Identification of RNA structures and their roles in RNA functions.

The development of high-throughput RNA structure profiling methods in the past decade has greatly facilitated our ability to map and characterize different aspects of RNA structures transcriptome-wide in cell populations, single cells and single molecules. The resulting high-resolution data have provided insights into the static and dynamic nature of RNA structures, revealing their complexity as they perform their respective functions in the cell. In this Review, we discuss recent technical advances in the determination of RNA structures, and the roles of RNA structures in RNA biogenesis and functions, including in transcription, processing, translation, degradation, localization and RNA structure-dependent condensates. We also discuss the current understanding of how RNA structures could guide drug design for treating genetic diseases and battling pathogenic viruses, and highlight existing challenges and future directions in RNA structure research.

In vivo single-molecule analysis reveals COOLAIR RNA structural diversity.

Cellular RNAs are heterogeneous with respect to their alternative processing and secondary structures, but the functional importance of this complexity is still poorly understood. A set of alternatively processed antisense non-coding transcripts, which are collectively called COOLAIR, are generated at the Arabidopsis floral-repressor locus FLOWERING LOCUS C (FLC)1. Different isoforms of COOLAIR influence FLC transcriptional output in warm and cold conditions2-7. Here, to further investigate the function of COOLAIR, we developed an RNA structure-profiling method to determine the in vivo structure of single RNA molecules rather than the RNA population average. This revealed that individual isoforms of the COOLAIR transcript adopt multiple structures with different conformational dynamics. The major distally polyadenylated COOLAIR isoform in warm conditions adopts three predominant structural conformations, the proportions and conformations of which change after cold exposure. An alternatively spliced, strongly cold-upregulated distal COOLAIR isoform6 shows high structural diversity, in contrast to proximally polyadenylated COOLAIR. A hyper-variable COOLAIR structural element was identified that was complementary to the FLC transcription start site. Mutations altering the structure of this region changed FLC expression and flowering time, consistent with an important regulatory role of the COOLAIR structure in FLC transcription. Our work demonstrates that isoforms of non-coding RNA transcripts adopt multiple distinct and functionally relevant structural conformations, which change in abundance and shape in response to external conditions.

CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS.

The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERα-target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. Anti-sense oligonucleotide (ASO)-targeting circPVT1 inhibits ERα-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERα-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα-positive breast cancer in the clinic.

Evaluation of mandibular motion in adolescents with skeletal class II division 1 malocclusion during mandibular advancement using clear functional aligners: a prospective study.

BACKGROUND: This study aimed to evaluate the characteristics of mandibular protrusive condylar trajectory in adolescents with skeletal Class II Division 1 malocclusion and the changes of condylar trajectory during mandibular advancement (MA) treatment using clear functional aligners. METHODS: This prospective study consisted of a cross-sectional study and a longitudinal study. In cross-sectional study, sixty-one adolescents were divided into two groups: Class I (n = 30) and Class II Division 1 (n = 31). The condylar trajectory was measured and compared using the Mann-Whitney U test. The longitudinal study was the MA treatment group using clear functional aligner and consisted of 16 participants from Class II Division 1group. The condylar trajectory was collected at three-time points: pre-treatment (T1), during MA treatment at approximately 3 months (T2, 105.6 days average), and at the end of MA treatment (T3, 237.6 days average). The changes at T1, T2, and T3, as well as the symmetry between the left and right condyles across all groups, were examined using the Wilcoxon paired test. RESULTS: A greater increase in the anteroposterior displacement and space displacement during protrusive movements was observed in the Class II Division 1 group compared with that in the Class I group, with a large difference being observed in the left and right condylar movements. The condylar anteroposterior displacement and space displacement decreased significantly at T2 and increased significantly at T3; however, no significant difference was observed between T1 and T3. A significant difference was observed between the condylar movement on the left and right sides at T1; however, no significant difference was observed at T2 and T3. CONCLUSIONS: Adolescents with Class II Division 1 malocclusion had higher protrusive capacity than those with Class I. Moreover, their left and right condylar motion was more asymmetric. The range of condyle motion decreased first and then increased during MA therapy, and the left and right condyle movement became more symmetrical, which may be the adaptive response of neuromuscular function to the changes in jaw position.

A 3D Hierarchical Host with Gradient-Distributed Dielectric Properties toward Dendrite-free Lithium Metal Anode.

The conventional conductive three-dimensional (3D) host fails to effectively stabilize lithium metal anodes (LMAs) due to the internal incongruity arising from nonuniform lithium-ion gradient and uniform electric fields. This results in undesirable Li "top-growth" behavior and dendritic Li growth, significantly impeding the practical application of LMAs. Herein, we construct a 3D hierarchical host with gradient-distributed dielectric properties (GDD-CH) that effectively regulate Li-ion diffusion and deposition behavior. It comprises a 3D carbon fiber host modified by layer-by-layer bottom-up attenuating Sb particles, which could promote Li-ion homogeneously distribution and reduce ion concentration gradient via unique gradient dielectric polarization. Sb transforms into superionic conductive Li3Sb alloy during cycling, facilitating Li-ion dredging and pumps towards the bottom, dominating a bottom-up deposition regime confirmed by COMSOL Multiphysics simulations and physicochemical characterizations. Consequently, a stable cycling performance of symmetrical cells over 2000 h under a high current density of 10 mA cm-2 is achieved. The GDD-CH-based lithium metal battery shows remarkable cycling stability and ultra-high energy density of 378 Wh kg-1 with a low N/P ratio (1.51). This strategy of dielectric gradient design broadens the perspective for regulating the Li deposition mechanism and paves the way for developing high-energy-density lithium metal anodes with long durability.

Establishment of a potent weighted risk model for determining the progression of diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is a severe complication of diabetes. Currently, no effective measures are available to reduce the risk of DKD progression. This study aimed to establish a weighted risk model to determine DKD progression and provide effective treatment strategies. METHODS: This was a hospital-based, cross-sectional study. A total of 1104 patients with DKD were included in this study. The random forest method was used to develop weighted risk models to assess DKD progression. Receiver operating characteristic curves were used to validate the models and calculate the optimal cutoff values for important risk factors. RESULTS: We developed potent weighted risk models to evaluate DKD progression. The top six risk factors for DKD progression to chronic kidney disease were hemoglobin, hemoglobin A1c (HbA1c), serum uric acid (SUA), plasma fibrinogen, serum albumin, and neutrophil percentage. The top six risk factors for determining DKD progression to dialysis were hemoglobin, HbA1c, neutrophil percentage, serum albumin, duration of diabetes, and plasma fibrinogen level. Furthermore, the optimal cutoff values of hemoglobin and HbA1c for determining DKD progression were 112 g/L and 7.2%, respectively. CONCLUSION: We developed potent weighted risk models for DKD progression that can be employed to formulate precise therapeutic strategies. Monitoring and controlling combined risk factors and prioritizing interventions for key risk factors may help reduce the risk of DKD progression.

Three-dimensional spatial analysis of the temporomandibular joint in adult patients with Class II division 2 malocclusion before and after orthodontic treatment: a retrospective study.

BACKGROUND: To investigate changes in the three-dimensional (3D) spatial morphology of the temporomandibular joint (TMJ) and condyle position in adult patients with Class II division 2 malocclusion using a 3D spatial measurement method and to investigate the similarities and differences in the effects of fixed appliance and clear aligner treatments on the TMJ. METHODS: Cone-beam computed tomography (CBCT) data of 47 adult patients with Class II division 2 malocclusion (25, fixed appliance group; 22, clear aligner group) were collected before and after treatment. Mimics 21.0 was used to reconstruct the TMJ 3D model. Fourteen measurement items, such as the anterior, upper, and posterior joint spaces, were measured directly on the 3D model and compared. RESULTS: Post-orthodontic treatment, the shape and position of the condyle changed in adult patients with Class II division 2 malocclusion. Reduction in the anterior joint space and increase in the posterior joint space after orthodontic treatment were significant in both fixed appliance and clear aligner treatments; the condyle moved forward to the center of the fossa. The superior joint space and depth of the glenoid fossa increased after clear aligner treatment, but there was no significant change after fixed appliance treatment. CONCLUSIONS: The condylar shape and position in patients with Class II division 2 malocclusion changed significantly post-treatment, indicating that the condyle undergoes adaptive reconstruction during orthodontic treatment in these patients. These results provide a reference for diagnosis, design of treatment plan, and monitoring of treatment in orthodontic clinics.

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OBJECTIVES: To investigate the therapeutic effect of recombinant human growth hormone (rhGH) on children with growth hormone deficiency (GHD) and different pituitary developmental conditions. METHODS: A prospective study was performed on 90 children with GHD who were admitted to Xuchang Maternity and Child Health Hospital from June 2020 to December 2021. According to pituitary height on the median sagittal plane, they were divided into three groups: pituitary dysplasia group (n=45), normal pituitary group (n=31), and enlarged pituitary growth group (n=14). The changes in body height, growth velocity, height standard deviation score and serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) were examined after treatment in the above three groups, and the differences of the above indices before and after treatment were compared among the three groups. RESULTS: After treatment, all three groups had significant increases in body height, growth velocity, height standard deviation score, and the serum levels of IGFBP-3 and IGF-1 (P<0.05). Compared with the normal pituitary group, the pituitary dysplasia group and the enlarged pituitary growth group had significantly higher values in terms of the differences in body height, growth velocity, height standard deviation score, IGF-1, and IGFBP-3 before and after treatment (P<0.05). There was no significant difference in the incidence rate of adverse reactions among the three groups (P>0.05). CONCLUSIONS: In GHD children with different pituitary developmental conditions, rhGH can promote bone growth and increase body height, especially in children with pituitary dysplasia and pituitary hyperplasia, with good safety.

Transcriptional Repression of the APC/C Activator Genes CCS52A1/A2 by the Mediator Complex Subunit MED16 Controls Endoreduplication and Cell Growth in Arabidopsis.

Endoreduplication, the replication of the nuclear genome in the absence of mitosis, is often associated with cell growth and differentiation in plants and animals, but the molecular mechanisms underlying endoreduplication in plants have not been fully elucidated. Here, we show that the Mediator complex subunit MED16 acts as a negative regulator of endoreduplication to influence cell growth in Arabidopsis (Arabidopsis thaliana). The med16 mutant exhibits larger and more numerous cells than the wild type, resulting in enlarged organs. The large cells in med16 are associated with high DNA ploidy levels. MED16 associates with the promoters of the Anaphase Promoting Complex/Cyclosome activators CELL CYCLE SWITCH52 A1 (CCS52A1) and CCS52A2 (encoding important factors for endoreduplication and cell growth) and represses their expression. MED16 interacts physically with the transcriptional repressor DEL1 to repress the expression of CCS52A2 Genetic analysis suggested that MED16 is partially dependent on CCS52A1/A2 to control endoreduplication and cell growth. Our results indicate that the transcriptional repression of CCS52A1/A2 by MED16 regulates endoreduplication and cell growth in Arabidopsis.

Intact RNA structurome reveals mRNA structure-mediated regulation of miRNA cleavage in vivo.

MicroRNA (miRNA)-mediated cleavage is involved in numerous essential cellular pathways. miRNAs recognize target RNAs via sequence complementarity. In addition to complementarity, in vitro and in silico studies have suggested that RNA structure may influence the accessibility of mRNAs to miRNA-induced silencing complexes (miRISCs), thereby affecting RNA silencing. However, the regulatory mechanism of mRNA structure in miRNA cleavage remains elusive. We investigated the role of in vivo RNA secondary structure in miRNA cleavage by developing the new CAP-STRUCTURE-seq method to capture the intact mRNA structurome in Arabidopsis thaliana. This approach revealed that miRNA target sites were not structurally accessible for miRISC binding prior to cleavage in vivo. Instead, we found that the unfolding of the target site structure plays a key role in miRISC activity in vivo. We found that the single-strandedness of the two nucleotides immediately downstream of the target site, named Target Adjacent nucleotide Motif, can promote miRNA cleavage but not miRNA binding, thus decoupling target site binding from cleavage. Our findings demonstrate that mRNA structure in vivo can modulate miRNA cleavage, providing evidence of mRNA structure-dependent regulation of biological processes.

G-quadruplex structures trigger RNA phase separation.

Liquid-liquid phase separation plays an important role in a variety of cellular processes, including the formation of membrane-less organelles, the cytoskeleton, signalling complexes, and many other biological supramolecular assemblies. Studies on the molecular basis of phase separation in cells have focused on protein-driven phase separation. In contrast, there is limited understanding on how RNA specifically contributes to phase separation. Here, we described a phase-separation-like phenomenon that SHORT ROOT (SHR) RNA undergoes in cells. We found that an RNA G-quadruplex (GQ) forms in SHR mRNA and is capable of triggering RNA phase separation under physiological conditions, suggesting that GQs might be responsible for the formation of the SHR phase-separation-like phenomenon in vivo. We also found the extent of GQ-triggered-phase-separation increases on exposure to conditions which promote GQ. Furthermore, GQs with more G-quartets and longer loops are more likely to form phase separation. Our studies provide the first evidence that RNA can adopt structural motifs to trigger and/or maintain the specificity of RNA-driven phase separation.

Observation of the interplay between seeded and self-seeded nondegenerate four-wave mixing in cesium vapor.

Nondegenerate four-wave mixing (NFWM) is a practical and effective technique for generating or amplifying light fields at different wavelengths, and could be used to create color correlation and entanglement. Here we experimentally investigate the NFWM process in diamond atomic system via two-photon excitation with two pumps at 852 nm and 921 nm, demonstrating that a seeded NFWM with a third laser at 895 nm and two self-seeded NFWMs due to amplified spontaneous emission (ASE) occur simultaneously. We compare the two kinds of processes and show that the single- and two-photon detunings hold the key role in distinguishing them. As a result, the enhancement of seeded NFWM is obtained by selecting large one- and two-photon detunings, in which case the ASE induced self-seeded NFWM can be largely suppressed. In contrast, the ASE and its induced NFWM are effectively achieved with one- and two-photon resonant excitations allowing for population inversion for efficient ASE.

ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-κB signaling pathway.

BACKGROUND: Excision Repair Cross-Complementation group 6-like (ERCC6L) has been shown to exhibit carcinogenic effect in several malignant tumors. However, the function and molecular mechanism of the ERCC6L in hepatocellular carcinoma (HCC) have not been investigated extensively. METHODS: Immunohistochemistry analyses were used to detect ERCC6L expression in a HCC tissue microarray, and the Chi-square test was used to assess the correlation between ERCC6L expression and patients' clinicopathological features. shRNA was used to down-regulation ERCC6L expression in HCC cell lines. MTT assay, plate clone formation assay, flow cytometry, caspase 3/7 activity and migration assays were performed to evaluate the impact of ERCC6L on HCC cells in vitro. Nude mice xenograft models were used to assess the role of ERCC6L in vivo. The regulatory of mechanism of PI3K/AKT pathway was evaluated by western blotting. RESULTS: ERCC6L was highly expressed in HCC tissue compared with tumor adjacent tissues in 90 paired samples. ERCC6L expression positively correlated with gender, tumor encapsulation, and pathological stage. Patients with low ERCC6L expression had significantly longer OS than those with high ERCC6L expression. Knockdown of ERCC6L expression significantly inhibited proliferation, invasion and metastasis in vitro and tumor growth in vivo, and it promoted cell cycle arrest and apoptosis. Mechanistic analyses revealed that PI3K/AKT and NF-κB signaling pathway were inhibited by silencing ERCC6L. CONCLUSION: These results demonstrate that ERCC6L plays a critical role in HCC progression, and thereby might be a potential therapeutic target for HCC patients.

SMA1, a homolog of the splicing factor Prp28, has a multifaceted role in miRNA biogenesis in Arabidopsis.

MicroRNAs (miRNAs) are a class of small non-coding RNAs that repress gene expression. In plants, the RNase III enzyme Dicer-like (DCL1) processes primary miRNAs (pri-miRNAs) into miRNAs. Here, we show that SMALL1 (SMA1), a homolog of the DEAD-box pre-mRNA splicing factor Prp28, plays essential roles in miRNA biogenesis in Arabidopsis. A hypomorphic sma1-1 mutation causes growth defects and reduces miRNA accumulation correlated with increased target transcript levels. SMA1 interacts with the DCL1 complex and positively influences pri-miRNA processing. Moreover, SMA1 binds the promoter region of genes encoding pri-miRNAs (MIRs) and is required for MIR transcription. Furthermore, SMA1 also enhances the abundance of the DCL1 protein levels through promoting the splicing of the DCL1 pre-mRNAs. Collectively, our data provide new insights into the function of SMA1/Prp28 in regulating miRNA abundance in plants.

PA5470 Counteracts Antimicrobial Effect of Azithromycin by Releasing Stalled Ribosome in Pseudomonas aeruginosa.

Pseudomonas aeruginosa causes various acute and chronic infections in humans. Treatment with azithromycin (AZM) has been shown to benefit patients with chronic P. aeruginosa infections. By binding to the exit tunnel of the 50S ribosome, AZM causes ribosome stalling and depletion of the intracellular tRNA pool. It has been shown that AZM is able to kill stationary-phase P. aeruginosa cells and repress quorum sensing-regulated virulence factors as well as swarming motility. In P. aeruginosa, the PA5470 gene encodes a putative peptide chain release factor whose expression is highly induced by macrolide antibiotics. However, its function remains unknown. Here, we found that overexpression of PA5470 increased bacterial tolerance against AZM and alleviated the repression of swarming motility. Ribosome pulldown assays revealed that PA5470 contributes to the release of ribosome stalled by AZM. We further demonstrate that overexpression of PA5470 counteracts AZM-mediated repression of the translation of the quorum sensing regulator RhlR. Overall, our results revealed a novel role of PA5470 in the bacterial response to AZM.

Transcription factors SOD7/NGAL2 and DPA4/NGAL3 act redundantly to regulate seed size by directly repressing KLU expression in Arabidopsis thaliana.

Although seed size is one of the most important agronomic traits in plants, the genetic and molecular mechanisms that set the final size of seeds are largely unknown. We previously identified the ubiquitin receptor DA1 as a negative regulator of seed size, and the Arabidopsis thaliana da1-1 mutant produces larger seeds than the wild type. Here, we describe a B3 domain transcriptional repressor NGATHA-like protein (NGAL2), encoded by the suppressor of da1-1 (SOD7), which acts maternally to regulate seed size by restricting cell proliferation in the integuments of ovules and developing seeds. Overexpression of SOD7 significantly decreases seed size of wild-type plants, while the simultaneous disruption of SOD7 and its closest homolog DEVELOPMENT-RELATED PcG TARGET IN THE APEX4 (DPA4/NGAL3) increases seed size. Genetic analyses indicate that SOD7 and DPA4 act in a common pathway with the seed size regulator KLU to regulate seed growth, but do so independently of DA1. Further results show that SOD7 directly binds to the promoter of KLUH (KLU) in vitro and in vivo and represses the expression of KLU. Therefore, our findings reveal the genetic and molecular mechanisms of SOD7, DPA4, and KLU in seed size regulation and suggest that they are promising targets for seed size improvement in crops.

Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors.

Multitarget inhibitors design has generated great interest in cancer treatment. Based on the synergistic effects of topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC50 values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC50 = 0.90 µM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50 µM. Moreover, compound 8c could interact with DNA and induce U937 apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory anticancer agent.

Comparison of a loading dose of dexmedetomidine combined with propofol or sevoflurane for hemodynamic changes during anesthesia maintenance: a prospective, randomized, double-blind, controlled clinical trial.

BACKGROUND: There may be great individual variability in the hemodynamic effects of this dexmedetomidine. For this reason, the dose must be carefully adjusted to achieve the desired clinical effect. Whether a loading dose of dexmedetomidine produces hemodynamic side effects during the anesthesia maintenance is unknown. The aim of this study was to compare the effects of a loading dose of dexmedetomidine combined with propofol or sevoflurane on hemodynamics during anesthesia maintenance. METHODS: Eighty-four patients who were scheduled for general surgery under balanced general anesthesia were randomly allocated into 4 groups (n = 21): the propofol and dexmedetomidine group, the sevoflurane and dexmedetomidine group, the propofol and normal saline group, or the sevoflurane and normal saline group. The hemodynamic indexes at the time of just before, 5 min after and the end of study drug infusion (dexmedetomidine or normal saline) were recorded. The incidence rates of increasing blood pressure at the end of study drug infusion (greater than 20% compared to baseline or before study drug infusion) were evaluated. RESULTS: Mean arterial pressure increased significantly (P < 0.01) only in the propofol and dexmedetomidine group after intravenous dexmedetomidine compared administration. 80% of cases with propofol and dexmedetomidine had increased mean arterial blood pressure compared to only 5% of cases in the sevoflurane and dexmedetomidine group (P < 0.05). Heart rates in the propofol and dexmedetomidine and the sevoflurane and dexmedetomidine groups decreased significantly after dexmedetomidine infusion (P < 0.01). CONCLUSIONS: Intraoperative administration of a loading dose of dexmedetomidine combined with propofol in anesthesia maintenance proceeded a significant increase in blood pressure. In contrast, it combines with sevoflurane didn't produce increased blood pressure. Meanwhile it is not unexpected that dexmedetomidine combined with propofol or sevofurance decreased heart rate, due to the known side effects of DEX. Therefore, dexmedetomidine should be used cautiously during the entire intravenous anesthesia maintenance period, especially during maintenance with propofol. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IOR-17010423 , registered on 13 January 2017.

The ubiquitin receptor DA1 regulates seed and organ size by modulating the stability of the ubiquitin-specific protease UBP15/SOD2 in Arabidopsis.

Although the control of organ size is a fundamental question in developmental biology, little is known about the genetic and molecular mechanisms that determine the final size of seeds in plants. We previously demonstrated that the ubiquitin receptor DA1 acts synergistically with the E3 ubiquitin ligases DA2 and ENHANCER1 OF DA1 (EOD1)/BIG BROTHER to restrict seed growth in Arabidopsis thaliana. Here, we describe UBIQUITIN-SPECIFIC PROTEASE15 (UBP15), encoded by SUPPRESSOR2 OF DA1 (SOD2), which acts maternally to regulate seed size by promoting cell proliferation in the integuments of ovules and developing seeds. The sod2/ubp15 mutants form small seeds, while overexpression of UBP15 increases seed size of wild-type plants. Genetic analyses indicate that UBP15 functions antagonistically in a common pathway with DA1 to influence seed size, but does so independently of DA2 and EOD1. Further results reveal that DA1 physically associates with UBP15 in vitro and in vivo and modulates the stability of UBP15. Therefore, our findings establish a genetic and molecular framework for the regulation of seed size by four ubiquitin-related proteins DA1, DA2, EOD1, and UBP15 and suggest that they are promising targets for increasing seed size in crops.

Lysosome Inhibitors Enhance the Chemotherapeutic Activity of Doxorubicin in HepG2 Cells.

The lysosome inhibitors bafilomycin A1 and chloroquine have both lysosomotropic properties and autophagy inhibition ability, and are promising clinical agents to be used in combination with anticancer drugs. In order to investigate this combination effect, HepG2 cells were treated with bafilomycin A1, chloroquine, or/and doxorubicin, and their proliferative ability, induction of apoptosis, and the changes of lysosomal membrane permeabilization and mitochondrial membrane potential were studied. The results demonstrate that treatment with bafilomycin A1 or chloroquine alone at a relatively low concentration promotes the inhibitory effect of doxorubicin on cell growth and apoptosis. Further studies reveal that bafilomycin A1 and chloroquine promote lysosomal membrane permeabilization and the reduction of mitochondrial membrane potential induced by doxorubicin. Our findings suggest that bafilomycin A1 and chloroquine potentiate the anticancer effect of doxorubicin in hepatic cancer cells and that supplementation of conventional chemotherapy with lysosome inhibitors may provide a more efficient anticancer therapy.