ClusterCAD 2.0: an updated computational platform for chimeric type I polyketide synthase and nonribosomal peptide synthetase design.

Megasynthase enzymes such as type I modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) play a central role in microbial chemical warfare because they can evolve rapidly by shuffling parts (catalytic domains) to produce novel chemicals. If we can understand the design rules to reshuffle these parts, PKSs and NRPSs will provide a systematic and modular way to synthesize millions of molecules including pharmaceuticals, biomaterials, and biofuels. However, PKS and NRPS engineering remains difficult due to a limited understanding of the determinants of PKS and NRPS fold and function. We developed ClusterCAD to streamline and simplify the process of designing and testing engineered PKS variants. Here, we present the highly improved ClusterCAD 2.0 release, available at https://clustercad.jbei.org. ClusterCAD 2.0 boasts support for PKS-NRPS hybrid and NRPS clusters in addition to PKS clusters; a vastly enlarged database of curated PKS, PKS-NRPS hybrid, and NRPS clusters; a diverse set of chemical 'starters' and loading modules; the new Domain Architecture Cluster Search Tool; and an offline Jupyter Notebook workspace, among other improvements. Together these features massively expand the chemical space that can be accessed by enzymes engineered with ClusterCAD.

Hydroxylase-like Biomimetic Nanozyme Synthesized via a Urea-Mediated MOF Pyrolytic Reconstruction Strategy for Non-"o-Phenol hydroxyl"-Dependent Dopamine Electrochemical Sensing.

Dopamine (DA), an essential neurotransmitter, is closely associated with various neurological disorders, whose real-time dynamic monitoring is significant for evaluating the physiological activities of neurons. Electrochemical sensing methods are commonly used to determine DA, but they mostly rely on the redox reaction of its o-phenolic hydroxyl group, which makes it difficult to distinguish it from substances with this group. Here, we design a biomimetic nanozyme inspired by the coordination structure of the copper-based active site of dopamine ß-hydroxylase, which was successfully synthesized via a urea-mediated MOF pyrolysis reconstruction strategy. Experimental studies and theoretical calculations revealed that the nanozyme with Cu-N3 coordination could hydroxylate the carbon atom of the DA ß-site at a suitable potential and that the active sites of this Cu-N3 structure have the lowest binding energy for the DA ß-site. With this property, the new oxidation peak achieves the specific detection of DA rather than the traditional electrochemical signal of o-phenol hydroxyl redox, which would effectively differentiate it from neurotransmitters, such as norepinephrine and epinephrine. The sensor exhibited good monitoring capability in DA concentrations from 0.05 to 16.7 µM, and its limit of detection was 0.03 µM. Finally, the sensor enables the monitoring of DA released from living cells and can be used to quantitatively analyze the effect of polystyrene microplastics on the amount of DA released. The research provides a method for highly specific monitoring of DA and technical support for initial screening for neurocytotoxicity of pollutants.

P4HA2-mediated HIF-1α stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer.

Erdafitinib is a novel fibroblast growth factor receptor (FGFR) inhibitor that has shown great therapeutic promise for solid tumor patients with FGFR3 alterations, especially in urothelial carcinoma. However, the mechanisms of resistance to FGFR inhibitors remain poorly understood. In this study, we found Erdafitinib could kill cells by inducing incomplete autophagy and increasing intracellular reactive oxygen species levels. We have established an Erdafitinib-resistant cell line, RT-112-RS. whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis performed on Erdafitinib-resistant RT-112-RS cells and parental RT-112 cells introduced P4HA2 as a linchpin to Erdafitinib resistance. The gain and loss of function study provided evidence for P4HA2 conferring such resistance in RT-112 cells. Furthermore, P4HA2 could stabilize the HIF-1α protein which then activated downstream target genes to reduce reactive oxygen species levels in bladder cancer. In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.

Label-Free Chemiresistive Sensors Based on Self-Assembled Ti3C2Tx MXene Films for Monitoring of Microcystin-LR in Water Samples.

Herein, we propose a label-free chemiresistive sensor for the highly sensitive and selective detection of microcystin (MC)-LR in water samples. The sensor uses a layer-by-layer (LBL) assembled conductive film consisting of Ti3C2Tx nanosheets as the sensing channel. It is further modified by using an aptamer for the specific recognition of MC-LR. The response signal is based on the change in resistance of the conductive channel upon binding of MC-LR with the aptamer. Our novel strategy is the first concept proposed for immobilizing the aptamer containing -SH on the channel surface through a Ti-S bond under weakly alkaline condition. The resulting sensor is highly sensitive and stable for the detection of MC-LR, with a detection limit of 0.18 ng L-1 and a wide linear range from 1 to 104 ng L-1. We used the sensor to continuously monitor MC-LR released by cultivated Microcystis aeruginosa, showing a strong relationship between MC-LR and cell density. Furthermore, the sensor was successfully used to measure MC-LR in freshwater lakes with moderate algal blooms, and the results agreed well with those obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The present study provides a reliable method for highly sensitive and selective detection of MC-LR in environmental waters.

Lactoferrin Alleviates Ethanol-Induced Injury via Promoting Nrf2 Nuclear Translocation in BRL-3A Rat Liver Cells.

Our previous animal studies found that the preventive effects of lactoferrin (Lf) on alcoholic liver injury (ALI) are associated with nuclear factor E2-related factor 2 (Nrf2). To further explore the causality, experiments were performed using rat normal liver BRL-3A cells. Lf treatment reduced ethanol-induced death and apoptosis; meanwhile, Lf treatment alleviated excessive LDH release. These findings confirmed the protection of Lf against ethanol-induced injury in BRL-3A cells. Mechanistically, Lf treatment reversed the reduction in nuclear Nrf2 induced by ethanol without affecting the cytoplasmic Nrf2 level, which led to antioxidant enzyme activity restoration. However, the blocking of Nrf2 nuclear translocation by ML385 eliminated the protective effects of Lf. In a conclusion, Lf protects BRL-3A cells from ethanol-induced injury via promoting Nrf2 nuclear translocation.

CEMIP promotes extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis.

Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death, and the survival of ECM-detached cells is one of the prerequisites for the metastatic cascade. Ferroptosis, a form of iron-dependent programmed cell death, has recently been found to be involved in matrix-detached cancer cells. However, the molecular mechanisms by which ECM-detached cells escape ferroptosis are not fully understood. Here, we observed that cell migration-inducing protein (CEMIP) upregulation facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake in prostate cancer (PCa) cells. Meanwhile, silencing CEMIP causes it to lose its ability to promote cystine uptake and inhibit ferroptosis. Mechanistically, the interaction of CEMIP with inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca2+ ) leakage from the endoplasmic reticulum, activating calcium/calmodulin-dependent protein kinase II (CaMKII), which further facilitates nuclear factor erythroid 2-related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Our findings delineate a novel role of CEMIP in ferroptosis resistance during ECM detachment and provide new insights into therapeutic strategies for metastatic PCa.

Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification.

BACKGROUND: Prostatic cancer (PCa) is one of the most common malignant tumors in men worldwide. Emerging evidence indicates significance of hypoxia and immunity in PCa invasion and metastasis. This study aimed to develop a hypoxia- and immune-related gene risk signature and explore the molecular mechanisms to formulate a better prognostic tool for PCa patients. METHODS: The hypoxia and immune scores of all PCa patients in The Cancer Genome Atlas (TCGA) dataset were calculated via the maximally selected rank statistics method and the ESTIMATE algorithm. From common genes identified overlapping hypoxia- and immune-related differentially expressed genes (DE-HRGs and DE-IRGs), a hypoxia- and immune-related gene risk signature was developed utilizing univariate and multivariate Cox regression analyses, and validated in the Memorial Sloan Kettering Cancer Centre (MSKCC) database. The immune cell infiltration level of PCa samples were evaluated with ssGSEA algorithm. Differential expression of prognostic genes was evidenced by immunohistochemistry and western blot (WB) in paired PCa samples. Expression levels of these genes and their variations under regular and hypoxic conditions were examined in cell lines. The functional effects of the prognostic gene on PCa cells were examined by wound healing and transwell assays. RESULTS: A hypoxia- and immune-related gene risk signature constructed by ISG15 and ZFP36 displays significant predictive potency, with higher risk score representing worse survival. A nomogram based on independent prognostic factors including the risk score and Gleason score exhibited excellent clinical value in the survival prediction of PCa. Infiltration levels of eosinophils, neutrophils, Tcm, Tem, TFH, Th1 cells, and Th17 cells were significantly lower in the high-risk group. Conversely, aDC, pDC, T helper cells, and Tregs were significantly higher. Additionally, the two prognostic genes were closely correlated with the tumor-infiltrating immune cell subset in PCa progression. RT-qPCR and WB presented higher and lower expression of ISG15 and ZFP36 in PCa cells, respectively. They were correspondingly increased and decreased in PCa cells under hypoxic conditions. Wound healing and transwell assays showed that over-expression of ISG15 promoted the migration and invasion of PCa cells. CONCLUSION: Our study identified a novel hypoxia- and immune-related gene signature, contributing a new perspective to the treatment of PCa.

Preliminary assessment of a portable Raman spectroscopy system for post-operative urinary stone analysis.

PURPOSE: We aimed to evaluate the reliability of a portable device that applies Raman spectroscopy at an excitation wavelength of 1064 nm for the post-operative analysis of urinary stone composition. MATERIALS AND METHODS: Urinary stone samples were obtained post-operatively from 300 patients. All samples were analyzed by the portable Raman spectroscopy system at an excitation wavelength of 1064 nm as well as by infrared spectroscopy (IR), and the results were compared. RESULTS: Both Raman spectroscopy and IR could detect multiple stone components, including calcium oxalate monohydrate, calcium oxalate dihydrate, calcium phosphate, uric acid, cystine, and magnesium ammonium phosphate hexahydrate. The results from 1064-nm Raman analysis matched those from IR analysis for 96.0% (288/300) of cases. Although IR detected multiple components within samples more often than Raman analysis (239 vs 131), the Raman analysis required less time to complete than IR data acquisition (5 min vs 30 min). CONCLUSIONS: These preliminary results indicate that 1064-nm Raman spectroscopy can be applied in a portable and automated analytical system for rapid detection of urinary stone composition in the post-operative clinical setting. TRIAL REGISTRATION: Chinese Clinical Trail Register ID: ChiCTR2000039810 (approved WHO primary register) http://www.chictr.org.cn/showproj.aspx?proj=63662 .

Activation of BDNF/TrkB pathway promotes prostate cancer progression via induction of epithelial-mesenchymal transition and anoikis resistance.

Prostate cancer (PCa) is one of the most common malignant diseases in male worldwide, yet, the molecular mechanisms involved in PCa progression are still poorly understood. This study aimed to investigate the roles of the brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) pathway in PCa progression. It was demonstrated by immunohistochemical analysis that both BDNF and TrkB were overexpressed in PCa tissues and elevated TrkB expression was tightly related with lymph node metastasis and advanced stage of PCa. In vitro studies showed that stimulation with rhBDNF or overexpression of TrkB in PCa cells promoted cell migration, invasion, and anoikis resistance. Overexpression of TrkB also resulted in epithelial-mesenchymal transition (EMT)-like transformation in cell morphology, whereas RNA interference-mediated TrkB depletion caused reversion of EMT. Further investigation demonstrated that protein kinase B (AKT) was responsible for BDNF/TrkB signaling-induced pro-migratory and pro-invasive effects, EMT, and anoikis resistance. Finally, in vivo studies confirmed that enhanced TrkB expression facilitated tumor growth, whereas downregulation of TrkB suppressed tumor growth. Our findings illustrate that BDNF/TrkB pathway is crucial for PCa progression, which may provide a novel therapeutic strategy for the treatment of advanced PCa.

miR-190b promotes tumor growth and metastasis via suppressing NLRC3 in bladder carcinoma.

Bladder cancer is one of the most common urogenital malignancies. However, its pathogenesis, especially molecular mechanisms remain elusive. Thus, understanding the molecular mechanisms underlying bladder cancer is important for the discovery of novel therapeutic paradigms for these diseases. In current study, we found that micro-RNA (miR)-190b is highly expressed in bladder cancer tissues and cells. Overexpression of miR-190b enhanced the proliferation, growth, migration and invasion capabilities, and angiogenesis of bladder cancer cells, whereas downregulation of miR-190b reversed these effects. Target prediction and dual luciferase reporter assays identified NLR family CARD domain containing 3 (NLRC3) as a potential target of miR-190b. Pathway analysis indicated that miR-190b promotes bladder cancer progression via the Wnt/ß-catenin and mTOR signaling pathways. Taken together, our findings imply that miR-190b acts as a critical regulator for bladder cancer development by repressing NLRC3 and partly through the Wnt/ß-catenin and mTOR pathways. Our study suggests that miR-190b may be served as a potential therapeutic target for bladder cancer treatment.

Ultrasensitive detection of butyrylcholinesterase activity based on the inner filter effect of MnO2 nanosheets on sulfur nanodots.

Butyrylcholinesterase (BChE) activity is an important index for a variety of diseases. In this work, a "turn-on" assay is proposed based on controlling the inner filter effect (IFE) of MnO2 nanosheets (NSs) on sulfur nanodots (S-dots). The fluorescence of S-dots is effectively quenched by the MnO2 NSs, due to the wide overlap of the emission spectrum of S-dots and absorption spectrum of MnO2 NSs, together with the superior light absorption capability of MnO2 NSs. BChE can catalyze acetylthiocholine and produce thiocholine, which effectively decomposes the MnO2 NSs into Mn2+, resulting in the disappearance of the IFE and recovery of fluorescence of S-dots. Two-stage linear relationships between the ratio of fluorescence intensity and concentration of BChE are observed from 0.05 to 10 and from 10 to 500 U L-1. A limit of detection of 0.035 U L-1 is achieved, which is the best performance so far. The as-proposed assay is robust enough for practical detection in human serum, and it can avoid interference from its sister enzyme (acetylcholinesterase) and glutathione at the micromolar level. The presented results provide a clue for the functionalization of S-dots, and offer a powerful tool as an analytic technique for nanomedicine and environmental science.

AMPK/GSK3ß/ß-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming.

Prostate cancer (PCa) represents one of the most common solid neoplasms, and metastasis is the second leading cause of death in adult males. Anoikis is a programmed cell death that is induced upon cell detachment from the extracellular matrix (ECM), which behaves as a critical protective mechanism for anchorage-independent cell growth and metastasis formation. However, in the absence of ECM attachment, shift of metabolic pattern and tolerance to anoikis facilitate the survival of aggressive cancer cells in the circulatory system as well as their metastasis to distant sites. Few molecular targets in PCa have thus far been reported to prevent anoikis resistance, metabolic reprogramming, and metastasis simultaneously. In the present study, elevated migration, invasion, pyruvate production, lactate generation, ATP level, and impaired detachment-induced apoptosis were found in anoikis-resistant PCa cells, and genome microarray analysis demonstrated that the cell migration-inducing protein (CEMIP) was a potential molecular target for the regulation of the aforementioned malignant behaviors. Additional investigation revealed that the AMPK/glycogen synthase kinase 3ß (GSK3ß)/ß-catenin cascade-triggered CEMIP overexpression in anoikis-resistant PCa cells might be implicated in local progression, metabolic shift, and cellular migration and invasion, whereas knockout of CEMIP by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 in anoikis-resistant PCa cells reversed the described bioeffects by reducing expressions of matrix metalloproteinase 2 (MMP2), VEGF, pyruvate dehydrogenase kinase isoform 4 (PDK4), and lactate dehydrogenase A. In addition, inhibition of glycolysis by CEMIP-mediated PDK4 down-regulation impaired the migration and invasion of anoikis-resistant PCa cells by attenuating MMP2 and VEGF expressions. Our findings establish that AMPK/GSK3ß/ß-catenin cascade-triggered CEMIP overexpression might promote migration and invasion in anoikis-resistant PCa cells by enhancing PDK4-associated metabolic reprogramming, which may provide a novel, promising therapeutic target for the treatment of advanced PCa.-Zhang, P., Song, Y., Sun, Y., Li, X., Chen, L., Yang, L., Xing, Y. AMPK/GSK3ß/ß-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming.

Tetraiodothyroacetic acid and transthyretin silencing inhibit pro-metastatic effect of L-thyroxin in anoikis-resistant prostate cancer cells through regulation of MAPK/ERK pathway.

UNLABELLED: Prostate cancer is one of the most common malignancies in adult males and metastasis is the leading cause of death cases without satisfactory treatment options. Anoikis-resistance and migration are crucial aspects for the metastasis of various human cancer cells including prostate cancer and L-thyroxin (T4) has been proved to play vital roles in tumor metastasis. The present study demonstrated that T4 promoted migration and depressed detachment-induced apoptosis in anoikis-resistant prostate cancer cells while tetraiodothyroacetic acid (tetrac), a competitive antagonist of T4 at integrin αvß3, reversed T4 induced effects through diminishing expressions of XIAP, MMP-2, VEGF together with inhibited activity of MAPK/ERK pathway. In addition, we illustrated that over-expression of transthyretin (TTR) was positively correlated to the progression and metastatic potential in prostate cancer. Similar to tetrac, TTR silencing also inverted T4 mediated bioeffects on anoikis-resistant PC-3 cells. The current study sheds light on novel therapeutic strategies for metastatic prostate cancer. IMPLICATIONS: This study identified novel compound and target for preventing metastasis in anoikis-resistant prostate cancer cells, which might offer potential therapeutic alternatives for advanced prostate cancer.

Oleanolic acid inhibits cell survival and proliferation of prostate cancer cells in vitro and in vivo through the PI3K/Akt pathway.

Oleanolic acid (OA) is a naturally occurring pentacyclic triterpenoid and possesses diverse pharmacological activities, including anti-cancer effects that have been confirmed in multiple types of human cancers. However, the potential effect of natural OA on human prostate cancer is still unclear. The present study aimed to explore whether and how OA exerted anti-cancer effects in prostate cancer. Our data showed that OA inhibited cell viability and proliferation, and promoted cell apoptosis and G0/G1 phase cell cycle arrest in prostate cancer PC-3, DU145, and LNCaP cells, in a dose-dependent manner. In addition, OA was found to regulate the expression levels of apoptosis-related and cell cycle-related proteins, as well as the activity of PI3K/Akt pathway, in a dose-dependent manner. Mechanistically, our data revealed that OA exerted anti-cancer effects in vitro in PC-3 and DU145 cells by repressing the PI3K/Akt pathway. In agreement, OA also suppressed the tumor growth of PC-3 cells in vivo via inhibition of the PI3K/Akt pathway. In conclusion, our findings demonstrate the anti-cancer properties of OA in prostate cancer cells, both in vitro and in vivo, and provide the experimental evidence for the use of OA as an adjuvant agent for prostate cancer patients.

Long non-coding RNA ANRIL is up-regulated in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic pathway.

Antisense non-coding RNA in the INK4 locus (ANRIL) is a member of long non-coding RNAs and has been reported to be dysregulated in several human cancers. However, the role of ANRIL in bladder cancer remains unclear. This present study aimed to investigate whether and how ANRIL involved in bladder cancer. Our results showed up-regulation of ANRIL in bladder cancer tissues versus the corresponding adjacent non-tumor tissues. To explore the specific mechanisms, ANRIL was silenced by small interfering RNA or short hairpin RNA transfection in human bladder cancer T24 and EJ cells. Knockdown of ANRIL repressed cell proliferation and increased cell apoptosis, along with decreased expression of Bcl-2 and increased expressions of Bax, cytoplasmic cytochrome c and Smac and cleaved caspase-9, caspase-3 and PARP. However, no change of cleaved caspase-8 level was observed. Furthermore, in vivo experiment confirmed that knockdown of ANRIL inhibited tumorigenic ability of EJ cells in nude mice. Meanwhile, in accordance with in vitro study, knockdown of ANRIL inhibited expression of Bcl-2 and up-regulated expressions of Bax and cleaved caspase-9, but did not affect cleaved caspase-8 level. In conclusion, we first report that ANRIL possibly serves as an oncogene in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic apoptosis pathway.

Metal-pyrimidine nanocubes immobilized enzymes with pH-switchable multienzyme-like activity for broad-pH-responsive sensing assay for organophosphorus pesticides.

Peroxidase (POD)-like can only function in acidic environments and the pH mismatch restricts the application of enzyme-nanozyme cascade catalytic sensing platforms in the broad-pH-responsive assay for organophosphorus pesticides (OPs). Herein, the metal-pyrimidine nanocubes (MPNCs) with intrinsic pH-switchable POD-like and catalase (CAT)-like properties were synthesized via the coordination of pyrimidin-2-ol with Cu2+. Meanwhile, acetylcholinesterase (AChE) and choline oxidase (CHO) were simultaneously encapsulated in MPNCs to construct an enzyme-nanozyme cascade catalytic platform (AChE/CHO@MPNCs). AChE/CHO@MPNCs could catalyze the hydrolysis of acetylcholine to choline, which was subsequently converted to H2O2. The POD-like activity of MPNCs was dominant under acidic conditions, while the CAT-like activity prevailed under neutral and alkaline conditions, which could catalyze H2O2 to •OH and O2, respectively, then oxidizing dopamine (DA) to polydopamine quantum dots (PDA QDs) with different fluorescence characteristics. Consequently, OPs could be detected in a linear range from 0.05 to 1000 nM with a LOD of 0.015 nM in acidic environments and a linear range from 0.05 to 500 nM with a LOD of 0.023 nM in alkaline environments. Overall, our work expands the horizon of constructing enzyme@MOFs composites with high catalytic activity. Meanwhile, the intrinsic pH-switchable multienzyme-like property opens avenues to construct sensing platforms with broad-pH-responsive for OPs and other analytes detection.

Detection and discrimination of glutathione among biological thiols based on oxalyl dihydrazide decorated sulfur nanodots.

The quantitative detection and discrimination of glutathione (GSH) were achieved based on oxalyl dihydrazide (ODH) decorated sulfur nanodots. ODH resulted in the aggregation and fluorescence quenching of the sulfur nanodots, and GSH selectively triggered fluorescence recovery through forming stronger hydrogen bonds with ODH than other biological thiols.

Hsa_circ_0001583 fuels bladder cancer metastasis by promoting staphylococcal nuclease and tudor domain containing 1-mediated MicroRNA decay.

Muscle-invasive and metastatic bladder cancer indicates extra worse prognosis. Accumulating evidence roots for the prominent role of circular RNAs(circRNAs) in bladder cancer, while the mechanisms linking circRNAs and bladder cancer metastasis remain limitedly investigated. Here, we identified a significantly upregulated circRNA candidate, hsa_circ_0001583, from online datasets. Validated by qRT-PCR, PCR, sanger sequencing, actinomycin D and RNase R digestion experiments, hsa_circ_0001583 was proved to be a genuine circular RNA with higher expression levels in bladder cancer tissue. Through gain and loss of function experiments, hsa_circ_0001583 exhibited potent migration and invasion powers both in vitro and in vivo. The staphylococcal nuclease and Tudor domain containing 1 (SND1) was identified as an authentic binding partner for hsa_circ_0001583 through RNA pulldown and RIP experiments. Elevated levels of hsa_circ_0001583 could bind more to SND1 and protect the latter from degradation. Rescue experiments demonstrated that such interaction-induced increased in SND1 levels in bladder cancer cells enabled the protein to pump its endonuclease activity, leading to the degradation of tumor-suppressing MicroRNAs (miRNAs) including miR-126-3p, the suppressor of Disintegrin And Metalloproteinase Domain-Containing Protein 9 (ADAM9), ultimately driving cells into a highly migrative and invasive state. In summary, our study is the first to highlight the upregulation of hsa_circ_0001583 in bladder cancer and its role in downregulating miR-126-3p by binding to and stabilizing the SND1 protein, thereby promoting bladder cancer cell migration and invasion. This study adds hsa_circ_0001583 to the pool of bladder cancer metastasis biomarkers and therapeutic targets.

PROX1 drives neuroendocrine plasticity and liver metastases in prostate cancer.

With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.

Lactobacillus rhamnosus GG alleviates radiation-induced intestinal injury by modulating intestinal immunity and remodeling gut microbiota.

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10 Gy total abdominal irradiation (TAI) group, or a group pretreated with 108 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.