The value of nomogram based on MRI functional imaging in differentiating cerebral alveolar echinococcosis from brain metastases.

OBJECTIVE: This study aims to evaluate the effectiveness of a nomogram model constructed using Diffusion Kurtosis Imaging (DKI) and 3D Arterial Spin Labeling (3D-ASL) functional imaging techniques in distinguishing between cerebral alveolar echinococcosis (CAE) and brain metastases (BM). METHODS: Prospectively collected were 24 cases (86 lesions) of patients diagnosed with CAE and 16 cases (69 lesions) of patients diagnosed with BM at the affiliated hospital of Qinghai University from 2018 to 2023, confirmed either pathologically or through comprehensive diagnosis. Both patient groups underwent DKI and 3D-ASL scanning. DKI parameters (Kmean, Dmean, FA, ADC) and cerebral blood flow (CBF) were analyzed for the parenchymal area, edema area, and symmetrical normal brain tissue area in both groups. There were 155 lesions in total in the two groups of patients. We used SPSS to randomly select 70% as the training set (108 lesions) and the remaining 30% as the test set (47 lesions) and performed a difference analysis between the two groups. The independent factors distinguishing CAE from BM were identified using univariate and multivariate logistic regression analyses. Based on these factors, a diagnostic model was constructed and expressed as a nomogram. RESULT: Univariate and multivariate logistic regression analyses identified nDmean1 and nCBF1 in the lesion parenchyma area, as well as nKmean2 and nDmean2 in the edema area, as independent factors for distinguishing CAE from BM. The model's performance, measured by the area under the ROC curve (AUC), had values of 0.942 and 0.989 for the training and test sets, respectively. Calibration curves demonstrated that the predicted probabilities were highly consistent with the actual values, and DCA confirmed the model's high clinical utility. CONCLUSION: The nomogram model, which incorporates DKI and 3D-ASL functional imaging, effectively distinguishes CAE from BM. It offers an intuitive, accurate, and non-invasive method for differentiation, thus providing valuable guidance for subsequent clinical decisions.

The value of nomogram analysis in prediction of cerebral spread of hepatic alveolar echinococcosis.

BACKGROUND: The prognosis after brain metastasis of alveolar echinococcosis is inferior, but there is currently no effective method to predict brain metastasis. PURPOSE: To explore the value of a nomogram constructed based on a CT plain scan and enhanced imaging features combined with clinical indicators in predicting brain metastasis of hepatic alveolar echinococcosis (HAE). MATERIALS AND METHODS: The imaging characteristics and clinical indicators of 116 patients diagnosed with HAE in the Affiliated Hospital of Qinghai University from 2015 to 2022 were retrospectively collected. The data were randomly divided into a training set and a validation set according to 7:3, and the difference between the two groups was analyzed. Binary logistic regression analysis was used to obtain independent predictors of brain metastasis in HAE, and a prediction model was constructed based on this and expressed in the form of a nomogram. Receiver operating characteristic (ROC) curve and calibration curve (CRC) were used to evaluate model performance, and decision curve analysis (DCA) was used to assess the clinical value of the predictive model. RESULT: A total of 116 HAE patients were included (average age 38.07±15.09 years old, 54 males and 62 females, 81 patients (70 %) in the training set, and 35 patients (30 %) in the validation set). There was no statistically significant difference between CT plain scan and enhanced imaging features combined with clinical indicators between the training set and the validation set (p > 0.05). After statistical analysis, it was found that whether there is invasion of the inferior vena cava, whether there is invasion of the hepatic artery, and whether there is metastasis to other organs are independent predictors of brain metastasis in HAE. A prediction model was built based on these three variables. The area under the ROC curve (AUC), cutoff value, sensitivity, and specificity of the training set and validation set were 0.922 and 0.886, 0.6934 and 0.6643, 75.00 and 84.62, 94.34 and 81.82, respectively. CRC shows good consistency between the predicted probability and the actual value of the sample. DCA showed that the clinical value of the model was high. CONCLUSION: The nomogram constructed based on imaging features combined with clinical indicators can effectively predict whether HAE will develop brain metastasis, which is helpful for clinicians to quickly screen out high-risk patients with HAE developing brain metastases, evaluate patient prognosis, and is more conducive to the realization of individualized and precise medical decisions.

Fucoidan prevents diabetic cognitive dysfunction via promoting TET2-mediated active DNA demethylation in high-fat diet induced diabetic mice.

Diabetic cognitive dysfunction (DCD) refers to cognitive impairment in individuals with diabetes, which is one of the most important comorbidities and complications. Preliminary evidence suggests that consuming sufficient dietary fiber could have benefits for both diabetes and cognitive function. However, the effect and underlying mechanism of dietary fiber on DCD remain unclear. We conducted a cross-sectional analysis using data from NHANES involving 2072 diabetics and indicated a significant positive dose-response relationship between the dietary fiber intake and cognitive performance in diabetics. Furthermore, we observed disrupted cognitive function and neuronal morphology in high-fat diet induced DCD mice, both of which were effectively restored by fucoidan supplementation through alleviating DNA epigenetic metabolic disorders. Moreover, fucoidan supplementation enhanced the levels of short-chain fatty acids (SCFAs) in the cecum of diabetic mice. These SCFAs enhanced TET2 protein stability by activating phosphorylated AMPK and improved TETs activity by reducing the ratio of (succinic acid + fumaric acid)/ α-ketoglutaric acid, subsequently enhancing TET2 function. The positive correlation between dietary fiber intake and cognitive function in diabetics was supported by human and animal studies alike. Importantly, fucoidan can prevent the occurrence of DCD by promoting TET2-mediated active DNA demethylation in the cerebral cortex of diabetic mice.

Waste Tea-Derived Theabrownins for Solar-Driven Steam Generation.

Solar-driven seawater desalination has been considered an effective and sustainable solution to mitigate the global freshwater crisis. However, the substantial cost associated with photothermal materials for evaporator fabrication still hinders large-scale manufacturing for practical applications. Herein, we successfully obtained high yields of theabrownins (TB), which were oxidation polymerization products of polyphenols from waste and inferior tea leaves using a liquid-state fermentation strategy. Subsequently, a series of photothermal complexes were prepared based on the metal-phenolic networks assembled from TB and metal ions (Fe(III), Cu(II), Ni(II), and Zn(II)). Also, the screened TB@Fe(III) complexes were directly coated on a hydrophilic poly(vinylidene fluoride) (PVDF) membrane to construct the solar evaporation device (TB@Fe(III)@PVDF), which not only demonstrated superior light absorption property and notable hydrophilicity but also achieved a high water evaporation rate of 1.59 kg m-2 h-1 and a steam generation efficiency of 90% under 1 sun irradiation. More importantly, its long-term stability and exceptionally low production cost enabled an important step toward the possibility of large-scale practical applications. We believe that this study holds the potential to pave the way for the development of sustainable and cost-effective photothermal materials, offering new avenues for utilization of agriculture resource waste and solar-driven water remediation.

A Risk Model for Prognosis and Treatment Response Prediction in Colon Adenocarcinoma Based on Genes Associated with the Characteristics of the Epithelial-Mesenchymal Transition.

The epithelial-mesenchymal transition (EMT) is an important process during metastasis in various tumors, including colorectal cancer (CRC). Thus, the study of its characteristics and related genes is of great significance for CRC treatment. In this study, 26 EMT-related gene sets were used to score each sample from The Cancer Genome Atlas program (TCGA) colon adenocarcinoma (COAD) database. Based on the 26 EMT enrichment scores for each sample, we performed unsupervised cluster analysis and classified the TCGA-COAD samples into three EMT clusters. Then, weighted gene co-expression network analysis (WGCNA) was used to investigate the gene modules that were significantly associated with these three EMT clusters. Two gene modules that were strongly positively correlated with the EMT cluster 2 (worst prognosis) were subjected to Cox regression and least absolute shrinkage and selection operator (LASSO) regression analysis. Then, a prognosis-related risk model composed of three hub genes GPRC5B, LSAMP, and PDGFRA was established. The TCGA rectal adenocarcinoma (READ) dataset and a CRC dataset from the Gene Expression Omnibus (GEO) were used as the validation sets. A novel nomogram that incorporated the risk model and clinicopathological features was developed to predict the clinical outcomes of the COAD patients. The risk model served as an independent prognostic factor. It showed good predictive power for overall survival (OS), immunotherapy efficacy, and drug sensitivity in the COAD patients. Our study provides a comprehensive evaluation of the clinical relevance of this three-gene risk model for COAD patients and a deeper understanding of the role of EMT-related genes in COAD.

Synthesis and Cytotoxicity Assessment against Human Colorectal Cancer Cell Lines of Quaternary 8-Dichloromethyl Protoberberine Alkaloids.

Twenty-two quaternary 8-dichloromethylprotoberberine alkaloids were synthesized from unmodified quaternary protoberberine alkaloids (QPAs) to improve their physical and chemical properties and to obtain selectively anticancer derivatives. The synthesized derivatives showed more appropriate octanol/water partition coefficients by up to values 3-4 compared to unmodified QPA substrates. In addition, these compounds exhibited significant antiproliferative activity against colorectal cancer cells and lower toxicity on normal cells, resulting in more significant selectivity indices than unmodified QPA compounds in vitro. The IC50 values of antiproliferative activity of quaternary 8-dichloromethyl-pseudoberberine 4-chlorobenzenesulfonate and quaternary 8-dichloromethyl-pseudopalmatine methanesulfonate against colorectal cancer cells are 0.31 µM and 0.41 µM, respectively, significantly stronger than those of other compounds and positive control 5-fluorouracil. These findings suggest that 8-dichloromethylation can be used as one of the modification strategies to guide the structural modification and subsequent investigation of anticancer drugs for CRC based on QPAs.

Chemoproteomics Reveals That Quaternary Protoberberine Alkaloids Inhibit Telomerase Activity Oncologically by Binding to PES1.

Natural QPAs have anti-cancer property. The prodrugs of QPAs synthesized in our work with significantly improved solubility showed significantly stronger activity in animal experiments. Nevertheless, the mechanism of action of QPAs for treating cancers remains poorly understood. Here, a chemoproteomic study reveals that QPAs non-covalently and multivalently bind to PES1 in CRC cells, which impinges on the direct interaction between hTERT and hTR in the assembly of the telomerase complex, downregulates telomerase activity, and so promotes the aging process of CRC cells. This study is beneficial for us to conduct extensively the pharmaceutical chemistry research of QPAs.

A robust and 3D-printed solar evaporator based on naturally occurring molecules.

The interfacial solar desalination has been considered a promising method to address the worldwide water crisis without sophisticated infrastructures and additional energy consumption. Although various advanced solar evaporators have been developed, their practical applications are still restricted by the unsustainable materials and the difficulty of precise customization for structure to escort high solar-thermal efficiency. To address these issues, we employed two kinds of naturally occurring molecules, tannic acid and iron (III), to construct a low-cost, highly efficient and durable interfacial solar evaporator by three-dimensional (3D) printing. Based on a rational structural design, a robust and 3D-printed evaporator with conical array surface structure was developed, which could promote the light harvesting capacity significantly via the multiple reflections and anti-reflection effects on the surface. By optimizing the height of the conical arrays, the 3D-printed evaporator with tall-cone structure could achieve a high evaporation rate of 1.96 kg m-2 h-1 under one sun illumination, with a photothermal conversion efficiency of 94.4%. Moreover, this evaporator was also proved to possess excellent desalination performance, recycle stability, anti-salt property, underwater oil resistance, as well as adsorption capacity of organic dye contaminants for multipurpose water purification applications. It was believed that this study could provide a new strategy to fabricate low-cost, structural regulated solar evaporators for alleviating the dilemma of global water scarcity using abundant naturally occurring building blocks.

Robust and multifunctional natural polyphenolic composites for water remediation.

The scarcity of clean water has become a global environmental problem which constrains the development of public health, economy, and sustainability. In recent years, natural polyphenols have drawn increasing interests as promising platforms towards diverse water remediation composites and devices, owing to their abundant and renewable resource in nature, highly active surface chemistry, and multifunctionality. This review aims to summarize the most recent advances and highlights of natural polyphenol-based composite materials (e.g., nanofibers, membranes, particles, and hydrogels) for water remediation, by focusing on their structural and functional features, as well as their diversified applications including membrane filtration, solar distillation, adsorption, advanced oxidation processes, and disinfection. Finally, the future challenges in this field are also prospected. It is anticipated that this review will provide new opportunities towards the future development of natural polyphenols and other kinds of naturally occurring molecules in water purification applications.

Aqueous Humor Cytokine Response in the Contralateral Eye after First-Eye Cataract Surgery in Patients with Primary Angle-Closure Glaucoma, High Myopia or Type 2 Diabetes Mellitus.

BACKGROUND: Bilateral sequential cataract surgery within a short period is becoming more prevalent because of the efficiency and safety of modern cataract surgery. It has been reported that the first surgical eye might affect the contralateral eye. This study investigated the cytokines involved in the immunopathogenesis of pre-existing ocular or systemic conditions, as well as the inflammatory biomarkers in response to topical stimuli, by analyzing the cytokine profile of aqueous humor (AH) from cataract patients without these morbidities as control and with type 2 diabetes mellitus (DM), primary angle-closure glaucoma (PACG) or high myopia (HM) in each eye at the beginning of first (defined as baseline) and second eye cataract surgery. METHODS: Forty patients were recruited in this cohort study (10/group). Bilateral sequential cataract surgeries were conducted at intervals of 12.08 ± 1.2 days. Aqueous humor samples (100-200 µL/eye) were separately collected from 40 first-eyes and 40 second-eyes at the beginning of the cataract surgeries. Twenty-seven selected cytokines were detected with Luminex-multiplex immunoassay. The concentrations of cytokines in the aqueous humor and their association with pre-existing ocular or systemic conditions were analyzed and compared between and within the groups. RESULTS: Before first-eye surgery (baseline), the levels of interleukin (IL)-1ra, IL-13 and tumor necrosis factor (TNF)-alpha were significantly increased in PACG compared with controls. The levels of IL-13 were increased while that of IL-15 were decreased in HM. Compared with controls, 11 cytokines were significantly increased in DM. In the AH of the contralateral eye after first-eye cataract surgery, basic fibroblast growth factor (bFGF) was significantly more abundant in PACG and HM, while the levels of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein 10 (IP-10) were decreased in PACG. We also identified 6 significantly upregulated cytokines in DM compared with controls. Compared with baseline, there was an overlap of 5 altered cytokines in the AH of contralateral eyes after first-eye surgery between the four groups. Some were exclusively altered in each subgroup, with 1 in the control group, 4 cytokines in the PACG and HM groups, and none in the DM group. CONCLUSIONS: From the initial profile, it is observed that patients with pre-existing ocular or systemic conditions have some degree of inflammation in their eyes before surgery and in the contralateral eye after the first eye cataract surgery, which could be peculiar of the morbid conditions of the patients. Inflammation was more detectable in patients with type 2 DM before surgery. PACG and HM patients showed stronger intraocular inflammatory reactions to topical stimuli compared with controls and DM patients. Our data suggest that ophthalmologists should pay closer attention to inflammatory responses, especially in cataract patients with pre-existing conditions, although the clinical significance of these changes following surgery remains to be further investigated.

Experimental and Numerical Study of the Laminar Burning Velocity and Pollutant Emissions of the Mixture Gas of Methane and Carbon Dioxide.

This paper presents the experimental and numerical study of the laminar burning velocity and pollutant emissions of the mixture gas of methane and carbon dioxide. Compared to previous research, a wider range of experimental conditions was realized in this paper: CO2 dilution level up to 60% (volume fraction) and equivalence ratio of 0.7-1.3. The burning velocities were measured using the heat flux method. The CO and NO emissions after premixed combustion were measured by a gas analyzer placed 20 cm downstream of the flame. The one-dimensional free flames were simulated using the in-house laminar flame code CHEM1D. Four chemical kinetic mechanisms, GRI-Mech 3.0, San Diego, Konnov, and USC Mech II were used in Chem1D. The results showed that, for laminar burning velocity, the simulation results are all lower than the experimental results. GRI Mech 3.0 showed the best agreement when the CO2 content was below 20%. USC Mech II showed the best consistency when the CO2 content was between 40 and 60%. For CO emission, these four mechanisms all showed a small error compared with the experiments. When CO2 content is higher than 40%, the deviation between simulation and experiment becomes bigger. When the CO2 ratio is more than 20%, the proportion of CO2 does not affect CO emission so much. For NO emission, when the CO2 content is 40%, the results from simulation and experiment showed a good agreement. As the proportion of CO2 increases, the difference in NO emissions decreases.

Therapeutic effects of CXCL9-overexpressing human umbilical cord mesenchymal stem cells on liver fibrosis in rats.

Umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has become a promising treatment for liver fibrosis. However, UC-MSCs have limited anti-fibrosis ability, and their homing ability of UC-MSCs to the injured liver seems to be poor. In our study, we aimed to determine if the CXCL9-overexpressing UC-MSCs could have synergistic anti-fibrosis effects and whether it can promote the homing ability of UC-MSCs. Overexpression of CXCL9 in UC-MSCs (CXCL9-UC-MSCs) was attained by transfecting the lenti-CXCL9-mCherry to naive UC-MSCs. The therapeutic effect of transducted CXCL9-UC-MSCs on both repairing of hepatic fibrosis and target homing were evaluated by comparing with the control of UC-MSCs transfected with empty lenti-mCherry vector. The results revealed that the liver function of CXCL9-UC-MSCs treated group was significantly improved when compared with that of control UC-MSCs (P < 0.05), and the histopathology indicated an obvious decrease of the collagen fiber content and significant disappearing of pseudo-lobules with basically normal morphology of hepatic lobules. Furthermore, liver frozen sections confirmed that CXCL9-UC-MSCs have significantly stronger chemotaxis and stable persistence in the injured liver tissues. In summary, overexpression of CXCL9 could improve the efficacy of UC-MSCs therapy for liver fibrosis repairing on account of an enhanced ability of UC-MSCs in homing to and staying in the injured sites of liver fibrosis in rat models.

Polyphenol scaffolds in tissue engineering.

Polyphenols are a class of ubiquitous compounds distributed in nature, with fascinating inherent biocompatible, bioadhesive, antioxidant, and antibacterial properties. The unique polyphenolic structures based on catechol or pyrogallol moieties allow for strong non-covalent interactions (e.g., multiple hydrogen bonding, electrostatic, and cation-π interactions) as well as covalent interactions (e.g., Michael addition/Schiff-base reaction, radical coupling reaction, and dynamic coordination interactions with boronate or metal ions). This review article provides an overview of the polyphenol-based scaffolds including the hydrogels, films, and nanofibers that have emerged from chemical and functional signatures during the past years. A full description of the structure-function relationships in terms of their utilization in wound healing, bone regeneration, and electroactive tissue engineering is also carefully discussed, which may pave the path towards the rational design and facile preparation of next-generation polyphenol scaffolds for tissue engineering applications.

A review of chemical constituents and health-promoting effects of citrus peels.

Citrus is one of the main fruits processed worldwide, producing a lot of industrial by-products. As the main part of citrus "residue", citrus peels have a wide application prospect. They could not only be directly used to produce various food products, but also be used as promising biofuels to produce ethanol and methane. Additionally, functional components (flavonoids, limonoids, alkaloids, essential oils and pectin) extracted from citrus peels have been related to the improvement of human health against active oxygen, inflammatory, cancer and metabolic disorders. Therefore, it is clear that the citrus peels have great potential to be developed into useful functional foods, medicines and biofuels. This review systematically summarizes the recent advances in current uses, processing, bioactive components and biological properties of citrus peels. A better understanding of citrus peels may provide reference for making full use of it.

Nanoparticle conjugation of ginsenoside Rb3 inhibits myocardial fibrosis by regulating PPARα pathway.

BACKGROUND: Cardiac fibrosis occurs in ischemic and non-ischemic heart failure, hereditary cardiomyopathy, diabetes and aging. Energy metabolism, which serves a crucial function in the course and treatment of cardiovascular diseases, might have therapeutic benefits for myocardial fibrosis. Ginsenoside Rb3 (G-Rb3) is one of the main components of Ginseng and exhibits poor oral bioavailability but still exerts regulate energy metabolism effects in some diseases. Therefore, the study investigated the effect of chitosan (CS) @ sodium tripolyphosphate (TPP) nanoparticles conjugation with ginsenoside Rb3 (NpRb3) on myocardial fibrosis and studied its possible mechanisms. The results showed that NpRb3 directly participates in the remodeling of myocardial energy metabolism and the regulation of perixisome proliferation-activated receptor alpha (PPARα), thereby improving the degree of myocardial fibrosis. The study also verifies the protective effect of NpRb3 on energy metabolism and mitochondrial function by targeting the PPARα pathway. Therefore, the prepared nanodrug carrier may be a potential solution for the delivery of G-Rb3, which is a promising platform for oral treatment of myocardial fibrosis.

Novel BAG3 Variants in African American Patients With Cardiomyopathy: Reduced ß-Adrenergic Responsiveness in Excitation-Contraction.

BACKGROUND: We reported 3 novel nonsynonymous single nucleotide variants of Bcl2-associated athanogene 3 (BAG3) in African Americans with heart failure (HF) that are associated with a 2-fold increase in cardiac events (HF hospitalization, heart transplantation, or death). METHODS AND RESULTS: We expressed BAG3 variants (P63A, P380S, and A479V) via adenovirus-mediated gene transfer in adult left ventricular myocytes isolated from either wild-type (WT) or cardiac-specific BAG3 haploinsufficient (cBAG3+/-) mice: the latter to simulate the clinical situation in which BAG3 variants are only found on 1 allele. Compared with WT myocytes, cBAG3+/- myocytes expressed approximately 50% of endogenous BAG3 levels and exhibited decreased [Ca2+]i and contraction amplitudes after isoproterenol owing to decreased L-type Ca2+ current. BAG3 repletion with WT BAG3 but not P380S, A479V, or P63A/P380S variants restored contraction amplitudes in cBAG3+/- myocytes to those measured in WT myocytes, suggesting excitation-contraction abnormalities partly account for HF in patients harboring these mutants. Because P63A is near the WW domain (residues 21-55) and A479V is in the BAG domain (residues 420-499), we expressed BAG3 deletion mutants (Δ1-61 and Δ421-575) in WT myocytes and demonstrated that the BAG but not the WW domain was involved in enhancement of excitation-contraction by isoproterenol. CONCLUSIONS: The BAG3 variants contribute to HF in African American patients partly by decreasing myocyte excitation-contraction under stress, and that both the BAG and PXXP domains are involved in mediating ß-adrenergic responsiveness in myocytes.

Antidotal effects of methylene blue against cyanide neurological toxicity: in vivo and in vitro studies.

The aim of the present study was to determine whether methylene blue (MB) could directly oppose the neurological toxicity of a lethal cyanide (CN) intoxication. KCN, infused at the rate of 0.375 mg/kg/min intravenously, produced 100% lethality within 15 min in unanaesthetized rats (n = 12). MB at 10 (n = 5) or 20 mg/kg (n = 5), administered 3 min into CN infusion, allowed all animals to survive with no sequelae. No apnea and gasping were observed at 20 mg/kg MB (P < 0.001). The onset of coma was also significantly delayed and recovery from coma was shortened in a dose-dependent manner (median of 359 and 737 seconds, respectively, at 20 and 10 mg/kg). At 4 mg/kg MB (n = 5), all animals presented faster onset of coma and apnea and a longer period of recovery than at the highest doses (median 1344 seconds, P < 0.001). MB reversed NaCN-induced resting membrane potential depolarization and action potential depression in primary cultures of human fetal neurons intoxicated with CN. MB restored calcium homeostasis in the CN-intoxicated human SH-SY5Y neuroblastoma cell line. We conclude that MB mitigates the neuronal toxicity of CN in a dose-dependent manner, preventing the lethal depression of respiratory medullary neurons and fatal outcome.

Transient receptor potential ion channel TRPM2 promotes AML proliferation and survival through modulation of mitochondrial function, ROS, and autophagy.

Transient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in maintaining cell survival following oxidant injury. Here, we show that TRPM2 is highly expressed in acute myeloid leukemia (AML). The role of TRPM2 in AML was studied following depletion with CRISPR/Cas9 technology in U937 cells. In in vitro experiments and in xenografts, depletion of TRPM2 in AML inhibited leukemia proliferation, and doxorubicin sensitivity was increased. Mitochondrial function including oxygen consumption rate and ATP production was reduced, impairing cellular bioenergetics. Mitochondrial membrane potential and mitochondrial calcium uptake were significantly decreased in depleted cells. Mitochondrial reactive oxygen species (ROS) were significantly increased, and Nrf2 was decreased, reducing the antioxidant response. In TRPM2-depleted cells, ULK1, Atg7, and Atg5 protein levels were decreased, leading to autophagy inhibition. Consistently, ATF4 and CREB, two master transcription factors for autophagosome biogenesis, were reduced in TRPM2-depleted cells. In addition, Atg13 and FIP200, which are known to stabilize ULK1 protein, were decreased. Reconstitution with TRPM2 fully restored proliferation, viability, and autophagy; ATF4 and CREB fully restored proliferation and viability but only partially restored autophagy. TRPM2 expression reduced the elevated ROS found in depleted cells. These data show that TRPM2 has an important role in AML proliferation and survival through regulation of key transcription factors and target genes involved in mitochondrial function, bioenergetics, the antioxidant response, and autophagy. Targeting TRPM2 may represent a novel therapeutic approach to inhibit myeloid leukemia growth and enhance susceptibility to chemotherapeutic agents through multiple pathways.

Effect of digestion on the phenolic content and antioxidant activity of celery leaf and the antioxidant mechanism via Nrf2/HO-1 signaling pathways against Dexamethasone.

The effect of digestion on the phenolic compounds and antioxidant activity of celery leaf were performed. In this work, 13 phenolic chemicals were discriminated by HPLC-MS, and content of phenolic and the antioxidant capacity were evaluated after digestion in vitro. After digestion, the content of phenols and flavonoids were increased by about 3-6-folds correlated with the average antioxidant activity (p < 0.05). It was found that the extraction of celery leaf (ET) decreased lipid peroxidation (MDA) and reactive oxygen species (ROS) level, and elevated the antioxidant activities of the liver, spleen, and thymus in Dexamethasone (Dex)-treated KM mice. Furthermore, ET increased the protein transcription of NF-E2-related factor 2 (Nrf2), hemeoxygenase-1 (HO-1) and glutathione s-transferase (GST) to against oxidation. These results suggested that ET can protect animals through the Nrf2/HO-1 signaling pathway from oxidative damage included by Dex. PRACTICAL APPLICATIONS: Celery is a daily edible vegetable with more pharmacological research focused on dietary fiber, yet fewer studies on the biological activity of small molecules, especially that in leaves. This study shows that the phenolic compounds from celery leaf have a distinct enhancement of oxidation after digestion in vitro, and the celery leaf reduces oxidative stress induced by Dex via Nrf2/HO-1 signaling pathway, indicating celery leaf or other food rich in phenolic compounds can be good source of functional food to fully use to promote the economic value. Moreover, it also provides theoretical information of celery leaf on digestion, which insinuates that food or Chinese medicine containing flavonoids, such as glycoside of apigenin or luteolin, have the similar digestion pattern, providing theoretical basis for later metabolism. Therefore, the absorption and metabolism of ET or flavonoids after digestion in body and the upstream signaling pathway activating Nrf2/HO-1, like PI3K or JNK phosphorylation, or downstream signaling pathway need further research.

Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation.

Mitochondrial Ca2+ uniporter (MCU)-mediated Ca2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca2+ (mCa2+) uptake, delays cytosolic Ca2+ (cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhep were a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhep hepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+ dynamics to hepatic lipid metabolism.