ABSTRACT
The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate cancer. Here, we designed, synthesized, and characterized a class of LX compounds targeting both AR/AR variants and AKR1C3. Molecular docking indicated that LX compounds bound to the AKR1C3 active sites. LX1 blocked AKR1C3 enzymatic activity, suppressing the conversion of androstenedione into testosterone. LX compounds also reduced AR/AR-V7 expression and downregulated their target genes. In vitro, LX1 inhibited the growth of prostate cancer cells resistant to antiandrogens, including enzalutamide, abiraterone, apalutamide, and darolutamide. Treatment with LX1 in vivo significantly decreased tumor growth, lowered serum PSA levels, and reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 overcame resistance to enzalutamide treatment, and the combination of LX1 with enzalutamide further suppressed tumor growth. Collectively, the dual effect of LX1 in reducing intratumoral testosterone and AR signaling, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.
ABSTRACT
N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved "SELILKR" motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70's dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.
Subject(s)
HSP70 Heat-Shock Proteins , Prostatic Neoplasms , Proteostasis , Ubiquitin-Protein Ligases , Ubiquitination , Male , Humans , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , HSP70 Heat-Shock Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination/drug effects , Cell Line, Tumor , Animals , Aurora Kinase A/metabolism , Aurora Kinase A/genetics , Aurora Kinase A/antagonists & inhibitors , N-Myc Proto-Oncogene Protein/metabolism , N-Myc Proto-Oncogene Protein/genetics , Mice , Carcinoma, Neuroendocrine/metabolism , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Neuroendocrine/pathology , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathologyABSTRACT
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.
Subject(s)
Drug Resistance, Neoplasm , Humans , Male , Animals , Mice , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/drug therapy , Cell Proliferation , Gene Expression Regulation, Neoplastic , Cell Lineage/genetics , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Xenograft Model Antitumor Assays , Cell Plasticity/genetics , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Prognosis , Membrane Glycoproteins , Intracellular Signaling Peptides and ProteinsABSTRACT
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 is highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression is associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibit neural lineage pathways, suppressing NEPC cell proliferation, PDX tumor organoid viability, and xenograft tumor growth. Mechanistically, the chaperone protein HSP70 regulates PLXND1 protein stability through degradation, and inhibition of HSP70 decreases PLXND1 expression and NEPC organoid growth. In summary, our findings suggest that PLXND1 could be a new therapeutic target and molecular indicator for NEPC.
ABSTRACT
Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.
Subject(s)
Androstenes , Apoptosis , Dihydroorotate Dehydrogenase , Oxidoreductases Acting on CH-CH Group Donors , Prostatic Neoplasms, Castration-Resistant , Xenograft Model Antitumor Assays , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/metabolism , Animals , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Mice , Androstenes/pharmacology , Androstenes/therapeutic use , Cell Line, Tumor , Apoptosis/drug effects , Cell Proliferation/drug effectsABSTRACT
Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, we found that IGFBP3 is highly expressed in acquired (OlapR) and intrinsic (Rv1) models of Olaparib resistance. We show that IGFBP3 expression promotes Olaparib resistance by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs. IGFBP3 depletion enhances efficacy of Olaparib by promoting DNA damage accumulation and subsequently, cell death in resistant models. Mechanistically, we show that silencing IGFBP3 or EGFR expression reduces cell viability and resensitizes OlapR cells to Olaparib treatment. Inhibition of EGFR by Gefitinib suppressed growth of OlapR cells and improved Olaparib sensitivity, thereby phenocopying IGFBP3 inhibition. Collectively, our results highlight IGFBP3 and EGFR as critical mediators of Olaparib resistance.
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AIM: This paper aimed to explore the application of three-dimensional (3D) printing in cardiovascular diseases, to reach an insight in this field and prospect the future trend. METHODS: The articles were selected from the Web of Science Core Collection database. Excel 2019, VOSviewer 1.6.16, and CiteSpace 6.1.R6 were used to analyze the information. RESULTS: A total of 467 papers of 3D printing in cardiovascular diseases were identified, and the first included literature appeared in 2000. A total of 692 institutions from 52 countries participated in the relevant research, while the United States of America contributed to 160 articles and were in a leading position. The most productive institution was Curtin University , and Zhonghua Sun who has posted the most articles ( n =8) was also from there. The Frontiers in Cardiovascular Medicine published most papers ( n =25). The Journal of Thoracic and Cardiovascular Surgery coveted the most citations ( n =520). Related topics of frontiers will still focus on congenital heart disease, valvular heart disease, and left atrial appendage closure. CONCLUSIONS: The authors summarized the publication information of the application of 3D printing in cardiovascular diseases related literature from 2000 to 2023, including country and institution of origin, authors, and publication journal. This study can reflect the current hotspots and novel directions for the application of 3D printing in cardiovascular diseases.
Subject(s)
Cardiovascular Diseases , Humans , Cardiovascular Diseases/surgery , Bibliometrics , Printing, Three-Dimensional , Databases, Factual , Health FacilitiesABSTRACT
As an immune checkpoint molecule, CD200 serves a foundational role in regulating immune homeostasis and promoting self-tolerance. While CD200 expression occurs in various immune cell subsets and normal tissues, its aberrant expression patterns in hematologic malignancies and solid tumors have been linked to immune evasion and cancer progression under pathological conditions, particularly through interactions with its cognate receptor, CD200R. Through this CD200/CD200R signaling pathway, CD200 exerts its immunosuppressive effects by inhibiting natural killer (NK) cell activation, cytotoxic T cell functions, and M1-polarized macrophage activity, while also facilitating expansion of myeloid-derived suppressor cells (MDSCs) and Tregs. Moreover, CD200/CD200R expression has been linked to epithelial-to-mesenchymal transition and distant metastasis, further illustrating its role in cancer progression. Conversely, CD200 has also been shown to exert anti-tumor effects in certain cancer types, such as breast carcinoma and melanoma, indicating that CD200 may exert bidirectional effects on cancer progression depending on the specific tumor microenvironment (TME). Regardless, modulating the CD200/CD200R axis has garnered clinical interest as a potential immunotherapeutic strategy for cancer therapy, as demonstrated by early-phase clinical trials. However, further research is necessary to fully understand the complex interactions of CD200 in the tumor microenvironment and to optimize its therapeutic potential in cancer immunotherapy.
ABSTRACT
Current common treatments for castration-resistant prostate cancer (CRPC) typically belong to one of three major categories: next-generation anti-androgen therapies (NGAT) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide; taxane therapy represented by docetaxel; and PARP inhibitors (PARPi) like olaparib. Although these treatments have shown efficacy and have improved outcomes for many patients, some do not survive due to the emergence of therapeutic resistance. The clinical landscape is further complicated by limited knowledge about how the sequence of treatments impacts the development of therapeutic cross-resistance in CRPC. We have developed multiple CRPC models of acquired therapeutic resistance cell sublines from C4-2B cells. These include C4-2B MDVR, C4-2B AbiR, C4-2B ApaR, C4-2B DaroR, TaxR, and 2B-olapR, which are resistant to enzalutamide, abiraterone, apalutamide, darolutamide, docetaxel, and olaparib, respectively. These models are instrumental for analyzing gene expression and assessing responses to various treatments. Our findings reveal distinct cross-resistance characteristics among NGAT-resistant cell sublines. Specifically, resistance to enzalutamide induces resistance to abiraterone and vice versa, while maintaining sensitivity to taxanes and olaparib. Conversely, cells with acquired resistance to docetaxel exhibit cross-resistance to both cabazitaxel and olaparib but retain sensitivity to NGATs like enzalutamide and abiraterone. OlapR cells, significantly resistant to olaparib compared to parental cells, are still responsive to NGATs and docetaxel. Moreover, OlapR models display cross-resistance to other clinically relevant PARP inhibitors, including rucaparib, niraparib, and talazoparib. RNA-sequencing analyses have revealed a complex network of altered gene expressions that influence signaling pathways, energy metabolism, and apoptotic signaling, pivotal to cancer's evolution and progression. The data indicate that resistance mechanisms are distinct among different drug classes. Notably, NGAT-resistant sublines exhibited a significant downregulation of androgen-regulated genes, contrasting to the stable expression noted in olaparib and docetaxel-resistant sublines. These results may have clinical implications by showing that treatments of one class can be sequenced with those from another class, but caution should be taken when sequencing drugs of the same class.
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The production of waste printed circuit boards (WPCBs) is increasing, and its complex composition makes recycling difficult. In addition, the presence of heavy metals and brominated flame retardants makes it a hazardous waste. Therefore, its recycling is a necessary way for resource recycling and green sustainable development. The purpose of this study is to propose a green, efficient, and pollution-free recycling process as an alternative to recycle WPCBs. In this work, an alkaline metal oxide catalytic pyrolysis process was used to recover WPCBs. In the presence of alkali metal oxides (such as Ca(OH)2) and coexisting copper, Ca(OH)2 and coexisting copper are transformed into CaBr2 and Cu Br by reacting with organic bromine in WPCBs and remaining in the solid phase product. The bromine content and the proportion of inorganic bromine in the solid phase products were 87.68% and 87.56%, respectively. In addition, the content of organic bromine in the pyrolysis oil obtained by co-pyrolysis was significantly reduced. This study demonstrated the feasibility of Ca(OH)2 catalytic pyrolysis for WPCB recovery.
Subject(s)
Electronic Waste , Metals, Heavy , Copper , Bromine , Pyrolysis , Electronic Waste/analysis , RecyclingABSTRACT
Visualizing polymer chain growth is always a hot topic for tailoring structure-function properties in polymer chemistry. However, current characterization methods are limited in their ability to differentiate the degree of polymerization in real-time without isolating the samples from the reaction vessel, let alone to detect insoluble polymers. Herein, a reliable relationship is established between polymer chain growth and fluorescence properties through polymerization induced emission. (TPE-C2)2 -Te is used to realize in situ oxidative polymerization, leading to the aggregation of fluorophores. The relationship between polymerization degree of growing polytelluoxane (PTeO) and fluorescence intensity is constructed, enabling real-time monitoring of the polymerization reaction. More importantly, this novel method can be further applied to the observation of the polymerization process for growing insoluble polymer via surface polymerization. Therefore, the development of visualization technology will open a new avenue for visualizing polymer chain growth in real-time, regardless of polymer solubility.
ABSTRACT
BACKGROUND: Uncertainties persist about whether to aggressively and effectively treat tricuspid regurgitation (TR) during mitral valve (MV) surgery. REVIEW METHODS: Systematic literature searches were performed in five databases to collect all relevant studies published before May 2022 on whether the tricuspid valve was treated during MV surgery. Separate meta-analyses were performed on data from unmatched studies and randomized controlled trials (RCT)/adjusted studies. MAIN RESULTS: A total of 44 publications were included, of which eight were RCT studies and the rest were retrospective studies. There was no difference in 30-day mortality [odds ratio (OR): 1.00, 95% CI: 0.71-1.42, OR: 0.66, 95% CI: 0.30-1.41)] or overall survival [hazard ratio (HR): 1.01, 95% CI: 0.85-1.19, HR: 0.77, 95% CI: 0.52-1.14] in unmatched studies and RCT/adjusted studies. Late mortality (OR: 0.37, 95% CI: 0.21-0.64) and cardiac-related mortality (OR: 0.36, 95% CI: 0.21-0.62) were lower in the tricuspid valve repair (TVR) group in the RCT/adjusted studies. In the unmatched studies, overall cardiac mortality (OR: 0.48, 95% CI: 0.26-0.88) was lower in the TVR group. In the late TR progression analysis, the late TR progression was lower among patients in the concomitantly intervened tricuspid group, and patients in the untreated tricuspid group were prone to TR progression in both studies (HR: 0.30, 95% CI: 0.22-0.41, HR: 0.37, 95% CI: 0.23-0.58). CONCLUSIONS: TVR concomitant with MV surgery is most effective in patients with significant TR and dilated tricuspid annulus, especially those with a significantly reduced risk of distant TR progression.
Subject(s)
Heart Valve Prosthesis Implantation , Mitral Valve Insufficiency , Tricuspid Valve Insufficiency , Humans , Tricuspid Valve/surgery , Mitral Valve/surgery , Mitral Valve Insufficiency/complications , Mitral Valve Insufficiency/surgery , Treatment Outcome , Heart Valve Prosthesis Implantation/adverse effects , Tricuspid Valve Insufficiency/surgery , Tricuspid Valve Insufficiency/complications , Retrospective StudiesABSTRACT
Background: Ventricular septal defects (VSDs) are one of the mechanical complications of acute myocardial infarction (AMI). Because of the high risks of mortality and postoperative complications, a new alternative method is needed. With the development of interventional medicine, transcatheter closure has been increasingly performed for postmyocardial infarction ventricular septal defects (PMIVSDs). The aim of this study is to explore the feasibility and safety of transcatheter closure of PMIVSDs by meta-analysis. Methods: The included studies were mainly single-arm studies of transcatheter closure of PMIVSDs. We compared VSD size, device size, preoperative risk factors and interventions among PMIVSD patients. We analysed the transcatheter closure success rate, the 30-day mortality rate, and the incidence of residual shunts. Results: A total of 12 single-arm articles (284 patients) were included. The combined incidences of preoperative hypertension, hyperlipidaemia, and diabetes were 66% [95% CI 0.56-0.75], 54% [95% CI 0.40-0.68], and 33% [95% CI] 0.21-0.46], respectively. Multiple studies reported the combined incidences of preoperative PCI, IABP, and CABG, which were 46% [95% CI 0.15-0.80], 60% [95% CI 0.44-0.75], and 8% [95% CI 0.02-0.18]. Eleven studies reported the number of successful closures and the 30-day mortality rate; the success rate was 90% [95% CI 0.86-0.94], and the 30-day mortality rate reached 27% [95% CI 0.86-0.94]. Conclusion: For patients with PMIVSD, transcatheter closure in the acute phase can be used as a rescue measure, while in the chronic phase, it is more effective and has a lower mortality rate, but the effect of selection bias should be considered. Residual shunts are a long-term complication that have a high incidence and long-lasting effects on patients. More large, multicentre, randomized controlled trials are needed in the future to confirm the safety and reliability of transcatheter closure of PMIVSDs.
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Polymerization inside living cells provides chemists with a multitude of possibilities to modulate cell activities. Considering the advantages of hyperbranched polymers, such as a large surface area for target sites and multilevel branched structures for resistance to the efflux effect, we reported a hyperbranched polymerization in living cells based on the oxidative polymerization of organotellurides and intracellular redox environment. The intracellular hyperbranched polymerization was triggered by reactive oxygen species (ROS) in the intracellular redox microenvironment, effectively disrupting antioxidant systems in cells by an interaction between Te (+4) and selenoproteins, thus inducing selective apoptosis of cancer cells. Importantly, the obtained hyperbranched polymer aggregated into branched nanostructures in cells, which could effectively evade drug pumps and decrease drug efflux, ensuring the polymerization for persistent treatment. Finally, in vitro and in vivo studies confirmed that our strategy presented selective anticancer efficacy and well biosafety. This approach provides a way for intracellular polymerization with desirable biological applications to regulate cell activities.
Subject(s)
Nanostructures , Neoplasms , Polymerization , Polymers/pharmacology , Polymers/chemistry , Drug Resistance, NeoplasmABSTRACT
In recent years, the association of chemodynamic therapy (CDT) with photodynamic therapy (PDT) has attracted much attention due to their mutually reinforced property. Nevertheless, how to further strengthen their performance is still a big challenge. Given the PDT/CDT therapeutic mechanism, the H2O2 amount might affect their final performance. Thus, in this paper, our synthesized pH-responsive Fenton agents (ferrocene-cinnamaldehyde conjugates, Fc-CA) were encapsulated in hyaluronic acid (HA) coated porphyrin-based MOF to obtain supramolecular nano-particles (Fc-CA-PCN-HA). After the CD44-receptor mediated internalization, the released Fc-CA could further dissociate in the acidic pH micro-environment. The released CA can activate the NADPH oxidase to elevate the H2O2 amount which could be preferable to produce more ·OH through Fenton reaction for cancer cells apoptosis. Additionally, O2 was also generated in the CDT which could alleviate tumor hypoxia condition and be provided as the reactant for PDT to produce more 1O2. Thus, given the excellent cascade reactions induced therapeutic performance of Fc-CA-PCN-HA in vitro and in vivo, the H2O2-elevation strategy might further enhance the PDT/CDT outcomes.
Subject(s)
Nanoparticles , Neoplasms , Photochemotherapy , Porphyrins , Humans , Hyaluronic Acid , Hydrogen Peroxide , Apoptosis , NADPH Oxidases , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
BACKGROUND: Emerging data suggest that patients with enzalutamide-treated prostate cancer with increased programmed death-ligand 1 (PD-L1) expression may benefit from anti-PD-L1 treatment. Unfortunately, the Phase III IMbassador250 clinical trial revealed that the combination of atezolizumab (a PD-L1 inhibitor) and enzalutamide failed to extend overall survival in patients with castration-resistant prostate cancer (CRPC). However, the mechanisms underlying treatment failure remain unknown. METHODS: Human CRPC C4-2B cells and murine Myc-CaP cells were chronically exposed to increasing concentrations of enzalutamide and the cells resistant to enzalutamide were referred to as C4-2B MDVR and Myc-CaP MDVR, respectively. The mechanisms of action in drug-resistant prostate cancer cells were determined using RNA sequencing analyses, RNA interference, real-time PCR, western blotting, and co-culturing technologies. Myc-CaP and Myc-CaP MDVR tumors were established in syngeneic FVB mice, and tumor-infiltrating leukocytes were isolated after enzalutamide treatment. The stained immune cells were determined by flow cytometry, and the data were analyzed using FlowJo. RESULTS: Immune-related signaling pathways (interferon alpha/gamma response, inflammatory response, and cell chemotaxis) were suppressed in human enzalutamide-resistant prostate cancer cells. PD-L1 was overexpressed and negatively regulated by androgen receptor signaling in resistant cells and patient with CRPC cohorts. Enzalutamide treatment decreased CD8+ T-cell numbers but increased monocytic myeloid-derived suppressor cell (M-MDSC) populations and PD-L1 expression within murine Myc-CaP tumors. Similarly, chemotaxis and immune response-regulating signaling pathways were suppressed, and PD-L1 expression was also increased using enzalutamide-resistant Myc-CaP MDVR cells. Notably, MDSC populations were significantly increased in Myc-CaP MDVR orthotopic tumors compared with those in Myc-CaP parental tumors. Co-culturing bone marrow cells with Myc-CaP MDVR cells significantly promoted MDSC differentiation and shifted towards M2 macrophage skewing. CONCLUSIONS: Our study suggests that immunosuppressive signaling can be promoted directly by enzalutamide-resistant prostate cancer cells and may be a potential means by which the efficacy of immune checkpoint inhibitors in enzalutamide-resistant prostate cancer is diminished.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptors, Androgen , Animals , Humans , Male , Mice , Drug Resistance, Neoplasm , Immunosuppressive Agents/therapeutic use , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Tumor MicroenvironmentABSTRACT
Supramolecular self-assembly of molecules into highly ordered architectures is attractive for developing various advanced functional materials. Compared to the assemblies of one single building block, supramolecular coassembly (SCA) of multiple component systems has recently emerged as a promising approach for generating highly functional and complex structures. The assembly and integration of multiple building blocks at the molecular level are of paramount importance for constructing SCA systems with sophisticated architectures and diverse functions. This feature article highlights the recent advances and future trends in SCAs, ranging from their synthetic strategies, morphological control, to functional applications. The monomer pairs used to synthesize SCAs are rationalized into two classes including structural monomer pairs and functional monomer pairs. The assembly behaviors are then discussed according to the dimensionality of the coassembled morphologies from zero to three dimensions. Finally, the emergent functions and applications of SCAs are highlighted such as adsorption, catalysis, optoelectronics, and biomedicines.
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OBJECTIVE: To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary sugar consumption and health outcomes. DESIGN: Umbrella review of existing meta-analyses. DATA SOURCES: PubMed, Embase, Web of Science, Cochrane Database of Systematic Reviews, and hand searching of reference lists. INCLUSION CRITERIA: Systematic reviews and meta-analyses of randomised controlled trials, cohort studies, case-control studies, or cross sectional studies that evaluated the effect of dietary sugar consumption on any health outcomes in humans free from acute or chronic diseases. RESULTS: The search identified 73 meta-analyses and 83 health outcomes from 8601 unique articles, including 74 unique outcomes in meta-analyses of observational studies and nine unique outcomes in meta-analyses of randomised controlled trials. Significant harmful associations between dietary sugar consumption and 18 endocrine/metabolic outcomes, 10 cardiovascular outcomes, seven cancer outcomes, and 10 other outcomes (neuropsychiatric, dental, hepatic, osteal, and allergic) were detected. Moderate quality evidence suggested that the highest versus lowest dietary sugar consumption was associated with increased body weight (sugar sweetened beverages) (class IV evidence) and ectopic fatty accumulation (added sugars) (class IV evidence). Low quality evidence indicated that each serving/week increment of sugar sweetened beverage consumption was associated with a 4% higher risk of gout (class III evidence) and each 250 mL/day increment of sugar sweetened beverage consumption was associated with a 17% and 4% higher risk of coronary heart disease (class II evidence) and all cause mortality (class III evidence), respectively. In addition, low quality evidence suggested that every 25 g/day increment of fructose consumption was associated with a 22% higher risk of pancreatic cancer (class III evidence). CONCLUSIONS: High dietary sugar consumption is generally more harmful than beneficial for health, especially in cardiometabolic disease. Reducing the consumption of free sugars or added sugars to below 25 g/day (approximately 6 teaspoons/day) and limiting the consumption of sugar sweetened beverages to less than one serving/week (approximately 200-355 mL/week) are recommended to reduce the adverse effect of sugars on health. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022300982.
Subject(s)
Dietary Sugars , Weight Gain , Humans , Dietary Sugars/adverse effects , Cross-Sectional Studies , Systematic Reviews as Topic , Sugars , Beverages/adverse effectsABSTRACT
Collectin-11 (CL-11) is a recently described soluble C-type lectin that has distinct roles in embryonic development, host defence, autoimmunity, and fibrosis. Here we report that CL-11 also plays an important role in cancer cell proliferation and tumor growth. Melanoma growth was found to be suppressed in Colec11-/- mice in a s.c. B16 melanoma model. Cellular and molecular analyses revealed that CL-11 is essential for melanoma cell proliferation, angiogenesis, establishment of more immunosuppressive tumor microenvironment, and the reprogramming of macrophages to M2 phenotype within melanomas. In vitro analysis revealed that CL-11 can activate tyrosine kinase receptors (EGFR, HER3) and ERK, JNK, and AKT signaling pathways and has a direct stimulatory effect on murine melanoma cell proliferation. Furthermore, blockade of CL-11 (treatment with L-fucose) inhibited melanoma growth in mice. Analysis of open data sets revealed that COLEC11 gene expression is upregulated in human melanomas and that high COLEC11 expression has a trend toward poor survival. CL-11 also had direct stimulatory effects on human tumor cell proliferation in melanoma and several other types of cancer cells in vitro. Overall, our findings provide the first evidence to our knowledge that CL-11 is a key tumor growth-promoting protein and a promising therapeutic target in tumor growth.
Subject(s)
Cell Proliferation , Collectins , Melanoma, Experimental , Skin Neoplasms , Animals , Humans , Mice , Autoimmunity , Cell Proliferation/genetics , Cell Proliferation/physiology , Collectins/metabolism , Melanoma, Experimental/genetics , Melanoma, Experimental/metabolism , Neoplasm Proteins , Receptor Protein-Tyrosine Kinases , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Tumor Microenvironment/genetics , Tumor Microenvironment/physiologyABSTRACT
Ubiquitin proteasome activity is suppressed in enzalutamide resistant prostate cancer cells, and the heat shock protein 70/STIP1 homology and U-box-containing protein 1 (HSP70/STUB1) machinery are involved in androgen receptor (AR) and AR variant protein stabilization. Targeting HSP70 could be a viable strategy to overcome resistance to androgen receptor signaling inhibitor (ARSI) in advanced prostate cancer. Here, we showed that a novel HSP70 allosteric inhibitor, JG98, significantly suppressed drug-resistant C4-2B MDVR and CWR22Rv1 cell growth, and enhanced enzalutamide treatment. JG98 also suppressed cell growth in conditional reprogramed cell cultures (CRCs) and organoids derived from advanced prostate cancer patient samples. Mechanistically, JG98 degraded AR/AR-V7 expression in resistant cells and promoted STUB1 nuclear translocation to bind AR-V7. Knockdown of the E3 ligase STUB1 significantly diminished the anticancer effects and partially restored AR-V7 inhibitory effects of JG98. JG231, a more potent analog developed from JG98, effectively suppressed the growth of the drug-resistant prostate cancer cells, CRCs, and organoids. Notably, the combination of JG231 and enzalutamide synergistically inhibited AR/AR-V7 expression and suppressed CWR22Rv1 xenograft tumor growth. Inhibition of HSP70 using novel small-molecule inhibitors coordinates with STUB1 to regulate AR/AR-V7 protein stabilization and ARSI resistance.