Molecular Mechanism of ARF5-AHL15-Mediated Auxin-Induced Embryogenic Cell Formation in Apples.

The somatic embryo (SE) has bipolar characteristics, which is an ideal material for large-scale microproduction of woody plants represented by apples, and the somatic embryo is also an excellent receptor for genetic transformation. The formation of embryogenic cells is a prerequisite for somatic embryogenesis to occur. The embryogenic cells of apples cannot be obtained without induction of exogenous auxin, but how the auxin pathway regulates this process remains unknown. In this study, via RNA sequencing, MdARF5 and MdAHL15 were identified as differentially expressed genes involved in this process. Overexpression of MdARF5 and MdAHL15 induced the formation and proliferation of embryogenic cells and thus substantially shortened the induction cycle and improved the somatic embryo proliferation efficiency. A yeast one-hybrid assay showed that MdARF5 can directly bind to the promoter of MdAHL15. ß-Glucuronidase (GUS) and dual-luciferase reporter assays revealed that MdARF5 activation of MdAHL15 transcription was substantial. In conclusion, our results suggest that MdAHL15 is induced by auxin and promotes the formation of embryogenic cells in early somatic embryogenesis via the positive regulation of MdARF5 in apples. The results will provide a theoretical basis for somatic embryogenesis-based development, reproduction, and transgenic breeding in apples.

Cannabinoid receptor 2 plays a key role in renal fibrosis through inhibiting lipid metabolism in renal tubular cells.

AIMS: Renal fibrosis is a common feature in various chronic kidney diseases (CKD). Tubular cell damage is a main characterization which results from dysregulated fatty acid oxidation (FAO) and lipid accumulation. Cannabinoid Receptor 2 (CB2) contributes to renal fibrosis, however, its role in FAO dysregulation in tubular cells is not clarified. In this study, we found CB2 plays a detrimental role in lipid metabolism in tubular cells. METHODS: CB2 knockout mice were adopted to establish a folic acid-induced nephropathy (FAN) model. CB2-induced FAO dysfunction, lipid deposition, and fibrogenesis were assessed in vivo and vitro. To explore molecular mechanisms, ß-catenin inhibitors and peroxisome proliferator-activated receptor alpha (PPARα) activators were also used in CB2-overexpressed cells. The mediative role of ß-catenin in CB2-inhibited PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) activation was analyzed. RESULTS: CB2 activates ß-catenin signaling, resulting in the suppression of PPARα/PGC-1α axis. This decreased FAO functions and led to lipid droplet formation in tubular cells. CB2 gene ablation effectively mitigated FAO dysfunction, lipid deposition and uremic toxins accumulation in FAN mice, consequently retarding renal fibrosis. Additionally, inhibition to ß-catenin or PPARα activation could greatly inhibit lipid accumulation and fibrogenesis induced by CB2. CONCLUSIONS: This study highlights CB2 disrupts FAO in tubular cells through ß-catenin activation and subsequent inhibition on PPARα/PGC-1α activity. Targeted inhibition on CB2 offers a perspective therapeutic strategy to fight against renal fibrosis.

Melatonin partially rescues defects induced by tranexamic acid exposure during oocyte maturation in mice.

Tranexamic acid (TXA) is widely used among young women because of its ability to whiten skin and treat menorrhagia. Nevertheless, its potential effects on oocyte maturation and quality have not yet been clearly clarified. Melatonin (MT) is an endogenous hormone released by the pineal gland and believed to protect cells from oxidative stress injury. In the present study, we used in vitro maturation model to investigate the toxicity of TXA and the protective role of MT in mouse oocyte. Compared with the control group, TXA-exposed group had significantly lower nuclear maturation (57.72% vs. 94.08%, P < 0.001) and early embryo cleavage rates (38.18% vs. 87.66%, P < 0.001). Further study showed that spindle organization (52.56% vs. 18.77%, P < 0.01) and chromosome alignment (33.23% vs. 16.66%, P < 0.01) were also disrupted after TXA treatment. Mechanistically, we have demonstrated that TXA induced early apoptosis of oocytes (P < 0.001) by raising the level of ROS (P < 0.001), which was consistent with an increase in mitochondrial damage (P < 0.01). Fortunately, all these effects except the spindle defect were successfully rescued by an appropriate level of MT. Collectively, our findings indicate that MT could partially reverse TXA-induced oocyte quality deterioration in mouse by effectively improving mitochondrial function and reducing oxidative stress-mediated apoptosis.

Unlocking fungal quorum sensing: Oxylipins and yeast interactions enhance secondary metabolism in monascus.

Exploring the symbiotic potential between fungal and yeast species, this study investigates the co-cultivation dynamics of Monascus, a prolific producer of pharmacologically relevant secondary metabolites, and Wickerhamomyce anomalous. The collaborative interaction between these microorganisms catalyzed a substantial elevation in the biosynthesis of secondary metabolites, prominently Monacolin K and natural pigments. Central to our discoveries was the identification and enhanced production of oxylipins (13S-hydroxyoctadecadienoic acid，13S-HODE), putative quorum-sensing molecules, within the co-culture environment. Augmentation with exogenous oxylipins not only boosted Monacolin K production by over half but also mirrored morphological adaptations in Monascus, affecting both spores and mycelial structures. This augmentation was paralleled by a significant upregulation in the transcriptional activity of genes integral to the Monacolin K biosynthetic pathway, as well as genes implicated in pigment and spore formation. Through elucidating the interconnected roles of quorum sensing, G-protein-coupled receptors, and the G-protein-mediate signaling pathway, this study provides a comprehensive view of the molecular underpinnings facilitating these metabolic enhancements. Collectively, our findings illuminate the profound influence of Wickerhamomyces anomalous co-culture on Monascus purpureus, advocating for oxylipins as a pivotal quorum-sensing mechanism driving the observed symbiotic benefits.

Biosynthesis and Biotechnological Synthesis of Hydroxytyrosol.

Hydroxytyrosol (HT), a plant-derived phenolic compound, is recognized for its potent antioxidant capabilities alongside a spectrum of pharmacological benefits, including anti-inflammatory, anti-cancer, anti-bacterial, and anti-viral properties. These attributes have propelled HT into the spotlight as a premier nutraceutical and food additive, heralding a new era in health and wellness applications. Traditional methods for HT production, encompassing physico-chemical techniques and plant extraction, are increasingly being supplanted by biotechnological approaches. These modern methodologies offer several advantages, notably environmental sustainability, safety, and cost-effectiveness, which align with current demands for green and efficient production processes. This review delves into the biosynthetic pathways of HT, highlighting the enzymatic steps involved and the pivotal role of genetic and metabolic engineering in enhancing HT yield. It also surveys the latest progress in the biotechnological synthesis of HT, examining innovative strategies that leverage both genetically modified and non-modified organisms. Furthermore, this review explores the burgeoning potential of HT as a nutraceutical, underscoring its diverse applications and the implications for human health. Through a detailed examination of both the biosynthesis and biotechnological advances in HT production, this review contributes valuable insights to the field, charting a course towards the sustainable and scalable production of this multifaceted compound.

Ultra-Fast Selenol-Yne Click (SYC) Reaction Enables Poly(selenoacetal) Covalent Adaptable Network Formation.

The emergence of covalent adaptable networks (CANs) based on dynamic covalent bonds (DCBs) presents a promising avenue for achieving resource recovery and utilization. In this study, we discovered a dynamic covalent bond called selenacetal, which is obtained through a double click reaction between selenol and activated alkynes. Density functional theory (DFT) calculations demonstrated that the ΔG for the formation of selenoacetals ranges from 12 to 18 kJ mol-1, suggesting its potential for dynamic reversibility. Dynamic exchange experiments involving small molecules and polymers provide substantial evidence supporting the dynamic exchange properties of selenoacetals. By utilizing this highly efficient click reaction, we successfully synthesized dynamic materials based on selenoacetal with remarkable reprocessing capabilities without any catalysts. These materials exhibit chemical recycling under alkaline conditions, wherein selenoacetal (SA) can decompose into active enone selenide (ES) and diselenides. Reintroducing selenol initiates a renewed reaction with the enone selenide, facilitating material recycling and yielding a newly developed dynamic material exhibiting both photo- and thermal responsiveness. The results underscore the potential of selenoacetal polymers in terms of recyclability and selective degradation, making them a valuable addition to conventional covalent adaptable networks.

Hydrogen peroxide positively regulates ABA signaling via oxidative modification of the C2H2-type zinc finger protein ZFP36 in rice.

The rice zinc finger protein ZFP36 serves as a pivotal regulator of the hydrogen peroxide (H2O2) signaling pathway in response to abscisic acid (ABA). Its role is crucial for integrating H2O2 signals with the plant defense mechanisms against water deficit and oxidative stress. However, it remains unclear whether ZFP36 directly modulates ABA-induced H2O2 signaling. This study explored the effects of oxidative post-translational modifications (OxiPTMs) on ZFP36 in rice, with an emphasis on the H2O2-induced oxidation through its cysteine (Cys) residues. We found that ZFP36 undergoes oxidative modification as a target of H2O2 in the presence of ABA, specifically at Cys32. Employing quantitative detection and fluorescence assays, we observed that ZFP36 oxidation enhances the expression and activity of genes encoding protective antioxidant enzymes. Moreover, our investigation into the thioredoxin (Trx) and glutaredoxin (Grx) families revealed that OsTrxh1 facilitates the reduction of oxidized ZFP36. Genetic evidence indicates that ZFP36 positively influences rice resilience to oxidative and water stress, while OsTrxh1 exerts an opposing effect. These insights reveal a distinctive pathway for plant cells to perceive ABA-induced H2O2 signaling, advance our comprehension of H2O2 signaling dynamics, and ABA-related plant responses, and lay a vital groundwork for enhancing crop stress tolerance.

Mitochondria transplantation alleviates cardiomyocytes apoptosis through inhibiting AMPKα-mTOR mediated excessive autophagy.

The disruption of mitochondria homeostasis can impair the contractile function of cardiomyocytes, leading to cardiac dysfunction and an increased risk of heart failure. This study introduces a pioneering therapeutic strategy employing mitochondria derived from human umbilical cord mesenchymal stem cells (hu-MSC) (MSC-Mito) for heart failure treatment. Initially, we isolated MSC-Mito, confirming their functionality. Subsequently, we monitored the process of single mitochondria transplantation into recipient cells and observed a time-dependent uptake of mitochondria in vivo. Evidence of human-specific mitochondrial DNA (mtDNA) in murine cardiomyocytes was observed after MSC-Mito transplantation. Employing a doxorubicin (DOX)-induced heart failure model, we demonstrated that MSC-Mito transplantation could safeguard cardiac function and avert cardiomyocyte apoptosis, indicating metabolic compatibility between hu-MSC-derived mitochondria and recipient mitochondria. Finally, through RNA sequencing and validation experiments, we discovered that MSC-Mito transplantation potentially exerted cardioprotection by reinstating ATP production and curtailing AMPKα-mTOR-mediated excessive autophagy.

Adverse events reporting of XPO1 inhibitor - selinexor: a real-word analysis from FAERS database.

As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019-June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients' health.

Therapeutic Potential of Fucoidan in Alleviating Histamine-Induced Liver Injury: Insights from Mice Studies.

Histamine, a bioactive component in certain foods such as Huangjiu has been associated with liver injury and disrupted intestinal balance. This study explored the potential therapeutic effects of fucoidan (FCD) in mitigating histamine-induced imbalances in mice. We found that FCD mitigated liver injury, reducing transaminases, oxidative stress, and inflammation. Histological improvements included decreased cell infiltration and necrosis. FCD restored tight junction proteins and suppressed inflammation-related genes. Western blot analysis revealed FCD's impact on TGF-ß1, p-AKT, AKT, CYP2E1, Grp78, NLRP3, Cas-1, and GSDMD. Gut LPS levels decreased with FCD. Gut microbiota analysis showed FCD's modulation effect, reducing Firmicutes and increasing Bacteroides. FCD demonstrates potential in alleviating histamine-induced liver injury, regulating inflammation, and influencing gut microbiota. Further research exploring higher dosages and additional parameters is warranted.

Carbon tax-driven technological innovation may accelerate the directional recovery of waste cooking oil into bio-jet fuel: An evolutionary game approach.

Biofuel production from waste cooking oil (WCO) offers an alternative to fossil fuels, especially for high-value bio-jet fuel. However, this industry is hindered by informal recyclers who covertly divert large amounts of WCO to illegal gutter oil production. Investigating the dynamic evolution of stakeholder behavior will help explore solutions. Thus, this study presents a tripartite evolutionary game model that includes the government, formal recyclers, and informal recyclers, aims to redesign the government intervention strategy to promote the directional flow of WCO from restaurant trash cans to bio-jet fuel production. We find that the evolutionary game model exists eight possible evolutionary stability strategies (ESSs), and the choice of each ESS depends mainly on the trade-off between costs and revenues for each stakeholder. The numerical study results reveal that formal recyclers are driven to carry out technological innovation by government support, profiting from bio-aviation kerosene products, and income from carbon emission reduction. These factors also have an indirect impact on the transformation of informal recyclers. Therefore, the government should provide adequate support for technological innovation to formal recyclers and increase their profitability of products to enable them to actively implement innovative strategies. This can be achieved by expanding the sales channels of bio-jet fuel products, implementing patent protection measures, and improving the carbon reduction trading mechanism. Furthermore, the government's high tax rate on formal recyclers and the significant profits earned by informal recyclers through illegal gutter oil production may dissuade them from transitioning their businesses. Above findings are in line with the actual issues of WCO recycling and provide a new dynamic decision-making method for enterprises and government managers.

Glutathione-depleting Liposome Adjuvant for Augmenting the Efficacy of a Glutathione Covalent Inhibitor Oridonin for Acute Myeloid Leukemia Therapy.

BACKGROUND: Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH. METHODS: We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets. RESULTS: We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells. CONCLUSION: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.

An antifouling electrochemical biosensor using self-signal for Salmonella typhimurium direct detection in food sample.

Eating food contaminated by foodborne pathogens can lead to illness. The development of electrochemical sensors for pathogen detection has received widespread attention. However, the analytical performance of electrochemical sensors is inevitably affected by the non-specific adsorption of molecules in the sample. Moreover, the external signal probes might be affected by the complex components in the sample accompanied with signal suppression. This work presents an electrochemical aptasensor for Salmonella typhimurium detection based on the self-signal of poly-xanthurenic acid and the antifouling ability of chondroitin sulfate. The detection time was 60 min. The linear range was from 101 to 107 CFU/mL, and the detection limit was 3 CFU/mL. The biosensors presented good repeatability and storage stability. And the biosensors has been successfully applied in milk and orange juice. This strategy is expected to be applied in the design of other antifouling biosensors, to achieve rapid detection of pathogens and ensure food safety.

The Role of miR-150-5p/SOCS1 Pathway in Arsenic-Induced Pyroptosis of LX-2 Cells.

This study aims to explore the mechanism of pyroptosis of human hepatocyte LX-2 cells induced by NaAsO2 through the miR-150-5p/SOCS1 pathway. LX-2 cells were transfected with different concentrations of NaAsO2, miR-150-5p inhibitor, and SOCS1 agonist. Cell activity, cell pyroptosis, and the expression of related genes and proteins were detected by scanning electron microscopy, CCK-8, qRT-PCR, western blot, and immunofluorescence. Compared with the control group, 10 µmol/L and 20 µmol/L NaAsO2 significantly elevated the protein expression levels of the pyroptosis-related proteins NLRP3, GSDMD, GSDMD-N, caspase1, and cleaved caspase1 as well as the mRNA levels of NLRP3, GSDMD, caspase1, IL-18, and IL-1ß. The typical pyroptosis with swelling and rupture of the plasma membrane was observed through scanning electron microscopy. The expression of miR-150-5p of the NaAsO2 intervention group increased, while the expression of SOCS1 decreased; then the level of NF-κB p65 elevated. With co-treatment of miR-150-5p inhibitor, SOCS1 agonist, and NaAsO2, the cell pyroptosis was attenuated, and the expressions of NLRP3, caspase1, GSDMD, GSDMD-N, IL-18, IL-1ß, p65 of the group of miR-150-5p inhibitor and NaAsO2 group, and of the group of SOCS1 agonist and NaAsO2 reduced compared with the NaAsO2 group. Arsenic exposure promotes miR-150-5p, inhibits the expression of SOCS1, and activates the NF-κB/NLRP3 pathway in LX-2 cell pyroptosis.

LINC00942 Alleviates NaAsO2-induced Apoptosis by Promoting GSH Synthesis Through Targeting miR-214-5p.

The mechanism of arsenic-induced liver toxicity is not fully understood. This study aimed to investigate the role of LINC00942 in arsenic-induced hepatotoxicity by regulating miR-214-5p. As the exposure dose of NaAsO2 gradually increases, cell viability, intracellular GSH content, ΔΨm, and the protein levels of GCLC and GCLM were reduced significantly. Apoptosis rate, ROS, and expression of apoptosis-related and NF-κB pathway proteins increased. The expression of LINC00942 was increased, while the expression of miR-214-5p was decreased. After suppressing LINC00942 levels, NaAsO2 exposure further decreased cell viability, intracellular GSH content, ΔΨm, GCLC protein, and miR-214-5p expression. The apoptosis rate, ROS, and apoptosis-related and NF-κB pathway proteins further increased. miR-214-5p is targeted and negatively regulated by LINC00942. After miR-214-5p was overexpressed, NaAsO2 further decreased cell viability, intracellular GSH content, ΔΨm, and GCLC protein expression compared to NaAsO2 exposure. The apoptosis rate, ROS, apoptosis-related and NF-κB pathway proteins p65, and IKKß were higher than those exposed to NaAsO2. LINC00942 inhibitor along with miR-214-5p inhibitor combined with NaAsO2 treatment resulted in increased cell viability, GSH, Bcl-2, and GCLC protein expression and decreased apoptosis rate, apoptosis related, p65, IKKß protein, and ΔΨm, as compared to the combined NaAsO2 and si LINC00942 group. NaAsO2 exposure induces oxidative damage and apoptosis in LX-2 cells by activating NF-κB and inhibiting GSH synthesis. During this process, the expression level of LINC00942 increases, targeting to reduce the level of miR-214-5p, then weakening the effect of NaAsO2 on NF-κB, thereby alleviating cellular oxidative damage and playing a protective role.

Preparation and evaluation of a piperidinium-sulfonate based zwitterionic monolith for HILIC separation.

In this study, a novel piperidinium-sulfonate based zwitterionic hydrophilic monolith was prepared through thermally initiated co-polymerization of a piperidinium-sulfonate monomer 3-(4-((methacryloyloxy)methyl)-1-methylpiperidin-1-ium-1-yl)propane-1-sulfonate (MAMMPS), and a hydrophilic crosslinker N,N'-methylenebisacrylamide (MBA) using n-propanol and H2O as porogenic system. Satisfactory mechanical and chemical stabilities, good repeatability and high column efficiency (120,000 N/m) were obtained on the optimal monolith. The resulting poly(MAMMPS-co-MBA) monolith showed a typical HILIC retention behavior over an ACN content range between 5 and 95 %. Furthermore, this column exhibited good separation performance for various polar compounds. Compared to quaternary ammonium-sulfonate based zwitterionic hydrophilic monolith, i.e. poly(N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl)ammonium betaine-co-MBA), the poly(MAMMPS-co-MBA) monolith displayed stronger retention and better selectivity for the tested phenolic and amine compounds at different pH conditions. Finally, this column was applied for the separation of six sulfonamide antibiotics, and the analytical characteristics of the method were evaluated in terms of precision, repeatability, limits of detection (LOD) and quantitation (LOQ). Overall, this study not only developed a novel HILIC monolithic column, but also proved the potential of piperidinium-sulfonate based zwitterionic chemistry as stationary phase, which further increased the structure diversity of zwitterionic HILIC stationary phases.

The causal relationship between sleep disturbances and the risk of frailty: a two-sample Mendelian randomization study.

OBJECTIVE: Adequate sleep is closely related to people's health. However, with increasing age, the quality of sleep worsens. At the same time, among elderly individuals, frailty is also a disturbing factor, which makes elderly individuals more vulnerable to negative factors. To explore the relationship between the two, we conducted this study. METHODS: In this paper, independent genetic variations related to insomnia, sleep duration and daytime sleepiness were selected as IVs, and related genetic tools were used to search published genome-wide association studies for a two-sample Mendelian randomization (TSMR) analysis. The inverse-variance weighted (IVW) method was used as the main Mendelian randomization analysis method. Cochran's Q test was used to test heterogeneity, MR‒Egger was used to test horizontal pleiotropy, and the MR-PRESSO test was used to remove outliers. RESULTS: According to our research, insomnia (OR = 1.10, 95% CI 1.03-1.17, P = 2.59e-97), long sleep duration (OR = 0.66, 95% CI 0.37-1.17, P = 0.02), short sleep duration (OR = 1.30, 95% CI 1.22-1.38, P = 2.23e-17) and daytime sleepiness (OR = 1.49, 95% CI 1.25-1.77, P = 0.96e-4) had a bidirectional causal relationship with frailty. CONCLUSIONS: Our research showed that there is a causal relationship between sleep disturbances and frailty. This result was obtained by a TSMR analysis, which involves the use of genetic variation as an IV to determine causal relationships between exposure and outcome. Future TSMR studies should include a larger sample for analysis.

The design, synthesis and bioactivity evaluation of novel androgen receptor degraders based on hydrophobic tagging.

Prostate Cancer (PCa) easily progress to metastatic Castration-Resistant Prostate Cancer (mCRPC) that remains a significant cause of cancer-related death. Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Proteolysis-targeting chimaera (PROTAC) technology based on Hydrophobic Tagging (HyT) represents an intriguing strategy to regulate the function of therapeutically androgen receptor proteins. In the present study, we have designed, synthesized, and evaluated a series of PROTAC-HyT AR degraders using AR antagonists, RU59063, which were connected with adamantane-based hydrophobic moieties by different alkyl chains. Compound D-4-6 exhibited significant AR protein degradation activity, with a degradation rate of 57 % at 5 µM and nearly 90 % at 20 µM in 24 h, and inhibited the proliferation of LNCaP cells significantly with an IC50 value of 4.77 ± 0.26 µM in a time-concentration-dependent manner. In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.

Polyvinylpyrrolidone-Coated Cubic Hollow Nanocages of PdPt3 and PdIr3 as Highly Efficient Self-Cascade Uricase/Peroxidase Mimics.

Uricase-catalyzed uric acid (UA) degradation has been applied for hyperuricemia therapy, but this medication is limited by H2O2 accumulation, which can cause oxidative stress of cells, resulting in many other health issues. Herein, we report a robust cubic hollow nanocage (HNC) system based on polyvinylpyrrolidone-coated PdPt3 and PdIr3 to serve as highly efficient self-cascade uricase/peroxidase mimics to achieve the desired dual catalysis for both UA degradation and H2O2 elimination. These HNCs have hollow cubic shape with average wall thickness of 1.5 nm, providing desired synergy to enhance catalyst's activity and stability. Density functional theory calculations suggest the PdIr3 HNC surface tend to promote OH*/O* desorption for better peroxidase-like catalysis, while the PdPt3 HNC surface accelerates the UA oxidation by facilitating O2-to-H2O2 conversion. The dual catalysis power demonstrated by these HNCs in cell studies suggests their great potential as a new type of nanozyme for treating hyperuricemia.

MAGL protects against renal fibrosis through inhibiting tubular cell lipotoxicity.

Rationale: Renal fibrosis, with no therapeutic approaches, is a common pathological feature in various chronic kidney diseases (CKD). Tubular cell injury plays a pivotal role in renal fibrosis. Commonly, injured tubular cells exhibit significant lipid accumulation. However, the underlying mechanisms remain poorly understood. Methods: 2-arachidonoylglycerol (2-AG) levels in CKD patients and CKD model specimens were measured using mass spectrometry. 2-AG-loaded nanoparticles were infused into unilateral ureteral obstruction (UUO) mice. Lipid accumulation and renal fibrosis were tested. Furthermore, monoacylglycerol lipase (MAGL), the hydrolyzing enzyme of 2-AG, was assessed in CKD patients and models. Tubular cell-specific MAGL knock-in mice were generated. Moreover, MAGL recombination protein was also administered to unilateral ischemia reperfusion injury (UIRI) mice. Besides, a series of methods including RNA sequencing, metabolomics, primary cell culture, lipid staining, etc. were used. Results: 2-AG was increased in the serum or kidneys from CKD patients and models. Supplement of 2-AG further induced lipid accumulation and fibrogenesis through cannabinoid receptor type 2 (CB2)/ß-catenin signaling. ß-catenin knockout blocked 2-AG/CB2-induced fatty acid ß-oxidation (FAO) deficiency and lipid accumulation. Remarkably, MAGL significantly decreased in CKD, aligning with lipid accumulation and fibrosis. Specific transgene of MAGL in tubular cells significantly preserved FAO, inhibited lipid-mediated toxicity in tubular cells, and finally retarded fibrogenesis. Additionally, supplementation of MAGL in UIRI mice also preserved FAO function, inhibited lipid accumulation, and protected against renal fibrosis. Conclusion: MAGL is a potential diagnostic marker for kidney function decline, and also serves as a new therapeutic target for renal fibrosis through ameliorating lipotoxicity.