Inhibition and transport mechanisms of the ABC transporter hMRP5.

Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.

Kinetic and reactivity of gas-phase reaction of acyclic dienes with hydroxyl radical in the 273-318 K temperature range.

As dienes contain two C[double bond, length as m-dash]C bonds, theoretically, they are much more chemically reactive with hydroxyl radical (˙OH) than alkenes and alkanes, and the reaction with ˙OH is one of the main atmospheric degradation routes of dienes during the daytime. In our work, rate coefficients of three types of acyclic dienes: conjugated as 3-methyl-1,3-pentadiene (3M13PD), isolated as 1,4-hexadiene (14HD), and cumulated as 1,2-pentadiene (12PD) reaction with ˙OH were measured in the temperature range of 273-318 K and 1 atm using the relative rate method. At 298 ± 3 K, the rate coefficients for those reactions were determined to be k3M13PD+OH = (15.09 ± 0.72) × 10-11, k14HD+OH = (9.13 ± 0.62) × 10-11, k12PD+OH = (3.34 ± 0.40) × 10-11 (as units of cm3 per molecule per s), in the excellent agreement with values of previously reported. The first measured temperature dependence for 3M13PD, 14HD and 12PD reaction with ˙OH can be expressed by the following Arrhenius expressions in units of cm3 per molecule per s: k3M13PD+OH = (8.10 ± 2.23) × 10-11 exp[(173 ± 71)/T]; k14HD+OH = (9.82 ± 5.10) × 10-12 exp[(666 ± 123)/T]; k12PD+OH = (1.13 ± 0.87) × 10-12 exp[(1038 ± 167)/T] (as units of cm3 per molecule per s). The kinetic discussion revealed that the relative position between these two C[double bond, length as m-dash]C could significantly affect the reactivity of acyclic dienes toward ˙OH. A simple structure-activity relationship (SAR) method was proposed to estimate the reaction rate coefficients of acyclic dienes with ˙OH.

Glycolysis-non-canonical glutamine dual-metabolism regulation nanodrug enhanced the phototherapy effect for pancreatic ductal adenocarcinoma treatment.

Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.

Decreased cadmium content in Solanum melongena induced by grafting was related to glucosinolates synthesis.

Grafting is an effective horticultural method to reduce Cd accumulation in crops. However, the mechanism of grafting inducing the decrease in Cd content in scions remains unclear. This study evaluated the effect of grafting on fruit quality, yield, and Cd content of Solanum melongena, and explored the potential mechanism of grafting reducing Cd content in scions. In the low Cd-contaminated soil, compared with un-grafted (UG) and self-grafted plants (SG), the fruit yield of inter-grafted plants (EG) increased by 38 %, and the fruit quality was not markedly affected. In EG, the decrease in total S and Cd content was not related to organic acids and thiol compounds. The decrease in total S and Cd content in EG leaves and fruits was closely related to the synthesis and transportation of glucosinolates (GSL). The genes encoding GSL synthesis in leaves, such as basic helix-loop-helix, myelocytomatosis proteins, acetyl-CoA, cytochrome P450, and glutathione S-transferases, were significantly downregulated. In EG leaves, the contents of five of the eight amino acids involved in GSL synthesis decreased significantly (P < 0.05). Notably, total GSL in EG stems, leaves, and fruits had a significant linear correlation with total S and Cd. In summary, the decrease in total S and Cd content in scions caused by grafting is closely related to GSL. Our findings provide a theoretical basis for the safe use of Cd-contaminated soil, exploring the long-distance transport of Cd in plants and cultivating crops with low Cd accumulation.

Enhanced wide-range gas pressure sensing with an all-solid open Fabry-Pérot interferometer.

The sensors with a wide gas pressure detection range are urgently demanded in many industrial applications. Here, we propose a gas pressure sensor based on an all-solid open Fabry-Pérot interferometer, which is prepared by using optical contact bonding to ensure high structural strength and high-quality factor of 8.8 × 105. The applied pressure induces a change in the refractive index of the air, leading to the shift of the resonant spectrum. The pressure is detected by calibrating this shift. The sensor exhibits a pressure sensitivity of 4.20 ± 0.01 nm/MPa in a pressure range of 0 to 10 MPa and has a minimum pressure resolution of 0.005 MPa. Additionally, it shows a lower temperature cross-sensitivity of -0.25 kPa/°C. These findings affirm that the sensor achieves high-sensitivity pressure sensing across a wide detection range. Moreover, owing to its exceptional mechanical strength, it holds great promise for applications in harsh environments, such as high temperature and high pressure.

Emerging role of interactions between tumor angiogenesis and cancer stem cells.

Tumor angiogenesis and cancer stem cells (CSCs) are two major hallmarks of solid tumors. They have long received attention for their critical roles in tumor progression, metastasis and recurrence. Meanwhile, plenty of evidence indicates the close association between CSCs and tumor vasculature. CSCs are proven to promote tumor angiogenesis, and the highly vascularized tumor microenvironment further maintains CSCs growth in return, thereby forming a hard-breaking vicious circle to promote tumor development. Hence, though monotherapy targeting tumor vasculature or CSCs has been extensively studied over the past decades, the poor prognosis has been limiting the clinical application. This review summarizes the crosstalk between tumor vasculature and CSCs with emphasis on small-molecule compounds and the associated biological signaling pathways. We also highlight the importance of linking tumor vessels to CSCs to disrupt the CSCs-angiogenesis vicious circle. More precise treatment regimens targeting tumor vasculature and CSCs are expected to benefit future tumor treatment development.

Conformational cycle of human polyamine transporter ATP13A2.

Dysregulation of polyamine homeostasis strongly associates with human diseases. ATP13A2, which is mutated in juvenile-onset Parkinson's disease and autosomal recessive spastic paraplegia 78, is a transporter with a critical role in balancing the polyamine concentration between the lysosome and the cytosol. Here, to better understand human ATP13A2-mediated polyamine transport, we use single-particle cryo-electron microscopy to solve high-resolution structures of human ATP13A2 in six intermediate states, including the putative E2 structure for the P5 subfamily of the P-type ATPases. These structures comprise a nearly complete conformational cycle spanning the polyamine transport process and capture multiple substrate binding sites distributed along the transmembrane regions, suggesting a potential polyamine transport pathway. Integration of high-resolution structures, biochemical assays, and molecular dynamics simulations allows us to obtain a better understanding of the structural basis of how hATP13A2 transports polyamines, providing a mechanistic framework for ATP13A2-related diseases.

Grafting with an invasive Xanthium strumarium improves tolerance and phytoremediation of native congener X. sibiricum to cadmium/copper/nickel tailings.

Invasive plants could play an important role in the restoration of tailings, but their invasiveness limits their practical application. In this study, the phytoremediation potentials and invasive risks of an exotic invasive plant (Xanthium strumarium, LT), a native plant (X. sibiricum, CR), and combinations of inoculations (EG, with CR as the scion and LT as the rootstock; SG, with CR as both the scion and rootstock) were evaluated on Cd/Cu/Ni tailings. LT rootstock has a stronger nutrient and metal transport capacity, compared with CR. EG not only had higher biomass and Cd/Cu/Ni accumulation, but also abundant rhizosphere microbial communities. Hydroponic and common garden experiments showed that the growth and metal enrichment characteristics of EG are not inherited by plant offspring, which reduces the risk of the biological diffusion in the process of using exotic species. Transcriptome analysis shows that a large number of differentially-expressed genes in EG leaves and roots are involved in phenylpropanoid biosynthesis, secondary metabolite generation, and signal transduction. The genes induced in EG leaves, including cyclic nucleotide-gated ion channel, calcium-binding protein, and WRKY transcription factor, were found to be differentially expressed compared to CR. The genes induced in EG roots, included phenylalanine ammonia-lyase, cinnamoyl-CoA reductase, caffeoyl-CoA O-methyltransferase, and beta-glucosidase. We speculate that lignin and glucosinolates play an important role in the metal accumulation and transportation of EG. The results demonstrate that grafting with LT not only improved CR tolerance and accumulation of Cd, Cu, and Ni, but also created a beneficial microbial environment for plants in tailings. More importantly, grafting with LT did not enhance the invasiveness of CR. Our results provide an example of the safe use of invasive plants in the restoration of Cd/Cu/Ni tailings.

A Long-Circulating Vector for Aptamers Based upon Polyphosphodiester-Backboned Molecular Brushes.

Aptamers face challenges for use outside the ideal conditions in which they are developed. These difficulties are most palpable in vivo due to nuclease activities, rapid clearance, and off-target binding. Herein, we demonstrate that a polyphosphodiester-backboned molecular brush can suppress enzymatic digestion, reduce non-specific cell uptake, enable long blood circulation, and rescue the bioactivity of a conjugated aptamer in vivo. The backbone along with the aptamer is assembled via solid-phase synthesis, followed by installation of poly(ethylene glycol) (PEG) side chains using a two-step process with near-quantitative efficiency. The synthesis allows for precise control over polymer size and architecture. Consisting entirely of building blocks that are generally recognized as safe for therapeutics, this novel molecular brush is expected to provide a highly translatable route for aptamer-based therapeutics.

Regulatory actions of rare earth elements (La and Gd) on the cell cycle of root tips in rice seedlings (Oryza sativa L.).

The continuous expansion of the application of rare earth elements (REEs) in various fields has attracted attention to their biosafety. At present, the molecular mechanisms underlying the biological effects of REEs are unclear. In this study, the effects of lanthanum (La) and gadolinium (Gd) on cell cycle progression in the root tips of rice seedlings were investigated. Low concentrations of REEs (0.1 mg L-1) induced an increase in the number of cells in the prophase and metaphase, while high concentrations of REEs (10 mg L-1) induced an increase in the number of cells in the late and terminal stages of the cell cycle, and apoptosis or necrosis. Additionally, low concentrations of REEs induced a significant increase in the expression of the cell cycle factors WEE1, CDKA;1, and CYCB1;1, and promoted the G2/M phase and accelerated root tip growth. However, at high REEs concentrations, the DNA damage response sensitized by BRCA1, MRE11, and TP53 could that prevent root tip growth by inhibiting the transcription factor E2F, resulting in obvious G1/S phase transition block and delayed G2/M phase conversion. Furthermore, by comparing the biological effect mechanisms of La and Gd, we found that these two REEs share regulatory actions on the cell cycle of root tips in rice seedlings.

Maintenance of grafting reducing cadmium accumulation in soybean (Glycinemax) is mediated by DNA methylation.

Cadmium (Cd) pollution in farmland soil increases the probability of wastage of land resources and compromised food safety. Grafting can change the absorption rates of elements in crops; however, there are few studies on grafting in bulk grain and cash crops. In this study, Glycine max was used as a scion and Luffa aegyptiaca as a rootstock for grafting experiments. The changes in total sulfur and Cd content in the leaves and grains of grafted species were determined for three consecutive generations, and the gene expression and DNA methylation status of the leaves were analyzed. The results show that grafting significantly reduced the total sulfur and Cd content in soybean leaves and grains; the Cd content in soybean leaves and grains decreased by >50 %. The plant's primary sulfur metabolism pathway was not significantly affected. Glucosinolates and DNA methylation may play important roles in reducing total sulfur and Cd accumulation. Notably, low sulfur and low Cd traits can be maintained over two generations. Our study establishes that grafting can reduce the total sulfur and Cd content in soybean, and these traits can be inherited. In summary, grafting technology can be used to prevent soybean from accumulating Cd in farmland soil. This provides a theoretical basis for grafting to cultivate crops with low Cd accumulation.

Dezocine induces apoptosis in human cervical carcinoma Hela cells via the endoplasmic reticulum stress pathway.

Dezocine, a dual agonist and antagonist of the µ-opioid receptor and κ-opioid receptor, is widely used as an analgesic in China. At present, there are few studies on anti-tumor effects of dezocine, most of which are used to treat cancer pain. However, it has recently been reported that dezocine can induce apoptosis of triple negative breast cancer cells. Dezocine may have some anti-tumor activity, but the effect and potential mechanism of dezocine in the treatment of other types of cancer remain to be fully studied. The purpose of the present study was to investigate the effect of dezocine on human Hela cervical carcinoma cells, and to elucidate the underlying molecular mechanisms. We performed CCK-8 assays, clone formation assays, xenograft, flow cytometry analysis, western blot and RNA-seq analysis to evaluate the effects of dezocine on Hela cells. In addition, the role of endoplasmic reticulum (ER) stress in dezocine-induced apoptosis was investigated using qPCR and western blot analysis. Dezocine inhibited Hela cell viability in dose-dependent and time-dependent manners, and notably did not achieve this effect by targeting the opioid receptors. Further mechanistic studies demonstrated that dezocine activated ER stress by upregulating the expression of GRP78, IRE1 and p-JNK, and that dezocine-induced apoptosis was attenuated when the ER stress pathway was blocked. Our results provide a foundation to support the redefinition of dezocine as a novel, adjuvant treatment for patients with cervical cancer, although further research will be required to support its application in clinical practice.

Phytoremediation potential of hybrids of the exotic plant Xanthium strumarium and its native congener Xanthium sibiricum for cadmium-contaminated soils.

Exotic plants could play an essential role in the restoration of heavy metal-contaminated soil. This study evaluated the tolerance of and extraction of cadmium (Cd) by ZCR (CR♀ × LT♂), hybrids of Xanthium strumarium (LT, exotic species) and X. sibiricum (CR, indigenous congener), and their parental species under different Cd treatments (0, 10, 40, and 80 mg·kg-1). The results showed that the hybrids had significantly improved tolerance to Cd. Under Cd stress, the biomass of ZCR increased by more than 50% on average compared with that of CR. Moreover, the hybrids showed a more remarkable ability to transport Cd from the root to the shoot. The Cd content of the shoots of ZCR increased by 128.33, 147.22, and 252.63% when treated with 10, 40, and 80 mg·kg-1 Cd, respectively. ZCR stored more than 70% of Cd in litter leaves, thereby reducing the toxic effects of Cd on photosynthesis and growth. The results showed that ZCR showed excellent Cd tolerance and enrichment in the presence of Cd. The hybrids of Xanthium strumarium and its native congener X. sibiricum may remediate soil Cd pollution.Novelty statementWith the changing world economy and increasing human activities, exotic plants have become a global issue of common concern to the international community. This study describes new findings on using hybrids of the exotic plant of Xanthium strumarium and its native congener Xanthium sibiricum for the restoration of cadmium-contaminated soils. Under Cd stress, the hybrids' biomass, tolerance, and ability to accumulate Cd were significantly higher than that of X. sibiricum, indicating that hybrids gained useful heavy metal extraction traits from X. strumarium.

A Framework to Predict Gastric Cancer Based on Tongue Features and Deep Learning.

Gastric cancer has become a global health issue, severely disrupting daily life. Early detection in gastric cancer patients and immediate treatment contribute significantly to the protection of human health. However, routine gastric cancer examinations carry the risk of complications and are time-consuming. We proposed a framework to predict gastric cancer non-invasively and conveniently. A total of 703 tongue images were acquired using a bespoke tongue image capture instrument, then a dataset containing subjects with and without gastric cancer was created. As the images acquired by this instrument contain non-tongue areas, the Deeplabv3+ network was applied for tongue segmentation to reduce the interference in feature extraction. Nine tongue features were extracted, relationships between tongue features and gastric cancer were explored by using statistical methods and deep learning, finally a prediction framework for gastric cancer was designed. The experimental results showed that the proposed framework had a strong detection ability, with an accuracy of 93.6%. The gastric cancer prediction framework created by combining statistical methods and deep learning proposes a scheme for exploring the relationships between gastric cancer and tongue features. This framework contributes to the effective early diagnosis of patients with gastric cancer.

Hybridization With an Invasive Plant of Xanthium strumarium Improves the Tolerance of Its Native Congener X. sibiricum to Cadmium.

Hybridization is one of the important factors influencing the adaptive evolution of invasive plants. According to previous studies, hybridization with an invasive plant reduces the adaptability of its native congener to environment. However, in this study, the hybridization with an invasive plant of Xanthium strumarium (LT) improves the tolerance and accumulation of its native congener Xanthium sibiricum (CR) to cadmium (Cd). Under Cd stress, X. sibiricum♀ × X. strumarium♂ (ZCR) showed higher biomass and Cd accumulation. Compared with CR, ZCR has longer vegetative and reproductive growth time. Moreover, ZCR adopted more reasonable biomass allocation strategy. ZCR increased the proportion of reproductive allocation and ensured its own survival with the increase of Cd stress. Furthermore, ZCR increased the translocation of Cd to aboveground parts and changed the distribution of Cd. A large amount of Cd is stored in senescent leaves and eliminated from the plant when the leaves fall off, which not only reduces the Cd content in the plant, but also reduces the toxicity of Cd in the normal leaves. Transcriptome analysis shows a total of 2055 (1060 up and 995 down) differentially expressed genes (DEGs) were detected in the leaves of Cd-stressed ZCR compared with CR, while only 792 (521 up and 271 down) were detected in X. strumarium♀ × X. sibiricum♂ (ZLT) compared with LT. A large number of DGEs in ZCR and ZLT are involved in abscisic acid (ABA) synthesis and signal transduction. The genes induced by ABA in ZCR, including CNGC5/20, CPK1/28, CML, PTI1-like tyrosine-protein kinase 3, respiratory burst oxidase homolog protein C, and WRKY transcription factor 33 were found differentially expressed compared CR. carotenoid cleavage dioxygenase 4, NCED1/2, phytoene synthase 2, and CYP707A involved in ABA synthesis and decomposition in ZLT were found differentially expressed compared LT. We speculated that ABA played an important role in Cd transportation of hybrids and Cd distribution in senescent and normal leaves. The results demonstrate that hybridization with an invasive plant improves the adaptability of the hybrid to Cd stress and may enhance the extinction risk of native congener in pollution environment.

Dezocine, An Opioid Analgesic, Exerts Antitumor Effects in Triple-Negative Breast Cancer by Targeting Nicotinamide Phosphoribosyltransferase.

Opioids are a potential adjuvant treatment for certain cancers; while they are primarily used to relieve chronic pain, these drugs may also affect cancer progression and recurrence. Dezocine is one opioid commonly used in China, but its effects on cancer cells are unknown. Here, we demonstrated the inhibitory effect of dezocine on triple-negative breast cancer (TNBC) cells, and determined the underlying molecular mechanism. We found that dezocine suppressed cell proliferation, migration and invasion, and induced apoptosis in TNBC cells. Xenograft models demonstrated the inhibitory effects of dezocine treatment on TNBC tumor growth in vivo. The anticancer effects of dezocine were independent of opioid receptors, which are not highly expressed by normal breast or breast cancer tissues. A pull-down assay and LC-MS/MS analysis indicated that dezocine directly targets NAMPT: computer modeling verified that the free energy of dezocine kinetically bound into the pocket of NAMPT was -17.4 kcal/mol. Consequently, dezocine treatment inhibited NAMPT enzyme activity, resulting in cellular NAD abolishment. We confirmed the dezocine-induced inhibition of cell proliferation by both NAMPT knockdown and upon treatment with the inhibitor FK866. Our results suggest that both dezocine and NAMPT might represent novel therapeutic targets for TNBC.

The Application of an Ultrasound Tomography Algorithm in a Novel Ring 3D Ultrasound Imaging System.

Currently, breast cancer is one of the most common cancers in women all over the world. A novel 3D breast ultrasound imaging ring system using the linear array transducer is proposed to decrease costs, reduce processing difficulties, and improve patient comfort as compared to modern day breast screening systems. The 1 × 128 Piezoelectric Micromachined Ultrasonic Transducer (PMUT) linear array is placed 90 degrees cross-vertically. The transducer surrounds the mammary gland, which allows for non-contact detection. Once the experimental platform is built, the breast model is placed through the electric rotary table opening and into a water tank that is at a constant temperature of 32 °C. The electric rotary table performs a 360° scan either automatically or mechanically. Pulse echo signals are captured through a circular scanning method at discrete angles. Subsequently, an ultrasonic tomography algorithm is designed, and a horizontal slice imaging is realized. The experimental results indicate that the preliminary detection of mass is realized by using this ring system. Circular scanning imaging is obtained by using a rotatable linear array instead of a cylindrical array, which allows the size and location of the mass to be recognized. The resolution of breast imaging is improved through the adjustment of the angle interval (>0.05°) and multiple slices are gained through different transducer array elements (1 × 128). These results validate the feasibility of the system design as well as the algorithm, and encourage us to implement our concept with a clinical study in the future.