesthesia three times. Further research is needed to confirm these findings.
Subject(s)
Anesthesiology , Kidney Calculi , Nephrolithotomy, Percutaneous , Child , Female , Male , Humans , Retrospective Studies , Kidney Calculi/diagnostic imaging , Kidney Calculi/surgery , Kidney/diagnostic imaging , Kidney/surgeryABSTRACT
Magnetic-free nonreciprocal optical devices have attracted great attention in recent years. Here, we investigated the magnetic-free polarization rotation of light in an atom vapor cell. Two mechanisms of magnetic-free nonreciprocity have been realized in ensembles of hot atoms, including electromagnetically induced transparency and optically-induced magnetization. For a linearly polarized input probe light, a rotation angle up to 86.4° has been realized with external control and pump laser powers of 10â mW and is mainly attributed to the optically-induced magnetization effect. Our demonstration offers a new approach to realize nonreciprocal devices, which can be applied to solid-state atom ensembles and may be useful in photonic integrated circuits.
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BACKGROUND: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is an uncommon subtype of squamous cell carcinoma (SCC) of the lung, closely associated with Epstein-Barr virus (EBV) infection. The pathological features of PPLELC closely resemble those of SCC, which makes it prone to misdiagnosis. Surgical intervention constitutes the primary treatment approach for PPLELC. CASE SUMMARY: This report describes a 44-year-old woman who was hospitalized for 1 mo due to left chest pain. Computed tomography revealed a mass shadow in the anterior basal segment of the left lower lobe, and a subsequent needle biopsy suggested SCC. The patient underwent radical tumor resection in the lower left lobe of the lung, and postoperative pathological examination indicated lymphoepithelial carcinoma, and the test for EBV encoded small RNA was positive. Following surgery, the patient was scheduled to receive four cycles of adjuvant chemotherapy, using the paclitaxel + carboplatin regimen, but the patient refused further treatment. CONCLUSION: PPLELC is an exceptionally rare subtype of lung SCC and is prone to misdiagnosis.
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Introduction: Clonorchis sinensis infection results in various complications in the liver and biliary systems and is a neglected tropical disease in Eastern Asia. In this study, we report that C. sinensis calcium-binding protein Cs16 activates host immune cells and induces immunopathology in liver. Methods: Immunohistochemistry was used to detect the localization of Cs16 in C. sinensis adult worms. ELISA was used to detect the serum levels of anti-Cs16 IgG antibody in infected humans and mice. Bile duct injection model was used to figure out the role of Cs16 in vivo. RT-qPCR and ELISA were used to detect the cytokine production from Cs16-treated BMMs in vitro. Seahorse assay was used to detect the metabolic pathway of Cs16-treated BMMs in vitro. Result: Cs16 localizes in the tegument and gut of C. sinensis. Humans and mice with C. sinensis infection exhibited increased levels of anti-Cs16-specific antibody. Using the bile duct injection technique, we found that Cs16 induced obvious inflammation and hepatic necrosis in vivo. Cs16 treatment caused the upregulation of inflammatory cytokines in innate immune cells. Moreover, Cs16-treated monocytes relied more on the glycolytic metabolic pathway. Discussion: Our findings suggest that Cs16 is a potential pathogenic factor derived from C. sinensis adult worm. By reprogramming the metabolic pathway of innate immune cells, Cs16 triggers pro-inflammatory responses in the liver, and therefore, Cs16 is a potential target for the prevention and treatment of clonorchiasis.
Subject(s)
Clonorchiasis , Clonorchis sinensis , Mice , Humans , Animals , Clonorchis sinensis/physiology , Monocytes/metabolism , Bone Marrow/metabolism , Bone Marrow/pathology , Liver/pathology , Clonorchiasis/pathology , Metabolic Networks and PathwaysABSTRACT
Chlorophyll a (Chla) and diatom community structure are two indicators of lake water quality. In this study, we investigated the environmental parameters, chlorophyll a, and diatom community of four small urban lakes in Kunming (Beitan, Beihu, Nanhu and Longtan lakes in the campus of Yunnan Normal University) between March 2017 and December 2019. The results showed that the concentrations of total nitrogen (TN), total phosphorus (TP), and Chla in the four lakes showed significant seasonal fluctuation. The Chla concentration in Nanhu Lake, which had the highest nutrient level among the four lakes, was significantly higher than that in the other three lakes and largely affected by TN. In comparison, water temperature significantly contributed to the increases in Chla concentration in the other three lakes. Water temperature and TN were significantly correlated with Chla across the four lakes. Diatom assemblages in Beitan, Nanhu, and Longtan lakes were dominated by planktonic diatoms, and benthic diatoms were dominant in the shallowest lake Beihu, suggesting that water depth significantly affected the proportion of planktonic diatoms and dominant taxa. Water depth, TN, TP, transparency, and water temperature affected the spatio-temporal changes of diatom community structure, with water temperature as the major factor in causing the seasonal variation in diatom community, and TN and TP as the major drivers for community variation among lakes within the same season.
Subject(s)
Diatoms , Humans , Chlorophyll A , Lakes/chemistry , Chlorophyll/analysis , Environmental Monitoring , China , Phosphorus/analysis , Nitrogen/analysis , EutrophicationABSTRACT
Cingulin (CGN) is a cytoskeleton-associated protein localized at the apical junctions of epithelial cells. CGN interacts with major cytoskeletal filaments and regulates RhoA activity. However, physiological roles of CGN in development and human diseases are currently unknown. Here, we report a multi-generation family presenting with autosomal dominant non-syndromic hearing loss (ADNSHL) that co-segregates with a CGN heterozygous truncating variant, c.3330delG (p.Leu1110Leufs*17). CGN is normally expressed at the apical cell junctions of the organ of Corti, with enriched localization at hair cell cuticular plates and circumferential belts. In mice, the putative disease-causing mutation results in reduced expression and abnormal subcellular localization of the CGN protein, abolishes its actin polymerization activity, and impairs the normal morphology of hair cell cuticular plates and hair bundles. Hair cell-specific Cgn knockout leads to high-frequency hearing loss. Importantly, Cgn mutation knockin mice display noise-sensitive, progressive hearing loss and outer hair cell degeneration. In summary, we identify CGN c.3330delG as a pathogenic variant for ADNSHL and reveal essential roles of CGN in the maintenance of cochlear hair cell structures and auditory function.
Subject(s)
Deafness , Hearing Loss , Animals , Humans , Mice , Cytoskeletal Proteins , Deafness/genetics , Hair Cells, Auditory/metabolism , Hearing/physiology , Hearing Loss/genetics , Hearing Loss/metabolismABSTRACT
Phytochemical investigation of 70% EtOH extract of the seeds of Capsella bursa-pastoris led to the isolation of a new cyclobutane organic acid (1), and fourteen known compounds, including two organosulfur compounds (2, 3), two quinonoids (4, 5), five flavonoids (6-10), three sterols (11-13) and two other types (14, 15). The structures of the compounds were elucidated by extensive spectroscopic analyses as well as comparison of their spectroscopic data with those reported in the literature. The antioxidant capacities of all compounds and extractive fractions were evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging test and ferric reducing antioxidant power (FRAP) assay. Then the antioxidative substances were evaluated for their neuroprotective effects against H2O2-induced HT22 cell injury. The results indicated the strong scavenging ability to free radical of the extractive fractions and compounds 1-3, 8-10 and 13, and the ferric reducing antioxidant power of the extractive fractions and compounds 1-3, 8 and 10, which were close to or higher than that of the positive control trolox. The EtOAc fraction, n-BuOH fraction, and compounds 1, 3 and 8 can protect HT-22 cells from oxidative damage.
Subject(s)
Antioxidants , Capsella , Antioxidants/analysis , Hydrogen Peroxide , Plant Extracts/chemistry , Phytochemicals/pharmacology , Seeds/chemistryABSTRACT
Background: Glycosylated hemoglobin (HbA1c) is recommended for diagnosing and monitoring type 2 diabetes. However, the monitoring frequency in real-world applications has not yet reached the recommended frequency in the guidelines. Developing machine learning models to screen patients with poor glycemic control in patients with T2D could optimize management and decrease medical service costs. Methods: This study was carried out on patients with T2D who were examined for HbA1c at the Sichuan Provincial People's Hospital from April 2018 to December 2019. Characteristics were extracted from interviews and electronic medical records. The data (excluded FBG or included FBG) were randomly divided into a training dataset and a test dataset with a radio of 8:2 after data pre-processing. Four imputing methods, four screening methods, and six machine learning algorithms were used to optimize data and develop models. Models were compared on the basis of predictive performance metrics, especially on the model benefit (MB, a confusion matrix combined with economic burden associated with therapeutic inertia). The contributions of features were interpreted using SHapley Additive exPlanation (SHAP). Finally, we validated the sample size on the best model. Results: The study included 980 patients with T2D, of whom 513 (52.3%) were defined as positive (need to perform the HbA1c test). The results indicated that the model trained in the data (included FBG) presented better forecast performance than the models that excluded the FBG value. The best model used modified random forest as the imputation method, ElasticNet as the feature screening method, and the LightGBM algorithms and had the best performance. The MB, AUC, and AUPRC of the best model, among a total of 192 trained models, were 43475.750 (¥), 0.972, 0.944, and 0.974, respectively. The FBG values, previous HbA1c values, having a rational and reasonable diet, health status scores, type of manufacturers of metformin, interval of measurement, EQ-5D scores, occupational status, and age were the most significant contributors to the prediction model. Conclusion: We found that MB could be an indicator to evaluate the model prediction performance. The proposed model performed well in identifying patients with T2D who need to undergo the HbA1c test and could help improve individualized T2D management.
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Primary pulmonary hyalinizing clear cell carcinoma (HCCC) is a rare salivary gland-type tumor newly recognized in recent years, with approximately 21 cases reported to date in the English literature, which constitutes a challenge in pathology diagnosis, particularly in small biopsy specimens. Here, we present a case of pulmonary HCCC diagnosed by computed tomography-guided percutaneous lung biopsy in a 70-year-old man's right lower lung. Although the morphology and immunophenotype of the tumor suggested the diagnosis of mucoepidermoid carcinoma, fluorescence in situ hybridization failed to reveal the rearrangement of MAML2 gene, which is characteristic of mucoepidermoid carcinoma. Instead, further molecular genetic testing showed that the tumor harbored a rare EWSR1::CREM fusion combined with a previously unreported IRF2::NTRK3 fusion. Pulmonary HCCC is commonly regarded as a low-grade malignant tumor with an indolent course, but this case has a different biological behavior, presenting extensive dissemination and metastases at the time of diagnosis, which expands our understanding of the prognosis of this tumor. The patient has had five cycles of combination chemotherapy and has been alive with the tumor for eight months.
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Tungsten and molybdenum carbides have shown great potential in catalysis and superconductivity. However, the synthesis of ultrathin W/Mo carbides with a controlled dimension and unique structure is still difficult. Here, inspired by the host-guest assembly strategy with single-walled carbon nanotubes (SWCNTs) as a transparent template, we reported the synthesis of ultrathin (0.8-2.0 nm) W2C and Mo2C nanowires confined in SWCNTs deriving from the encapsulated W/Mo polyoxometalate clusters. The atom-resolved electron microscope combined with spectroscopy and theoretical calculations revealed that the strong interaction between the highly carbophilic W/Mo and SWCNT resulted in the anisotropic growth of carbide nanowires along a specific crystal direction, accompanied by lattice strain and electron donation to the SWCNTs. The SWCNT template endowed carbides with resistance to H2O corrosion. Different from normal modification on the outer surface of SWCNTs, such M2C@SWCNTs (M = W, Mo) provided a delocalized and electron-enriched SWCNT surface to uniformly construct the negatively charged Pd catalyst, which was demonstrated to inhibit the formation of active PdHx hydride and thus achieve highly selective semihydrogenation of a series of alkynes. This work could provide a nondestructive way to design the electron-delocalized SWCNT surface and expand the methodology in synthesizing unusual 1D ultrathin carbophilic-metal nanowires (e.g., TaC, NbC, ß-W) with precise control of the anisotropy in SWCNT arrays.
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Growing application of zinc oxide nanoparticles (ZnO-NPs) in global market has led to the concern over their potential environmental impacts. Filter feeders like mussels are prone to nanoparticles due to their superior filter-feeding ability. Temperature and salinity of coastal and estuarine seawaters often vary seasonally and spatially, and their changes may jointly influence physicochemical properties of ZnO-NPs and thus their toxicity. This study, therefore, aimed to investigate the interactive effect of temperatures (15, 25 and 30 °C) and salinities (12 and 32 PSU) on physicochemical properties and sublethal toxicity of ZnO-NPs towards a marine mussel Xenostrobus securis, and to compare that with the toxicity caused by Zn2+ ions (zinc sulphate heptahydrate). The results revealed increased particle agglomeration but decreased zinc ion release of ZnO-NPs at the highest temperature and salinity condition (30 °C and 32 PSU). After exposure, ZnO-NPs significantly reduced survival, byssal attachment rate and filtration rate of the mussels at high temperature and salinity (30 °C and 32 PSU). Glutathione S-transferase and superoxide dismutase activities in the mussels were suppressed at 30 °C. These aligned with the augmented zinc accumulation with increasing temperature and salinity which could likely be attributable to increased particle agglomeration of ZnO-NP and enhanced intrinsic filtration rate of the mussels under these conditions. Together with the observed lower toxic potency of Zn2+ compared to ZnO-NPs, our results suggested that the mussels might accumulate more zinc through particle filtration under higher temperature and salinity, eventually resulting in elevated toxicity of ZnO-NPs. Overall, this study demonstrated the necessity to consider the interactive effect of environmental factors such as temperature and salinity during the toxicity assessment of nanoparticles.
Subject(s)
Metal Nanoparticles , Mytilidae , Nanoparticles , Zinc Oxide , Animals , Zinc Oxide/toxicity , Temperature , Salinity , Nanoparticles/toxicity , Zinc , Metal Nanoparticles/toxicityABSTRACT
There is growing contamination of copper (Cu) in the marine environment, particularly after the ban of organotin compounds and the increase of the use of Cu-based antifouling paints. Although there are increasing research interests in temperature-dependent chemical toxicity to aquatic organisms, most existing studies focused on acute impacts of chemicals at high concentrations. This study aimed to investigate the interacting effect of temperature and copper exposure at environmentally relevant concentrations on survival and development in the marine copepod Tigriopus japonicus with a partial life-cycle toxicity test. Expressions of five stress response genes in the copepod, namely two glutathione S-transferases (GST-S and GST-O), two heat shock proteins (HSP70 and HSP90), and glutathione reductase (GR) were also investigated. The copepod's survival was significantly impaired at 15 °C after development to adult stage, while its developmental time reduced significantly with increasing temperature. Copper at the two environmentally relevant test concentrations had no significant impacts on these apical endpoints whereas the interaction between Cu and temperature was more significant in modulating gene expressions. GST-S, GST-O and HSP90 genes in copepods exposed to 100 µg Cu L-1 were significantly upregulated at 20 °C. At 32 °C, most genes were either insignificantly expressed or down-regulated, compared to the control, likely suggesting that thermal stress inhibited the copepod's antioxidative defense system. Overall, the results revealed that the joint Cu and thermal stresses have significantly elicited antioxidative system in the copepods. It clearly demonstrated the need for more fundamental studies about potential impacts of different environmental factors such as temperature on chemical toxicity under realistic scenario of marine pollution.
Subject(s)
Copepoda , Water Pollutants, Chemical , Animals , Copper/toxicity , Copper/metabolism , Copepoda/genetics , Temperature , Toxicity Tests/methods , Antioxidants/metabolism , Water Pollutants, Chemical/toxicity , Water Pollutants, Chemical/metabolismABSTRACT
Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.
Subject(s)
Glioma , Immune Checkpoint Inhibitors , Interleukin-8 , Animals , Mice , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Glioma/drug therapy , Glioma/pathology , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy/methods , Interleukin-8/metabolism , T-Lymphocytes , Tumor MicroenvironmentABSTRACT
One new pentacyclic triterpenoid glycoside, ardisiapunine E (1), along with two known compounds were isolated from the root of Ardisia lindleyana D.Dietr. Their structures were elucidated by 1H and 13C NMR, DEPT, HMBC, HSQC, 1H-1H COSY and NOESY spectroscopic analyses, ESI-MS, and literature. Compounds 1-3 exhibited obvious anti-proliferative activities against the HeLa cell line in a dose- and time-dependent manner by inducing G2/M phase arrest and apoptosis in vitro, both consisting of pentacyclic triterpenes and sugar. Hence, this study identified a new and two known pentacyclic triterpenoid glycosides promoting apoptosis as a potential anti-proliferative agent.