To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/β-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells.

Bladder outlet obstruction (BOO) evokes urinary bladder wall remodeling significantly, including the phenotype shift of bladder smooth muscle cells (BSMCs) where transforming growth factor-beta1 (TGF-β1) plays a pivotal role given the emerging function of modulating cellular phenotype. miR-133 plays a role in cardiac and muscle remodeling, however, little is known about its roles in TGF-β1-induced BSMC hypertrophic and fibrotic response. Here, we verified BOO induced bladder wall remodeling and TGF-β1 expression mainly located in bladder endothelium. Furthermore, we uncovered miR-133a/b expression profile in BOO rats, and then explored its regulated effects on BSMCs' phenotypic shift. Our study found that miR-133 became down-regulated during rat bladder remodeling. Next, we sought to examine whether the expression of miR-133 was down-regulated in primary BSMCs in response to TGF-β1 stimulation and whether forced overexpression of miR-133 could regulate profibrotic TGF-β signaling. We found that stimulation of BSMCs with exogenous TGF-β1 of increasing concentrations resulted in a dose-dependent decrease of miR-133a/b levels and transfection with miR-133 mimics attenuated TGF-β1-induced α-smooth muscle actin, extracellular matrix subtypes and fibrotic growth factor expression, whereas it upregulated high molecular weight caldesmon expression compared with the negative control. Also, downregulation of p-Smad3, not p-Smad2 by miR-133 was detected. Additionally, miR-133 overexpression suppressed TGF-β1-induced BSMC hypertrophy and proliferation through influencing cell cycle distribution. Bioinformatics analyses predicted that connective tissue growth factor (CTGF) was the potential target of miR-133, and then binding to the 3'-untranslated region of CTGF was validated by luciferase reporter assay. These results reveal a novel regulator for miR-133 to modulate TGF-β1-induced BSMC phenotypic changes by targeting CTGF through the TGF-β-Smad3 signaling pathway. A novel antifibrotic functional role for miR-133 is presented which may represent a potential target for diagnostic and therapeutic strategies in bladder fibrosis.

Paclitaxel is generally used to treat cancers in clinic as an inhibitor of cell division. However, the acquired resistance in tumours limits its clinical efficacy. Therefore, the aim of this study was to detect whether co-treatment with lentinan enhanced the anti-cancer effects of paclitaxel in A549 cells. We found that the combination of paclitaxel and lentinan resulted in a significantly stronger inhibition on A549 cell proliferation than paclitaxel treatment alone. Co-treatment with paclitaxel and lentinan enhanced cell apoptosis rate by inducing caspase-3 activation. Furthermore, co-treatment with paclitaxel and lentinan significantly triggered reactive oxygen species (ROS) production, and increased thioredoxin-interacting protein (TXNIP) expression. Moreover, co-treatment with paclitaxel and lentinan enhanced TXNIP-NLRP3 interaction, and activated NLRP3 inflammasome whereat interleukin-1β levels were increased and cell apoptosis was induced. In addition, combination of paclitaxel and lentinan could activate apoptosis signal regulating kinase-1 (ASK1)/p38 mitogen-activated protein kinase (MAPK) signal which also contributed to cell apoptosis. Taken together, co-treatment with paclitaxel and lentinan exerts synergistic apoptotic effects in A549 cells through inducing ROS production, and activating NLRP3 inflammasome and ASK1/p38 MAPK signal pathway.

Most kidney cancers are renal cell carcinomas (RCC). RCC lacks early warning signs and 70 % of patients with RCC develop metastases. Among them, 50 % of patients having skeletal metastases developed a dismal survival of less than 10 % at 5 years. Therefore, exploring the key driving proteins and pathways involved in RCC bone metastasis could benefit patients' therapy and prolong their survival. We examined the difference between the OS-RC-2 cells and the OS-RC-2-BM5 cells (subpopulation from OS-RC-2) of RCC with proteomics. Then we employed Western-blot, immunohistochemistry and the clinical database (oncomine) to screen and verify the key proteins and then we analyzed the functions and the related pathways of selected key proteins with system biology approaches. Our proteomic data revealed 26 significant changed spots (fold change <0.5 and >1.9, P < 0.05) between two cells. The Western blotting results validated for these identified spots were consistent with the proteomics'. From the public clinical database, 23 out of 26 proteins were connected with RCC metastases and 9 out of 23 with survival time directly (P < 0.05). Finally, only 8 out of 9 proteins had significantly positive results in tissues of RCC patients with bone metastasis compared with primary tumor (P < 0.05). System biology analyzing results showed these eight proteins mainly distributed in oxidative phosphorylation which indicates that mitochondria dysfunction played the critical role to regulate cells metastasis. Our article used a variety of experimental techniques to find eight proteins which abnormally regulated mitochondrial function to achieve a successful induction for RCC metastasis to bone.

Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.

Hypertrophic scar (HS) is a fibrotic disease in which excessive extracellular matrix forms due to the response of fibroblasts to tissue damage. Novel evidence suggests that microRNAs (miRNAs or miRs) may contribute to hypertrophic scarring; however, the role of miRNAs in HS formation remains unclear. In the present study, miR-26a was significantly downregulated in HS tissues and human HS fibroblasts (hHSFs) was detected by reverse transcription-quantitative analysis. TargetScan was used to predict that mothers against decapentaplegic homolog 2 (Smad2) is a potential target gene of miR-26a and a dual-luciferase reporter assay confirmed that Smad2 was a target gene of miR-26a. The expression of Smad2 was upregulated in HS tissues and hHSFs. Cell Counting Kit-8 and flow cytometry analyses demonstrated that the overexpression of miR-26a significantly suppressed the proliferation ability of hHSFs and the apoptotic rate of hHSFs was significantly upregulated in response to miR-26a mimic transfection. Furthermore, the expression of B-cell lymphoma-2 (Bcl-2)-associated X protein was increased and Bcl-2 expression was decreased following miR-26a mimic transfection. The expression of collagens I and III was significantly inhibited following treatment with miR-26a mimics in hHSF cells. Conversely, miR-26a inhibitors served an opposing role in hHSFs. Furthermore, Smad2 overexpression enhanced the expression of collagens I and c III; however, Smad2 silencing inhibited the expression of collagens I and c III. In conclusion, the results of the present study indicate that miR-26a inhibits HS formation by modulating proliferation and apoptosis ad well as inhibiting the expression of extracellular matrix-associated proteins by targeting Smad2.

The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.

Aspergillus fumigatus is an opportunistic human pathogenic fungus responsible for deadly lung infections in immunocompromised individuals. Galactofuranose (Galf) residues are essential components of the cell wall and play an important role in A. fumigatus virulence. The flavoenzyme UDP-galactopyranose mutase (UGM) catalyzes the isomerization of UDP-galactopyranose to UDP-galactofuranose, the biosynthetic precursor of Galf. Thus, inhibitors of UGM that block the biosynthesis of Galf can lead to novel chemotherapeutics for treating A. fumigatus-related diseases. Here, we describe the synthesis of fluorescently labeled UDP analogs and the development of a fluorescence polarization (FP) binding assay for A. fumigatus UGM (AfUGM). High-affinity binding to AfUGM was only obtained with the chromophore TAMRA, linked to UDP by either 2 or 6 carbons with K(d) values of 2.6 ± 0.2 μM and 3.0 ± 0.7 μM, respectively. These values were ~6 times lower than when UDP was linked to fluorescein. The FP assay was validated against several known ligands and displayed an excellent Z' factor (0.79 ± 0.02) and good tolerance to dimethyl sulfoxide.

Metastatic bone disease caused by renal cell carcinoma (RCC) occurs frequently. Very little is currently known about the mechanism of preferential metastasis of RCC to bone. We hypothesize that RCCs that develop bone metastases have the capacity to facilitate their colonization in bone. To examine this hypothesis, we established bone-seeking (ACHN-BO) clones of the human RCC cell line ACHN by repeated four passages in nude mice and in vitro of metastatic cells obtained from bone. These clones were examined for distinguishing biological characteristics and compared with the ACHN parental cells (ACHN-P) in vivo and in vitro. Our results showed that the ACHN-BO cell line could be successfully obtained by in vivo selection through the lateral tail vein. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within four weeks after inoculation, with a success rate of 85-100% and no additional comorbidity. ACHN-P cells developed metastases in lung, bone, brain, ovary and adrenal glands. Conversely, ACHN-BO cells exclusively metastasized to bones with larger osteolytic lesions. Compared with the ACHN-P cell line, the proliferation ability in ACHN-BO6 was increased by 9.68 and 6.42%, respectively (P<0.05), while the apoptotic ratio decreased significantly (P<0.05) and cells were blocked in the S phase with suppressed migration and invasion capacities. The ACHN-BO₆ cell line produced greater amounts of the pro-angiogenic factors VEGF and TGF-β than ACHN-P. Our data suggest that these phenotypic changes allow RCC cells to promote osteoclastic bone resorption, survive and proliferate in bone, which consequently leads to the establishment of bone metastases. This model provides a reliable reproduction of the clinical situation and, therefore, is suitable for designing and evaluating more effective treatments for RCC bone metastasis.

Matrix metalloproteases are key regulatory molecules in the breakdown of extracellular matrix and in inflammatory processes. Matrix metalloproteinase-1 (MMP-1) can significantly enhance muscle regeneration by promoting the formation of myofibers and degenerating the fibrous tissue. Herein, we prepared novel MMP-1-loaded poly(lactide-co-glycolide-co-caprolactone) (PLGA-PCL) nanoparticles (NPs) capable of sustained release of MMP-1. We established quadratic equations as mathematical models and employed rotatable central composite design and response surface methodology to optimize the preparation procedure of the NPs. Then, characterization of the optimized NPs with respect to particle size distribution, particle morphology, drug encapsulation efficiency, MMP-1 activity assay and in vitro release of MMP-1 from NPs was carried out. The results of mathematical modeling show that the optimal conditions for the preparation of MMP-1-loaded NPs were as follows: 7 min for the duration time of homogenization, 4.5 krpm for the agitation speed of homogenization and 0.4 for the volume ratio of organic solvent phase to external aqueous phase. The entrapment efficiency and the average particle size of the NPs were 38.75 ± 4.74% and 322.7 ± 18.1 nm, respectively. Further scanning electron microscopy image shows that the NPs have a smooth and spherical surface, with mean particle size around 300 nm. The MMP-1 activity assay and in vitro drug release profile of NPs indicated that the bioactivity of the enzyme can be reserved where the encapsulation allows prolonged release of MMP-1 over 60 days. Taken together, we reported here novel PLGA-PCL NPs for sustained release of MMP-1, which may provide an ideal MMP-1 delivery approach for tissue reconstruction therapy.

Introduction: The associations between Prostate cancer (PCa) and germline copy number variations (CNVs) in genome-wide level based on Chinese population are unknown. The objective of this study was to identify possible PCa-risk associated CNV regions in Chinese population. Materials and Methods: We performed a genome-wide association study for CNV in 1,417 PCa cases and 1,008 controls in Chinese population. Results: 7 risk-associated CNVs were identified for PCa after association analyses (P <7.2×10-6). Another 34 CNVs were found to be potentially risk-associated CNVs (P<0.05). Among the total 41 CNVs, 27 CNVs were risk variations and the other 14 were found to be protective of PCa. 25 of the CNVs (19 duplications and 6 deletions) were located in gene regions while 16 CNVs (9 duplications and 7 deletions) were located in intergenic regions. We identified a higher burden of gaining PCa-risk CNVs and a lower frequency of protective CNVs in cases than controls. Bioinformatics analyses suggested that genes related to PCa risk-associated CNVs were significantly enriched in some biological processes, cellular components and molecular functions. Conclusion: These results provided additional information of genetic risks for PCa. Several CNV regions involved actionable genes that might be potential gene for target therapy. Additional validation and functional studies are warranted for these results.

On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca2+ ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.

We have shown that WT-161, a histone deacetylase 6 (HDAC6) inhibitor, shows remarkable anti-tumor activity in multiple myeloma (MM) in preclinical models. However, its activity in other type of cancers has not yet been shown. In this study, we further evaluated the biologic sequelae of WT161 in breast cancer cell lines. WT161 triggers apoptotic cell death in MCF7, T47D, BT474, and MDA-MB231 cells, associated with decreased expression of EGFR, HER2, and ERα and downstream signaling. However, HDAC6 knockdown shows that cytotoxicity and destabilization of these receptors triggered by WT161 are not dependent on HDAC6 inhibition. Moreover WT161 analog MAZ1793, which lacks HDAC inhibitory effect, similarly triggers cell line growth inhibition and downregulation of these receptors. We also confirm that WT161 significantly inhibits in vivo MCF7 cell growth, associated with downregulation of ERα, in a murine xenograft model. Finally, WT161 synergistically enhances bortezomib-induced cytotoxicity, even in bortezomib-resistant breast cancer cells. Our results therefore provide the rationale to develop a novel class of therapeutic agents targeting growth pathways central to the pathogenesis of breast cancer.

Gene-environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome-wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene-environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele-specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.

High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC. Notably, abolishing MYC expression cannot be achieved by targeting CDK7 alone, but requires the combined inhibition of CDK7, CDK12, and CDK13. In 11 patient-derived xenografts models derived from heavily pre-treated ovarian cancer patients, administration of THZ1 induces significant tumor growth inhibition with concurrent abrogation of MYC expression. Our study indicates that targeting these transcriptional CDKs with agents such as THZ1 may be an effective approach for MYC-dependent ovarian malignancies.

We aimed to verify the expression status and diagnostic significance of isocitrate dehydrogenase 1 (IDH1) in non-small-cell lung cancer (NSCLC), especially during early stages. Serum IDH1 levels were measured by ELISA. A total of 1223 participants (660 patients with NSCLC, 276 healthy controls [HCs], 95 patients with benign pulmonary conditions [BPCs], 135 patients with other cancers [OCs], and 57 samples with interfering factors) were divided into a training cohort and a validation cohort according to 3 testing centers. The IDH1 concentrations in the NSCLC group were obviously higher than those in the control groups (P < .001). Area under the receiver operating characteristic curves (AUCs) for discriminating NSCLC patients from controls (HC, BPC, and OC) were 0.870 and 0.745 (sensitivity, 63.3% and 55.0%; specificity, 86.8% and 86.3%) in the training cohort and validation cohort, respectively. The AUCs for discriminating stage 0-IA lung cancer patients from HCs were 0.907 and 0.788 (sensitivity, 58.6% and 59.1%; specificity, 92.9% and 89.3%) in 2 cohorts, respectively. Isocitrate dehydrogenase 1 showed specificity for NSCLC and had no diagnostic value for other common cancers. Furthermore, IDH1 was significantly reduced in postoperative serum. Isocitrate dehydrogenase 1 shows clinical utility as a serum protein biomarker for the early diagnosis of NSCLC.

Rationale: Prostate cancer has become one of the most threatening malignant tumors in men, leading to an imperative need to develop effective and safe therapies. Because of the unique metabolism of tumor cells, the tumor microenvironment (TME) exhibits distinctive properties compared with normal tissues, among which the pH difference has been utilized as an ideal antitumor strategy. Herein, we introduce a reactive oxygen species (ROS)-controlled-release nanosystem with TME-responsiveness by applying hollow mesoporous silica nanoparticles (HMSNs) as carriers loaded with calcium peroxide (CaO2) and coated with polyacrylic acid (PAA) to construct the functional material CaO2@HMSNs-PAA. The differences in pH values and exogenous ROS scavenging abilities between the tumor tissue and normal tissues and the dual pH-responsiveness from CaO2 and PAA lay a scientific foundation for the application of CaO2@HMSNs-PAA in the tumor-selective therapy for prostate cancer. Methods: The morphology and the structure of the nanosystem were characterized by the transmission electron microscope, scanning electron microscope, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, zeta potential, dynamic light scattering measurement, low-angle X-ray diffraction patterns and nitrogen adsorption/desorption isotherm. The CaO2 loading capacity and release profiles in different buffer solutions were determined by inductively coupled plasma-mass spectrometry. The in vitro intracellular uptake of CaO2@HMSNs-PAA was explored on the PC-3 prostate cancer cell line via confocal laser scanning microscopy. The CCK-8 cell proliferation assay was conducted to evaluate the cytotoxicity of CaO2@HMSNs-PAA against PC-3 cells. ROS produced by CaO2@HMSNs-PAA was observed by a fluorescence microscope. The flow cytometry was utilized to analyze the apoptosis of PC-3 cells induced by CaO2@HMSNs-PAA. The Western blot analysis was performed to detect expressions of critical mitochondria-mediated apoptosis markers in PC-3 cells after incubation with CaO2@HMSNs-PAA. The in vivo biosafety and antitumor efficacy were evaluated out on BALB/c mice and BALB/c nude mice subcutaneously transplanted with PC-3 cells, respectively. Results: Comprehensive characterizations indicated the successful synthesis of CaO2@HMSNs-PAA with significant TME-responsiveness. The experimental results demonstrated that the well-developed nanocarrier could efficiently deliver CaO2 to the tumor site and release ROS in response to the decreased pH value of TME, exerting ideal antitumor effects both in vitro and in vivo by activating the mitochondria-mediated apoptosis pathway. Simultaneously, this nanoplatform caused no detectable damage to normal tissues. Conclusions: After loading into the above nanocomposite, the free CaO2 without a significant antitumor effect can exert excellent antitumor efficacy by responsively releasing ROS under the acidic TME to induce the mitochondria-mediated apoptosis via remarkable oxidative stress and simultaneously minimize damages to normal tissues. The current study presents a new concept of "efficacy-shaping nanomedicine" for the tumor-selective treatment of prostate cancer.

Hybrid perovskite materials used for realization of efficient perovskite solar cells have drawn great attention in both academic and industrial sectors. It was reported that the crystallinity of hybrid thin-film perovskite materials plays an important role in device performance. In this study, we report a novel and simple method to tune the crystallinity of CH3NH3PbI3 thin film for device performance of perovskite solar cells. By employing tetraphenylphosphonium chloride on the top of PbI2 thin layer in the two-step perovskite deposition processes, the crystallinity of the resultant CH3NH3PbI3 thin film was tuned. As a result, perovskite solar cells by the CH3NH3PbI3 thin film with tuned crystallinity exhibit an enlarged open-circuit voltage and enhanced short-circuit current, thus boosted efficiency as well as reduced photocurrent hysteresis compared to pristine CH3NH3PbI3 thin film. These results indicate that our study provides a new simple way to boost device performance of perovskite solar cells through tuning the crystallinity of CH3NH3PbI3 thin film.

Microplastics (MPs) could act as vectors of synthetic chemicals; however, their influence on the adsorption of chemicals of natural origin (for example, MC-LR and intracellular organic matter (IOM), which could be concomitantly released by toxic Microcystis in water) is less understood. Here, we explored the adsorption of MC-LR by polyethylene (PE), polystyrene (PS), and polymethyl methacrylate (PMMA). The results showed that the MPs could adsorb both MC-LR and IOM, with the adsorption capability uniformly following the order of PS, PE, and PMMA. However, in the presence of IOM, the adsorption of MC-LR by PE, PS, and PMMA was reduced by 22.3%, 22.7% and 5.4%, respectively. This is because the benzene structure and the specific surface area of PS facilitate the adsorption of MC-LR and IOM, while the formation of Π-Π bonds favor its interaction with IOM. Consequently, the competition for binding sites between MC-LR and IOM hindered MC-LR adsorption. The C=O in PMMA benefits its conjunction with hydroxyl and carboxyl in the IOM through hydrogen bonding; thus, the adsorption of MC-LR is also inhibited. These findings highlight that the adsorption of chemicals of natural origin by MPs is likely overestimated in the presence of metabolites from the same biota.

Considering the dismal prognosis of castration-resistant prostate cancer (CRPC), it is critical to identify novel therapeutic targets in this disease. Malignant cells have metabolic dependencies distinct from their healthy counterparts, resulting in therapeutic vulnerabilities. Although PTEN and TP53 are the most frequently comutated or codeleted driver genes in lethal CRPC, the metabolic dependencies underlying PTEN/p53 deficiency-driven CRPC for therapeutic intervention remain largely elusive. In this study, PTEN/p53 deficient tumors were determined to be reliant on cholesterol metabolism. Moreover, PTEN/p53 deficiency transcriptionally upregulated squalene epoxidase (SQLE) via activation of sterol regulatory element-binding protein 2 (SREBP2). In addition, PTEN deficiency enhanced the protein stability of SQLE by inhibiting the PI3K/Akt/GSK3β-mediated proteasomal pathway. Consequently, SQLE increased cholesterol biosynthesis to facilitate tumor cell growth and survival. Pharmacologic blockade of SQLE with FR194738 profoundly suppressed the invasive program of CRPC. Collectively, these results demonstrate a synergistic relationship between SQLE and PTEN/p53 deficiency in CRPC development and progression. Therefore, pharmacologic interventions targeting SQLE may hold promise for the treatment of patients with CRPC.