Lysosomal cation channel TRPML1 suppression sensitizes acute myeloid leukemia cells to chemotherapeutics by inhibiting autophagy.

Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.

Global, regional, and national burden of ovarian cancer among young women during 1990-2019.

BACKGROUND: Ovarian cancer, the most devastating tumor in women globally, significantly impacts young women, compromising their daily lives and overall well-being. Ovarian cancer represents a significant public health concern due to its extensive physical and psychological consequences. MATERIAL AND METHODS: Data from the Global Burden of Disease were used to assess the global, regional, and national burden of ovarian cancer in young women aged 20-39 from 1990 to 2019. This analysis focused on trends measured by the estimated annual percentage change and explored the socioeconomic impacts via the socio-demographic index (SDI). RESULTS: During 1990-2019, the incidence and prevalence of ovarian cancer among young women increased globally, with annual rates of 0.74% and 0.89%, respectively. The mortality rate and disability-adjusted life years also rose annually by 0.20% and 0.23%, respectively. A significant burden shift was observed toward regions with lower SDI, with high fasting plasma glucose, BMI, and asbestos exposure identified as prominent risk factors, particularly in lower SDI regions. CONCLUSION: Our findings underscore ovarian cancer in young women as an escalating global health challenge, with the burden increasingly shifting toward lower socioeconomic areas. This underscores the necessity for targeted prevention and control strategies for ovarian cancer, focusing on reducing the identified risk factors and ensuring equitable health resource distribution.

Inhibition of lysosomal TRPML1 channel eliminates breast cancer stem cells by triggering ferroptosis.

Cancer stem cells (CSCs) are a sub-population of cells possessing high tumorigenic potential, which contribute to therapeutic resistance, metastasis and recurrence. Eradication of CSCs is widely recognized as a crucial factor in improving patient prognosis, yet the effective targeting of these cells remains a major challenge. Here, we show that the lysosomal cation channel TRPML1 represents a promising target for CSCs. TRPML1 is highly expressed in breast cancer cells and exhibits sensitivity to salinomycin, a drug known to selectively eliminate CSCs. Pharmacological inhibition and genetic depletion of TRPML1 promote ferroptosis in breast CSCs, reduce their stemness, and enhance the sensitivity of breast cancer cells to chemotherapy drug doxorubicin. The inhibition and knockout of TRPML1 also demonstrate significant suppression of tumor formation and growth in the mouse xenograft model. These findings suggest that targeting TRPML1 to eliminate CSCs may be an effective strategy for the treatment of breast cancer.

Basement membrane-related lncRNA signature for the prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main type of primary liver cancer. This study aimed to develop a basement membrane (BM) related lncRNAs risk signature to evaluate the prognosis of HCC patients. We screened differentially expressed BM-related lncRNAs (DE-BMRlncRNAs) for risk evaluation, and identified six DE-BMRlncRNAs (AC072054.1, NUP50-DT, AC026412.3, AC109322.2, POLH-AS1 and LINC00595) for prognostic risk signature. HCC patients were divided to high or low risk according to median risk score. Our prognostic model predicted that patients with higher risk score had worse prognosis. We also created a nomogram to assist clinical decision-making according to risk score and clinicopathological features. Meanwhile, we confirmed the expression of six lncRNAs in HCC tissue and cells. POLH-AS1 knockdown inhibited the migration and invasion of HCC cells. In conclusion, we established a predictive model based on BMRlncRNAs to predict the prognosis of HCC. Our findings offer a rationale to further explore BM-related biomarkers for HCC.

Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.

Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking. Here, we constructed lysosome-localized optogenetic actuators, named lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2, to achieve optogenetic manipulation of lysosomes. These new actuators enable light-dependent control of lysosomal membrane potential, pH, hydrolase activity, degradation, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy through the mTOR pathway, promotes Aß clearance in an autophagy-dependent manner in cellular models, and alleviates Aß-induced paralysis in the Caenorhabditis elegans model of Alzheimer's disease. Our lysosomal optogenetic actuators supplement the optogenetic toolbox and provide a method to dynamically regulate lysosomal physiology and function in living cells and animals.

Brazilin-7-2-butenoate inhibits amyloid ß-protein aggregation, alleviates cytotoxicity, and protects Caenorhabditis elegans.

The fibrillogenesis of amyloid ß-protein (Aß) gradually accumulates to form neurotoxic Aß aggregates in the human brain, which is the direct cause of Alzheimer's disease (AD) related symptoms. There are currently no effective therapies for AD. Brazilin, a natural polyphenol, inhibits Aß fibrillogenesis, disrupts the mature fibrils and alleviates the corresponding cytotoxicity, but it also has the high toxic. Therefore, brazilin-7-2-butenoate (B-7-2-B), a brazilin derivative, was designed and synthesized. B-7-2-B exhibited lower toxicity and stronger inhibitory effect on Aß aggregation than brazilin. B-7-2-B could prevent the formation of Aß fibrils and oligomers, and depolymerize pre-formed aggregates in a dose-dependent manner. Furthermore, B-7-2-B prominently alleviated the cytotoxicity and the oxidative stress induced by Aß aggregates in PC12 cells. The protective impacts of B-7-2-B were further demonstrated by using the Caenorhabditis elegans model, including decreasing the extent of Aß aggregation, improving the motility and sensation disorders. Eventually, B-7-2-B was proven to be no apparent damage to worms. In summarize, it can be concluded that B-7-2-B has the potential as a drug for treating AD.

Selenium Improves the Control Efficacy of Phytophthora nicotianae by Damaging the Cell Membrane System and Promoting Plant Energy Metabolism.

Tobacco black shank (TBS), caused by Phytophthora nicotianae, poses a significant threat to tobacco plants. Selenium (Se), recognized as a beneficial trace element for plant growth, exhibited inhibitory effects on P. nicotianae proliferation, disrupting the cell membrane integrity. This action reduced the energy supply and hindered hyphal transport through membrane proteins, ultimately inducing hyphal apoptosis. Application of 8 mg/L Se through leaf spraying resulted in a notable decrease in TBS incidence. Moreover, Se treatment preserved chloroplast structure, elevated chitinase activities, ß-1,3-GA, polyphenol oxidase, phenylalanine ammonia-lyase, and increased hormonal content. Furthermore, Se enhanced flavonoid and sugar alcohol metabolite levels while diminishing amino acid and organic acid content. This shift promoted amino acid degradation and flavonoid synthesis. These findings underscore the potential efficacy of Se in safeguarding tobacco and potentially other plants against P. nicotianae.

Selenium-molybdenum interactions reduce chromium toxicity in Nicotiana tabacum L. by promoting chromium chelation on the cell wall.

Chromium (Cr) is a hazardous heavy metal that negatively affects animals and plants. The micronutrients selenium (Se) and molybdenum (Mo) have been widely shown to alleviate heavy metal toxicity in plants. However, the molecular mechanism of Cr chelation on the cell wall by combined treatment with Se and Mo has not been reported. Therefore, this study aimed to explore the effects of Se-Mo interactions on the subcellular distribution of Cr (50 µM) and on cell wall composition, structure, functional groups and Cr content, in addition to performing a comprehensive analysis of the transcriptome. Our results showed that the cell walls of shoots and roots accumulated 51.0% and 65.0% of the Cr, respectively. Furthermore, pectin in the cell wall bound 69.5%/90.2% of the Cr in the shoots/roots. Se-Mo interactions upregulated the expression levels of related genes encoding galacturonosyltransferase (GAUT), UTP-glucose-1-phosphate uridylyltransferase (UGP), and UDP-glucose-4-epimerase (GALE), involved in polysaccharide biosynthesis, thereby increasing pectin and cellulose levels. Moreover, combined treatment with Se and Mo increased the lignin content and cell wall thickness by upregulating the expression levels of genes encoding cinnamyl alcohol dehydrogenase (CAD), peroxidase (POX) and phenylalanine amino-lyase (PAL), involved in lignin biosynthesis. Fourier-transform infrared (FTIR) spectroscopy results showed that Se + Mo treatment (in combination) increased the number of carboxylic acid groups (-COOH) groups, thereby enhancing the Cr chelation ability. The results not only elucidate the molecular mechanism of action of Se-Mo interactions in mitigating Cr toxicity but also provide new insights for phytoremediation and food safety.

A gene network database for the identification of key genes for diagnosis, prognosis, and treatment in sepsis.

Sepsis and sepsis-related diseases cause a high rate of mortality worldwide. The molecular and cellular mechanisms of sepsis are still unclear. We aim to identify key genes in sepsis and reveal potential disease mechanisms. Six sepsis-related blood transcriptome datasets were collected and analyzed by weighted gene co-expression network analysis (WGCNA). Functional annotation was performed in the gProfiler tool. DSigDB was used for drug signature enrichment analysis. The proportion of immune cells was estimated by the CIBERSORT tool. The relationships between modules, immune cells, and survival were identified by correlation analysis and survival analysis. A total of 37 stable co-expressed gene modules were identified. These modules were associated with the critical biology process in sepsis. Four modules can independently separate patients with long and short survival. Three modules can recurrently separate sepsis and normal patients with high accuracy. Some modules can separate bacterial pneumonia, influenza pneumonia, mixed bacterial and influenza A pneumonia, and non-infective systemic inflammatory response syndrome (SIRS). Drug signature analysis identified drugs associated with sepsis, such as testosterone, phytoestrogens, ibuprofen, urea, dichlorvos, potassium persulfate, and vitamin B12. Finally, a gene co-expression network database was constructed ( https://liqs.shinyapps.io/sepsis/ ). The recurrent modules in sepsis may facilitate disease diagnosis, prognosis, and treatment.

Citrus Flavonoid Hesperetin Inhibits α-Synuclein Fibrillogenesis, Disrupts Mature Fibrils, and Reduces Their Cytotoxicity: In Vitro and In Vivo Studies.

Misfolding and subsequent fibrillogenesis of α-synuclein (αSN) significantly influence the development of Parkinson's disease (PD). This study reports the inhibitory effect of citrus flavonoid hesperetin (Hst) on αSN fibrillation. Based on thioflavin T fluorometry and atomic force microscopy studies, Hst inhibited αSN fibrillation by interfering with initial nucleation and slowing the elongation rate. Furthermore, the inhibitory effect was concentration-dependent with a half-maximal inhibitory concentration of 24.4 µM. Cytotoxicity experiments showed that 100 µM Hst significantly reduced the cytotoxicity of αSN aggregates and maintained 98.4% cell activity. In addition, Hst disassembled the preprepared αSN fibrils into smaller and less-toxic aggregates. Excitingly, supplementation with 100 µM Hst inhibited the accumulation of 36.3% αSN in NL5901 and restored the amyloid-induced reduction in NL5901 lipid abundance, extending the mean lifespan of NL5901 to 23 d. These findings could support the use of Hst as a dietary supplement to regulate αSN fibrillation and prevent the development of PD.

The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila.

Infectious diseases caused by Aeromonas hydrophila (AH) have reduced the populations of Rana dybowskii). However, little is known about the immune response of R. dybowskii against AH infections. The toll-like receptor (TLR) signaling pathway has been identified as a critical component in innate immunity, responsible for identifying pathogen-associated molecular patterns in pathogens. Our study used the next-generation sequencing technique and single-molecule long-read sequencing to determine the structures of transcript isoforms and functions of genes in the kidneys of R. dybowskii, as well as identify and validate the related genes in the TLR4 signaling pathway. In total, 628,774 reads of inserts were identified, including 300,053 full-length non-chimeric reads and 233,592 non-full-length reads. Among the transcriptome sequences, 124 genes were identified as homologs of known genes in the TLR4 pathway especially inflammatory cytokines and receptors. Our findings shed light on the structures and functions of R. dybowskii genes exposed to AH and confirm the presence of both MyD88-dependent and independent pathways in R. dybowskii. Our work reveals how various functional proteins in amphibians at the initial stage of immune response are activated and complete their corresponding functions in a short time.

The Interplay between Immune and Metabolic Pathways in Kidney Disease.

Kidney disease is a significant health problem worldwide, affecting an estimated 10% of the global population. Kidney disease encompasses a diverse group of disorders that vary in their underlying pathophysiology, clinical presentation, and outcomes. These disorders include acute kidney injury (AKI), chronic kidney disease (CKD), glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetic kidney disease, and many others. Despite their distinct etiologies, these disorders share a common feature of immune system dysregulation and metabolic disturbances. The immune system and metabolic pathways are intimately connected and interact to modulate the pathogenesis of kidney diseases. The dysregulation of immune responses in kidney diseases includes a complex interplay between various immune cell types, including resident and infiltrating immune cells, cytokines, chemokines, and complement factors. These immune factors can trigger and perpetuate kidney inflammation, causing renal tissue injury and progressive fibrosis. In addition, metabolic pathways play critical roles in the pathogenesis of kidney diseases, including glucose and lipid metabolism, oxidative stress, mitochondrial dysfunction, and altered nutrient sensing. Dysregulation of these metabolic pathways contributes to the progression of kidney disease by inducing renal tubular injury, apoptosis, and fibrosis. Recent studies have provided insights into the intricate interplay between immune and metabolic pathways in kidney diseases, revealing novel therapeutic targets for the prevention and treatment of kidney diseases. Potential therapeutic strategies include modulating immune responses through targeting key immune factors or inhibiting pro-inflammatory signaling pathways, improving mitochondrial function, and targeting nutrient-sensing pathways, such as mTOR, AMPK, and SIRT1. This review highlights the importance of the interplay between immune and metabolic pathways in kidney diseases and the potential therapeutic implications of targeting these pathways.

Selenium in soil-plant system: Transport, detoxification and bioremediation.

Selenium (Se) is an essential micronutrient for humans and a beneficial element for plants. However, high Se doses always exhibit hazardous effects. Recently, Se toxicity in plant-soil system has received increasing attention. This review will summarize (1) Se concentration in soils and its sources, (2) Se bioavailability in soils and influencing factors, (3) mechanisms on Se uptake and translocation in plants, (4) toxicity and detoxification of Se in plants and (5) strategies to remediate Se pollution. High Se concentration mainly results from wastewater discharge and industrial waste dumping. Selenate (Se [VI]) and selenite (Se [IV]) are the two primary forms absorbed by plants. Soil conditions such as pH, redox potential, organic matter and microorganisms will influence Se bioavailability. In plants, excessive Se will interfere with element uptake, depress photosynthetic pigment biosynthesis, generate oxidative damages and cause genotoxicity. Plants employ a series of strategies to detoxify Se, such as activating antioxidant defense systems and sequestrating excessive Se in the vacuole. In order to alleviate Se toxicity to plants, some strategies can be applied, including phytoremediation, OM remediation, microbial remediation, adsorption technique, chemical reduction technology and exogenous substances (such as Methyl jasmonate, Nitric oxide and Melatonin). This review is expected to expand the knowledge of Se toxicity/detoxicity in soil-plant system and offer valuable insights into soils Se pollution remediation strategies.

Capturing the multifaceted function of adipose tissue macrophages.

Adipose tissue macrophages (ATMs) bolster obesity-induced metabolic dysfunction and represent a targetable population to lessen obesity-associated health risks. However, ATMs also facilitate adipose tissue function through multiple actions, including adipocyte clearance, lipid scavenging and metabolism, extracellular remodeling, and supporting angiogenesis and adipogenesis. Thus, high-resolution methods are needed to capture macrophages' dynamic and multifaceted functions in adipose tissue. Herein, we review current knowledge on regulatory networks critical to macrophage plasticity and their multifaceted response in the complex adipose tissue microenvironment.

The development of COVID-19 treatment.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic named coronavirus disease 2019 (COVID-19) that has become the greatest worldwide public health threat of this century. Recent studies have unraveled numerous mysteries of SARS-CoV-2 pathogenesis and thus largely improved the studies of COVID-19 vaccines and therapeutic strategies. However, important questions remain regarding its therapy. In this review, the recent research advances on COVID-19 mechanism are quickly summarized. We mainly discuss current therapy strategies for COVID-19, with an emphasis on antiviral agents, neutralizing antibody therapies, Janus kinase inhibitors, and steroids. When necessary, specific mechanisms and the history of therapy are present, and representative strategies are described in detail. Finally, we discuss key outstanding questions regarding future directions of the development of COVID-19 treatment.

Performance of 18F-DCFPyL PET/CT in Primary Prostate Cancer Diagnosis, Gleason Grading and D'Amico Classification: A Radiomics-Based Study.

This study aimed to investigate the performance of 18F-DCFPyL positron emission tomography/computerized tomography (PET/CT) models for predicting benign-vs-malignancy, high pathological grade (Gleason score > 7), and clinical D'Amico classification with machine learning. The study included 138 patients with treatment-naïve prostate cancer presenting positive 18F-DCFPyL scans. The primary lesions were delineated on PET images, followed by the extraction of tumor-to-background-based general and higher-order textural features by applying five different binning approaches. Three layer-machine learning approaches were used to identify relevant in vivo features and patient characteristics and their relative weights for predicting high-risk malignant disease. The weighted features were integrated and implemented to establish individual predictive models for malignancy (Mm), high path-risk lesions (by Gleason score) (Mgs), and high clinical risk disease (by amico) (Mamico). The established models were validated in a Monte Carlo cross-validation scheme. In patients with all primary prostate cancer, the highest areas under the curve for our models were calculated. The performance of established models as revealed by the Monte Carlo cross-validation presenting as the area under the receiver operator characteristic curve (AUC): 0.97 for Mm, AUC: 0.73 for Mgs, AUC: 0.82 for Mamico. Our study demonstrated the clinical potential of 18F-DCFPyL PET/CT radiomics in distinguishing malignant from benign prostate tumors, and high-risk tumors, without biopsy sampling. And in vivo 18F-DCFPyL PET/CT can be considered a noninvasive tool for virtual biopsy for personalized treatment management. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-023-00108-y.

Selenium and molybdenum synergistically alleviate chromium toxicity by modulating Cr uptake and subcellular distribution in Nicotiana tabacum L.

Chromium (Cr) is a harmful heavy metal that poses a serious threat to plants and animals. Selenium (Se) and molybdenum (Mo) are two beneficial elements for plant growth and resistance. However, their interactive effects on Cr uptake and distribution are poorly understood. Therefore, a hydroponics experiment was conducted to explore the effects of the use of Se and Mo alone and simultaneously on mitigating Cr toxicity. In this study, Nicotiana tabacum L. seedlings were exposed to control, 50 µM Cr, 50 µM Cr + 2 µM Se, 50 µM Cr + 1 µM Mo, or 50 µM Cr + 2 µM Se + 1 µM Mo in Hoagland solution. After 2 weeks, the plant biomass, Cr, Se and Mo contents, photosynthesis, leaf ultrastructure, antioxidant system, subcellular distribution and associated gene expression in Nicotiana tabacum L. were determined. The results showed that simultaneous use of Se and Mo promoted tobacco growth under Cr stress, as evidenced by reducing reactive oxygen species (ROS) content and reducing Cr translocation factor (TF) and inducing a 51.3% reduction in Cr content in shoots. Additionally, Se-Mo interactions increased the levels of glutathione (GSH) and phytochelatin (PC) and the distribution of Cr in the cell walls and organelles. Furthermore, the relative expression of PCS1 was upregulated, while those of NtST1 and MSN1 were downregulated. The results concluded that the simultaneous use of Se and Mo effectively alleviated Cr toxicity in Nicotiana tabacum L., which not only offers an efficient way for crops to resist Cr toxicity but also provides evidence for the benefit of Se combined with Mo.

Macrophages at the Crossroad of Meta-Inflammation and Inflammaging.

Macrophages are central players in systemic inflammation associated with obesity and aging, termed meta-inflammation and inflammaging. Activities of macrophages elicited by the two chronic conditions display shared and distinct patterns mechanistically, resulting in multifaceted actions for their pathogenic roles. Drastically expanded tissue macrophage populations under obesity and aging stress attribute to both enhanced recruitment and local expansion. Importantly, molecular networks governing the multifaceted actions of macrophages are directly altered by environmental cues and subsequently contribute to metabolic reprogramming, resulting in meta-inflammation in obesity or inflammaging in aging. In this review, we will summarize how meta-inflammation and inflammaging affect macrophages and the molecular mechanisms involved in these processes.

Deep residual neural-network-based robot joint fault diagnosis method.

A data driven method-based robot joint fault diagnosis method using deep residual neural network (DRNN) is proposed, where Resnet-based fault diagnosis method is introduced. The proposed method mainly deals with kinds of fault types, such as gain error, offset error and malfunction for both sensors and actuators, respectively. First, a deep residual network fault diagnosis model is derived by stacking small convolution cores and increasing the core size. meanwhile, the gaussian white noise is injected into the fault data set to verify the noise immunity for the proposed deep residual network. Furthermore, a simulation is conducted, where different fault diagnosis methods including support vector machine (SVM), artificial neural network (ANN), convolutional neural network (CNN), long-term memory network (LTMN) and deep residual neural network (DRNN) are compared, and the simulation results show the accuracy of fault diagnosis for robot system using DRNN is higher, meanwhile, DRNN needs less model training time. Visualization analysis proved the feasibility and effectiveness of the proposed method for robot joint sensor and actuator fault diagnosis using DRNN method.

Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease.

Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl-2 binds to and inhibits TMEM175 activity. Accordingly, Bcl-2 inhibitors activate the channel in a caspase-independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175-mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD).