ABSTRACT
Lysosomes require an acidic lumen between pH 4.5 and 5.0 for effective digestion of macromolecules. This pH optimum is maintained by proton influx produced by the V-ATPase and efflux through an unidentified "H+ leak" pathway. Here we show that TMEM175, a genetic risk factor for Parkinson's disease (PD), mediates the lysosomal H+ leak by acting as a proton-activated, proton-selective channel on the lysosomal membrane (LyPAP). Acidification beyond the normal range potently activated LyPAP to terminate further acidification of lysosomes. An endogenous polyunsaturated fatty acid and synthetic agonists also activated TMEM175 to trigger lysosomal proton release. TMEM175 deficiency caused lysosomal over-acidification, impaired proteolytic activity, and facilitated α-synuclein aggregation in vivo. Mutational and pH normalization analyses indicated that the channel's H+ conductance is essential for normal lysosome function. Thus, modulation of LyPAP by cellular cues may dynamically tune the pH optima of endosomes and lysosomes to regulate lysosomal degradation and PD pathology.
Subject(s)
Parkinson Disease , Endosomes/metabolism , Humans , Hydrogen-Ion Concentration , Intracellular Membranes/metabolism , Lysosomes/metabolism , Parkinson Disease/metabolism , Potassium Channels/metabolism , ProtonsABSTRACT
Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/-) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/- mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.
Subject(s)
Calgranulin A , Calgranulin B , Mice, Transgenic , Parkinson Disease , Ubiquitin Thiolesterase , alpha-Synuclein , Animals , Female , Humans , Male , Mice , alpha-Synuclein/metabolism , alpha-Synuclein/genetics , Calgranulin A/metabolism , Calgranulin A/genetics , Calgranulin B/metabolism , Calgranulin B/genetics , Disease Models, Animal , Mice, Inbred C57BL , Parkinson Disease/metabolism , Parkinson Disease/genetics , Parkinson Disease/pathology , Ubiquitin Thiolesterase/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/deficiencyABSTRACT
Accumulating evidence suggests that a wide variety of cell deaths are deeply involved in cancer immunity. However, their roles in glioma have not been explored. We employed a logistic regression model with the shrinkage regularization operator (LASSO) Cox combined with seven machine learning algorithms to analyse the patterns of cell death (including cuproptosis, ferroptosis, pyroptosis, apoptosis and necrosis) in The Cancer Genome Atlas (TCGA) cohort. The performance of the nomogram was assessed through the use of receiver operating characteristic (ROC) curves and calibration curves. Cell-type identification was estimated by using the cell-type identification by estimating relative subsets of known RNA transcripts (CIBERSORT) and single sample gene set enrichment analysis methods. Hub genes associated with the prognostic model were screened through machine learning techniques. The expression pattern and clinical significance of MYD88 were investigated via immunohistochemistry (IHC). The cell death score represents an independent prognostic factor for poor outcomes in glioma patients and has a distinctly superior accuracy to that of 10 published signatures. The nomogram performed well in predicting outcomes according to time-dependent ROC and calibration plots. In addition, a high-risk score was significantly related to high expression of immune checkpoint molecules and dense infiltration of protumor cells, these findings were associated with a cell death-based prognostic model. Upregulated MYD88 expression was associated with malignant phenotypes and undesirable prognoses according to the IHC. Furthermore, high MYD88 expression was associated with poor clinical outcomes and was positively related to CD163, PD-L1 and vimentin expression in the in-horse cohort. The cell death score provides a precise stratification and immune status for glioma. MYD88 was found to be an outstanding representative that might play an important role in glioma.
Subject(s)
Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Glioma , Machine Learning , Nomograms , Humans , Glioma/genetics , Glioma/immunology , Glioma/pathology , Prognosis , Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Brain Neoplasms/immunology , Brain Neoplasms/pathology , Brain Neoplasms/mortality , Cell Death/genetics , Male , Female , ROC Curve , Gene Expression Profiling , Middle Aged , Transcriptome , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolismABSTRACT
Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention tool for the noninvasive modulation of brain activity and behavior in neuroscience research and clinical settings. However, the resting-state dynamic evolution of large-scale functional brain networks following rTMS has rarely been investigated. Here, using resting-state fMRI images collected from 23 healthy individuals before (baseline) and after 1 Hz rTMS of the left frontal (FRO) and occipital (OCC) lobes, we examined the different effects of rTMS on brain dynamics across the human cortex. By fitting a pairwise maximum entropy model (pMEM), we constructed an energy landscape for the baseline and poststimulus conditions by fitting a pMEM. We defined dominant brain states (local minima) in the energy landscape with synergistic activation and deactivation patterns of large-scale functional networks. We calculated state dynamics including appearance probability, transitions and duration. The results showed that 1 Hz rTMS induced increased and decreased state probability, transitions and duration when delivered to the FRO and OCC targets, respectively. Most importantly, the shortest path and minimum cost between dominant brain states were altered after stimulation. The absolute sum of the costs from the source states to the destinations was lower after OCC stimulation than after FRO stimulation. In conclusion, our study characterized the dynamic trajectory of state transitions in the energy landscape and suggested that local rTMS can induce significant dynamic perturbation involving stimulated and distant functional networks, which aligns with the modern view of the dynamic and complex brain. Our results suggest low-dimensional mapping of rTMS-induced brain adaption, which will contribute to a broader and more effective application of rTMS in clinical settings.
Subject(s)
Magnetic Resonance Imaging , Nerve Net , Transcranial Magnetic Stimulation , Humans , Transcranial Magnetic Stimulation/methods , Adult , Male , Female , Nerve Net/physiology , Nerve Net/diagnostic imaging , Young Adult , Connectome/methods , Occipital Lobe/physiology , Occipital Lobe/diagnostic imaging , Frontal Lobe/physiology , Frontal Lobe/diagnostic imaging , Cerebral Cortex/physiology , Cerebral Cortex/diagnostic imagingABSTRACT
PURPOSE: To evaluate whether BeEAM is an alternative to BEAM for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). METHODS: Data of 60 patients with relapsed or refractory DLBCL who underwent ASCT from January 2018 to June 2023 in our center, including 30 patients in the BeEAM group and 30 patients in the BEAM group, were retrospectively analyzed. The time to hematopoietic reconstitution, treatment-related adverse events, number of hospitalization days, hospitalization cost, and survival benefit were compared between the two groups. RESULTS: The clinical characteristics of the patients did not significantly differ between the two groups. The median number of reinfused CD34 + cells was 5.06 × 106/kg and 5.17 × 106/kg in the BeEAM and BEAM groups, respectively, which did not significantly different (p = 0.8829). In the BeEAM and BEAM groups, the median time to neutrophil implantation was 10.2 and 10.27 days, respectively (p = 0.8253), and the median time to platelet implantation was 13.23 and 12.87 days, respectively (p = 0.7671). In the BeEAM and BEAM groups, the median hospitalization duration was 30.37 and 30.57 days, respectively (p = 0.9060), and the median hospitalization cost was RMB 83,425 and RMB 96,235, respectively (p = 0.0560). The hospitalization cost was lower in the BeEAM group. The most common hematologic adverse events were grade ≥ 3 neutropenia and thrombocytopenia, whose incidences were similar in the two groups. The most common non-hematologic adverse events were ≤ grade 2 and the incidences of these events did not significantly differ between the two groups. Median overall survival was not reached in either group, with predicted 5-year overall survival of 72.5% and 60% in the BeEAM and BEAM groups, respectively (p = 0.5872). Five-year progression-free survival was 25% and 20% in the BeEAM and BEAM groups, respectively (p = 0.6804). CONCLUSION: As a conditioning regimen for relapsed or refractory DLBCL, BeEAM has a desirable safety profile and is well tolerated, and its hematopoietic reconstitution time, number of hospitalization days, and survival benefit are not inferior to those of BEAM. BeEAM has a lower hospitalization cost and is an alternative to BEAM.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Hematopoietic Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse , Transplantation Conditioning , Transplantation, Autologous , Humans , Male , Female , Middle Aged , Adult , Lymphoma, Large B-Cell, Diffuse/therapy , Retrospective Studies , Transplantation Conditioning/methods , Hematopoietic Stem Cell Transplantation/economics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/economics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cytarabine/administration & dosage , Cytarabine/therapeutic use , Carmustine/administration & dosage , Melphalan/administration & dosage , Melphalan/therapeutic use , Aged , Etoposide/administration & dosage , Etoposide/therapeutic use , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Survival RateABSTRACT
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive approach to modulate brain activity and behavior in humans. Still, how individual resting-state brain dynamics after rTMS evolves across different functional configurations is rarely studied. Here, using resting state fMRI data from healthy subjects, we aimed to examine the effects of rTMS to individual large-scale brain dynamics. Using Topological Data Analysis based Mapper approach, we construct the precise dynamic mapping (PDM) for each participant. To reveal the relationship between PDM and canonical functional representation of the resting brain, we annotated the graph using relative activation proportion of a set of large-scale resting-state networks (RSNs) and assigned the single brain volume to corresponding RSN-dominant or a hub state (not any RSN was dominant). Our results show that (i) low-frequency rTMS could induce changed temporal evolution of brain states; (ii) rTMS didn't alter the hub-periphery configurations underlined resting-state brain dynamics; and (iii) the rTMS effects on brain dynamics differ across the left frontal and occipital lobe. In conclusion, low-frequency rTMS significantly alters the individual temporo-spatial dynamics, and our finding further suggested a potential target-dependent alteration of brain dynamics. This work provides a new perspective to comprehend the heterogeneous effect of rTMS.
Subject(s)
Brain , Transcranial Magnetic Stimulation , Humans , Transcranial Magnetic Stimulation/methods , Brain/diagnostic imaging , Magnetic Resonance Imaging/methods , Occipital Lobe , Neural Pathways/diagnostic imaging , Neural Pathways/physiologyABSTRACT
Identifying sediment phosphorus sources, the key to control eutrophication, is hindered in multi-source polluted urban rivers by the lack of appropriate methods and data resolution. Community-based microbial source tracking (MST) offers new insight, but the bacterial communities could be affected by environmental fluctuations during the migration with sediments, which might induce instability of MST results. Therefore, the effects of environmental-induced community succession on the stability of MST were compared in this study. Liangxi River, a highly eutrophic urban river, was selected as the study area where sediment phosphorus sources are difficult to track because of multi-source pollution and complicated hydrodynamic conditions. Spearman correlation analysis (P < 0.05) was conducted to recognize a close relationship between sediment, bacterial communities and phosphorus, verifying the feasibility of MST for identify sediment phosphorus sources. Two distinct microbial community fingerprints were constructed based on whether excluded 113 vulnerable species, which were identified by analyzing the differences of microorganisms across a concentration gradient of exogenous phosphorus input in microbial environmental response experiment. Because of the lower unknown proportion and relative standard deviations, MST results were more stable and reliable when based on the fingerprints excluding species vulnerable to phosphorus. This study presents a novel insight on how to identify sediment phosphorus sources in multi-source polluted urban river, and would help to develop preferential control strategies for eutrophication management.
Subject(s)
Microbiota , Water Pollutants, Chemical , Rivers , Environmental Monitoring/methods , Geologic Sediments , Phosphorus/analysis , Bacteria , China , Water Pollutants, Chemical/toxicity , Water Pollutants, Chemical/analysisABSTRACT
Water column mixing homogenizes thermal and chemical gradients which are known to define distribution of microbial communities and influence the prevailing biogeochemical processes. Little is however known about the effects of rapid water column mixing on the vertical distribution of microbial communities in stratified reservoirs. To address this knowledge gap, physicochemical properties and microbial community composition from 16 S rRNA amplicon sequencing were analyzed before and after mixing of vertically stratified water-column bioreactors. Our results showed that α-diversity of bacterial communities decreased from bottom to surface during periods of thermal stratification. After an experimental mixing event, bacterial community diversity experienced a significant decrease throughout the water column and network connectivity was disrupted, followed by slow recovery. Significant differences in composition were seen for both total (DNA) and active (RNA) bacterial communities when comparing surface and bottom layer during periods of stratification, and when comparing samples collected before mixing and after re-stratification. The dominant predicted community assembly processes for stratified conditions were deterministic while such processes were less important during recovery from episodic mixing. Water quality characteristics of stratified water were significantly correlated with bacterial community diversity and structure. Furthermore, structural equation modeling analyses showed that changes in sulfur may have the greatest direct effect on bacterial community composition. Our results imply that rapid vertical mixing caused by episodic weather extremes and hydrological operations may have a long-term effect on microbial communities and biogeochemical processes.
Subject(s)
Bacteria , Water Microbiology , Bacteria/genetics , Weather , Temperature , Water QualityABSTRACT
Both g-C3N4 and Bi2O2CO3 are good photocatalysts for the removal of antibiotic pollutants, but their morphological modulation and catalytic performance need to be further improved. In this study, the calcination-hydrothermal method is used to prepare a O-g-C3N4@Bi2O2CO3 (CN@BCO) composite photocatalyst from dicyandiamide and bismuth nitrate. The prepared catalyst is characterized through various methods, including X-ray diffraction (XRD) and transmission electron microscopy (TEM). Further, the effects of different parameters, such as catalyst concentration and initial pH of the reaction solution, on its photocatalytic activity are investigated. The results show that the CN@BCO sample achieves an optimal degradation rate of 98.1% for tetracycline hydrochloride (TCH) with a concentration of 20 mg/L and a removal rate of 69.4% for total organic carbon (TOC) at 40 min. The quenching experiments show that ·O2-, h+, and ·OH participate in the photocatalytic process, with ·O2- being the most dominant active species. The toxicity of the predicted TCH degradation intermediates is analyzed using Toxicity Estimation Software Tool (TEST). Overall, the CN@BCO composite exhibits excellent photocatalytic performance, making it a promising candidate for environmental purification and wastewater treatment.
Subject(s)
Bismuth , Tetracycline , Wastewater , Water Pollutants, Chemical , Tetracycline/chemistry , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/analysis , Wastewater/chemistry , Bismuth/chemistry , Catalysis , Anti-Bacterial Agents/chemistry , Nanowires/chemistry , Nitrogen Compounds/chemistry , Nitriles/chemistry , Porosity , GraphiteABSTRACT
INTRODUCTION: Tumor-associated macrophages, which are part of the tumor microenvironment, are a major factor in cancer progression. However, a complete understanding of the regulatory mechanism of M2 polarization of macrophages (Mø) in liver cancer is yet to be established. This study aimed to investigate the potential mechanism by which NEIL3 influenced M2 Mø polarization in liver cancer. METHODS: Bioinformatics analysis analyzed NEIL3 expression and its enriched pathways in liver cancer tissue, as well as its correlation with pathway genes. The upstream transcription factor of NEIL3, TFAP2A, was predicted and its expression in liver cancer tissue was analyzed. The binding relationship between the two was analyzed by dual-luciferase reporter and chromatin immunoprecipitation experiments. qRT-PCR assessed NEIL3 and TFAP2A levels in liver cancer cells. Cell viability was detected by CCK-8, while CD206 and CD86 expression was detected by immunofluorescence. IL-10 and CCR2 expressions were assessed using qRT-PCR, and M2 Mø quantity was detected using flow cytometry. Reagent kits tested glutamine (Gln) consumption, α-ketoglutarate, and glutamate content, as well as NADPH/NADP+ and GSH/GSSG ratios. Expression of Gln transport proteins was detected using Western blot. An animal model was established to investigate the influence of NEIL3 expression on liver cancer growth. RESULTS: NEIL3 was highly expressed in liver cancer and promoted Mø M2 polarization through Gln metabolism. TFAP2A was identified as the upstream transcription factor of NEIL3 and was highly expressed in liver cancer. Rescue experiments presented that overexpression of NEIL3 reversed the suppressive effect of TFAP2A knockdown on Mø M2 polarization in liver cancer. In vivo experiments demonstrated that the knockdown of NEIL3 could significantly repress the growth of xenograft tumors. CONCLUSION: This study suggested that the TFAP2A/NEIL3 axis promoted Mø M2 polarization through Gln metabolism, providing a theoretical basis for immune therapy targeting the liver cancer TME.
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BACKGROUND: This study aimed to investigate the prognostic value of the geriatric nutritional risk index (GNRI) in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) who underwent nephrectomy. METHODS: Patients with non-metastatic ccRCC who underwent nephrectomy between 2013 and 2021 were analyzed retrospectively. The GNRI was calculated within one week before surgery. The optimal cut-off value of GNRI was determined using X-tile software, and the patients were divided into a low GNRI group and a high GNRI group. The Kaplan-Meier method was used to compare the overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) between the two groups. Univariate and multivariate Cox proportional hazard models were used to determine prognostic factors. In addition, propensity score matching (PSM) was performed with a matching ratio of 1:3 to minimize the influence of confounding factors. Variables entered into the PSM model were as follows: sex, age, history of hypertension, history of diabetes, smoking history, BMI, tumor sidedness, pT stage, Fuhrman grade, surgical method, surgical approach, and tumor size. RESULTS: A total of 645 patients were included in the final analysis, with a median follow-up period of 37 months (range: 1-112 months). The optimal cut-off value of GNRI was 98, based on which patients were divided into two groups: a low GNRI group (≤ 98) and a high GNRI group (> 98). Kaplan-Meier analysis showed that OS (P < 0.001), CSS (P < 0.001) and RFS (P < 0.001) in the low GNRI group were significantly worse than those in the high GNRI group. Univariate and multivariate Cox analysis showed that GNRI was an independent prognostic factor of OS, CSS and RFS. Even after PSM, OS (P < 0.05), CSS (P < 0.05) and RFS (P < 0.05) in the low GNRI group were still worse than those in the high GNRI group. In addition, we observed that a low GNRI was associated with poor clinical outcomes in elderly subgroup (> 65) and young subgroup (≤ 65), as well as in patients with early (pT1-T2) and low-grade (Fuhrman I-II) ccRCC. CONCLUSION: As a simple and practical tool for nutrition screening, the preoperative GNRI can be used as an independent prognostic indicator for postoperative patients with non-metastatic ccRCC. However, larger prospective studies are necessary to validate these findings.
Subject(s)
Carcinoma, Renal Cell , Geriatric Assessment , Kidney Neoplasms , Nutrition Assessment , Nutritional Status , Propensity Score , Humans , Carcinoma, Renal Cell/surgery , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Male , Female , Aged , Prognosis , Retrospective Studies , Kidney Neoplasms/surgery , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Middle Aged , Geriatric Assessment/methods , Geriatric Assessment/statistics & numerical data , Nephrectomy/methods , Kaplan-Meier Estimate , Risk Factors , Proportional Hazards Models , Risk Assessment/methods , Aged, 80 and overABSTRACT
Parkinson's disease (PD) is a progressive movement disorder characterized by dopaminergic (DA) neuron degeneration and the existence of Lewy bodies formed by misfolded α-synuclein. Emerging evidence supports the benefits of dietary interventions in PD due to their safety and practicality. Previously, dietary intake of α-ketoglutarate (AKG) was proved to extend the lifespan of various species and protect mice from frailty. However, the mechanism of dietary AKG's effects in PD remains undetermined. In the present study, we report that an AKG-based diet significantly ameliorated α-synuclein pathology, and rescued DA neuron degeneration and impaired DA synapses in adeno-associated virus (AAV)-loaded human α-synuclein mice and transgenic A53T α-synuclein (A53T α-Syn) mice. Moreover, AKG diet increased nigral docosahexaenoic acid (DHA) levels and DHA supplementation reproduced the anti-α-synuclein effects in the PD mouse model. Our study reveals that AKG and DHA induced microglia to phagocytose and degrade α-synuclein via promoting C1q and suppressed pro-inflammatory reactions. Furthermore, results indicate that modulating gut polyunsaturated fatty acid metabolism and microbiota Lachnospiraceae_NK4A136_group in the gut-brain axis may underlie AKG's benefits in treating α-synucleinopathy in mice. Together, our findings propose that dietary intake of AKG is a feasible and promising therapeutic approach for PD.
Subject(s)
Parkinson Disease , Synucleinopathies , Mice , Animals , Humans , Parkinson Disease/pathology , Ketoglutaric Acids/pharmacology , Mice, Transgenic , Nerve Degeneration/pathology , Dopamine , Eating , Disease Models, AnimalABSTRACT
BACKGROUND: This study aimed to identify potential biomarkers for the diagnosis and treatment of osteoporosis (OP). METHODS: Data sets were downloaded from the Gene Expression Omnibus database, and differentially programmed cell death-related genes were screened. Functional analyses were performed to predict the biological processes associated with these genes. Least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF) machine learning algorithms were used to screen for characteristic genes, and receiver operating characteristics were used to evaluate the diagnosis of disease characteristic gene values. Gene set enrichment analysis (GSEA) and single-sample GSEA were conducted to analyze the correlation between characteristic genes and immune infiltrates. Cytoscape and the Drug Gene Interaction Database (DGIdb) were used to construct the mitochondrial RNA-mRNA-transcription factor network and explore small-molecule drugs. Reverse transcription real-time quantitative PCR (RT-qPCR) analysis was performed to evaluate the expression of biomarker genes in clinical samples. RESULTS: In total, 25 differential cell death genes were identified. Among these, two genes were screened using the LASSO, SVM, and RF algorithms as characteristic genes, including BRSK2 and VPS35. In GSE56815, the area under the receiver operating characteristic curve of BRSK2 was 0.761 and that of VPS35 was 0.789. In addition, immune cell infiltration analysis showed that BRSK2 positively correlated with CD56dim natural killer cells and negatively correlated with central memory CD4 + T cells. Based on the data from DGIdb, hesperadin was associated with BRSK2, and melagatran was associated with VPS35. BRSK2 and VPS35 were expectably upregulated in OP group compared with controls (all p < 0.05). CONCLUSIONS: BRSK2 and VPS35 may be important diagnostic biomarkers of OP.
Subject(s)
Apoptosis , Machine Learning , Humans , Cell Death/genetics , Biomarkers , Databases, FactualABSTRACT
In the present study, we aimed to explore the effect and underlying mechanism of metformin on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). A total of 24 BALB/C mice were randomly divided into four groups: control group, LPS group and metformin group (50 or 100 mg/kg). The histological changes and cell apoptosis in kidney tissues were detected by hematoxylin-eosin staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling assay, respectively. Enzyme-linked immunosorbent assay was applied to determine serum levels of blood urea nitrogen (BUN), kidney injury molecule-1 (Kim-1), creatinine (Cre), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). Western blotting analysis were carried out to confirm the expressions of monocyte chemotactic protein-inducible protein 1 (MCPIP1), silent information regulator sirtuin 1 (SIRT1), and NF-κB p65 (acetyl K310). Compared with the control group, the mice in LPS group had glomerular capillary dilatation, renal interstitial edema, tubular cell damage and apoptosis. The serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß in LPS group were significantly higher than those in control group. Moreover, LPS also elevated the expressions of MCPIP1 and NF-κB p65 (acetyl K310) but decreased the expression of SIRT1 in kidney tissues. However, metformin distinctly decreased LPS-induced renal dysfunction, the serum levels of BUN, KIM-1, Cre, TNF-α, and IL-1ß. In addition, metformin markedly increased the expressions of MCPIP1 and SIRT1 but decreased the expression of NF-κB p65 (acetyl K310) in kidney tissues. Metformin prevented LPS-induced AKI by up-regulating the MCPIP1/SIRT1 signaling pathway and subsequently inhibiting NF-κB-mediated inflammation response.
ABSTRACT
Here, we present a case of choriocarcinoma with metastasis only to the right inferior pulmonary vein and heart, which is unusual, as the skipping of lung metastasis is extremely rare. The 34-year-old patient presented with cough and hemoptysis. The diagnosis was challenging due to the absence of gynecological abnormalities and elevated ß-HCG levels, only revealing a cardiac mass upon imaging. While no abnormalities were found through gynecological ultrasound or gynecological examination, the serum human chorionic gonadotropin ß subunit (ß-HCG) level was abnormally raised. Echocardiography showed a left atrial myxoma with a size of approximately 6.3×1.81 cm. A left atrial mass resection was performed during cardiac surgery, where it was found that the left atrial mass had originated from the right inferior pulmonary vein. It was approximately 6×3×3 cm in size, with a flesh-red color and firm tissue. Postoperative pathology and immunohistochemistry indicated choriocarcinoma. The cardiac surgery unearthed a mass originating from the right inferior pulmonary vein. Its size and characteristics, along with the chemotherapy regimens that followed, are crucial details for understanding treatment approaches for such atypical cases. Highlight the patient's recovery post-treatment and the effectiveness of the chemotherapy regimen. This offers insights into the potential for successful treatment outcomes in atypical choriocarcinoma cases. The patient underwent chemotherapy regimens with etoposide, cisplatin (EP) ,etoposide, and methotrexate, and dactinomycin alternating with cyclophosphamide and vincristine (EMACO). A satisfactory result was achieved. This case enhances understanding of choriocarcinoma metastasis patterns. It underscores the need for a multidisciplinary approach in diagnosing and managing such rare presentations.
Subject(s)
Choriocarcinoma , Heart Atria , Heart Neoplasms , Pulmonary Veins , Humans , Female , Adult , Heart Atria/pathology , Choriocarcinoma/diagnosis , Choriocarcinoma/pathology , Heart Neoplasms/secondary , Uterine NeoplasmsABSTRACT
Dihydrochalcones (DHCs) constitute a specific class of flavonoids widely known for their various health-related advantages. Melatonin (MLT) has received attention worldwide as a master regulator in plants, but its roles in DHC accumulation remain unclear. Herein, the elicitation impacts of MLT on DHC biosynthesis were examined in Lithocarpus litseifolius, a valuable medicinal plant famous for its sweet flavor and anti-diabetes effect. Compared to the control, the foliar application of MLT significantly increased total flavonoid and DHC (phlorizin, trilobatin, and phloretin) levels in L. litseifolius leaves, especially when 100 µM MLT was utilized for 14 days. Moreover, antioxidant enzyme activities were boosted after MLT treatments, resulting in a decrease in the levels of intracellular reactive oxygen species. Remarkably, MLT triggered the biosynthesis of numerous phytohormones linked to secondary metabolism (salicylic acid, methyl jasmonic acid (MeJA), and ethylene), while reducing free JA contents in L. litseifolius. Additionally, the flavonoid biosynthetic enzyme activities were enhanced by the MLT in leaves. Multiple differentially expressed genes (DEGs) in RNA-seq might play a crucial role in MLT-elicited pathways, particularly those associated with the antioxidant system (SOD, CAT, and POD), transcription factor regulation (MYBs and bHLHs), and DHC metabolism (4CL, C4H, UGT71K1, and UGT88A1). As a result, MLT enhanced DHC accumulation in L. litseifolius leaves, primarily by modulating the antioxidant activity and co-regulating the physiological, hormonal, and transcriptional pathways of DHC metabolism.
Subject(s)
Chalcones , Gene Expression Regulation, Plant , Melatonin , Plant Growth Regulators , Plant Leaves , Plant Leaves/metabolism , Plant Leaves/genetics , Chalcones/metabolism , Melatonin/metabolism , Plant Growth Regulators/metabolism , Gene Expression Profiling , Flavonoids/metabolism , Reactive Oxygen Species/metabolism , Antioxidants/metabolismABSTRACT
Nitrogen, phosphorus and potassium are essential for crop growth, which are abundant in urine. Although numerous studies have developed techniques to recover ammonium and phosphorus from urine, limited research made efforts on the recovery of potassium, which is a non-renewable resource with uneven global distribution. In this study, we explored the possibility of zeolite based mixed matrix membranes (MMMs) to selectively recover ammonium and potassium from urine, with minimal detention of sodium. The findings demonstrated that upon the pre-treatment of zeolites with sodium chloride solution, a 70 wt% zeolite loaded MMM could achieve 69.3 % recovery of potassium and almost full recovery of ammonium. By varying the desorption temperatures and MMMs production process, it was discovered that stepwise backwash at low temperature (276 K) greatly lowered sodium recovery whilst simultaneously enhancing the recovery of potassium and ammonium. This study demonstrates the potential of recovering potassium and ammonium from urine using zeolite-loaded MMMs, coupled with achieving low-sodium recovery.
Subject(s)
Ammonium Compounds , Potassium , Zeolites , Zeolites/chemistry , Potassium/urine , Potassium/chemistry , Ammonium Compounds/chemistry , Urine/chemistry , Phosphorus/chemistry , Sodium/urine , Sodium/chemistryABSTRACT
Rainwater Harvesting Systems (RHS) are widely implemented to mitigate urban water shortages, yet the impacts of compatibility between rainwater availability and water demand on their performance are often overlooked. This study introduces novel rainwater deficit and surplus indices to quantitatively assess the impacts of compatibility between rainwater availability and water demand on the performance of RHS across 16 cities in different climate zones and under 3 daily water demand scenarios. The rainwater deficit and surplus indices, and the water saving efficiency and reliability of RHS are calculated based on long-term (1991-2020) continuous simulations using a daily water balance model. Results show the rainwater deficit index effectively quantifies water supply pressure on RHS, while the rainwater surplus index quantitatively evaluates their water saving potential. Both of water saving efficiency and reliability of RHS significantly linearly decrease with the rainwater deficit index (P < 0.05), and the coefficients of determination (R2) decrease from 0.96 to 0.80 as tank size increases from 1 to 300 m3. Both of water saving efficiency and reliability increase along sigmoid curves with the rainwater surplus index (P < 0.05), and R2 values increase from 0.91 to 0.99 with tank size. The results indicate that tank size optimization enhances water saving performance of RHS through reducing deficits and surpluses. However, the performance enhancement by tank size optimization could be limited by the compatibility between rainwater availability and water demand. Taken Kashgar (arid climate) as an example, the thresholds of water saving efficiency under all water demand scenarios are below 15% due to high rainwater deficit and low surplus. This study emphasizes that the compatibility between rainwater availability and water demand should be considered in planning and design of RHS.
ABSTRACT
Hydraulic mixing of stratified reservoirs homogenizes physicochemical gradients and microbial communities. This has potential repercussions for microbial metabolism and water quality, not least in dams and hydraulically controlled waters. A better understanding of how key taxa respond to mixing of such stratified water bodies is needed to understand and predict the impact of hydraulic operations on microbial communities and nutrient dynamics in reservoirs. We studied taxa transitions between cyanobacteria and sulfur-transforming bacteria following mixing of stratified water columns in bioreactors and complemented the experimental approach with a biogeochemical model. Model predictions were consistent with experimental observations, suggesting that stable stratification of DO is restored within 24 h after episodic and complete mixing, at least in the absence of other more continuous disturbances. Subsequently, the concentration of S2- gradually return to pre-mixing states, with higher concentration at the surface and lower in the bottom waters, while the opposite pattern was seen for SO42-. The total abundance of sulfate-reducing bacteria and phototrophic sulfur bacteria increased markedly after 24h of mixing. The model further predicted that the rapid re-oxygenation of the entire water column by aeration will effectively suppress the water stratification and the growth of sulfur-transforming bacteria. Based on these results, we suggest that a reduction of thermocline depth by optimal flow regulation in reservoirs may also depress sulfur transforming bacteria and thereby constrain sulfur transformation processes and pollutant accumulation. The simulation of microbial nutrient transformation processes in vertically stratified waters can provide new insights about effective environmental management measures for reservoirs.
Subject(s)
Bacteria , Bacteria/metabolism , Cyanobacteria , Water Quality , Water Microbiology , Models, TheoreticalABSTRACT
Ten novel hydrophobic dicationic ionic liquids (DILs) were synthesized and applied for the extraction of heavy metals in aqueous solutions. Their physicochemical properties were measured at ambient temperature, and the leaching behaviors of the as-prepared DILs in water were assessed by TOC analysis. Metal extraction experiments were carried out to evaluate the extraction performances of the DILs. It was found that the extraction rates of up to 0.45 and 0.53 mg·(g·min)-1 were achieved with 100 mg DILs for 5 mL of 5 mg/L Cd2+ and Pb2+ solutions. Besides, the extraction efficiencies of Cd2+ and Pb2+ were respectively up to 95.48% and 98.46%, when the volumes of the simulated wastewater were expanded by a factor of 20 at a constant extraction phase ratio (1000 mg DILs for 50 mL of 5 mg/L Cd2+ or Pb2+ solutions). The reusability of the novel DILs was successfully proved by the back-extraction experiments with 0.5 M HNO3. Finally, taking Cd2+ extraction as an example, the extraction mechanism based on FTIR analysis and quantum chemical calculations showed that both S and O atoms in the anions of DILs had physical and quasi-chemical interactions with Cd2+, which were stronger than the electrostatic attraction.