Pyroptosis-Related Genes as Diagnostic Markers in Chronic Obstructive Pulmonary Disease and Its Correlation with Immune Infiltration.

Background: Chronic obstructive pulmonary disease (COPD) stands as a predominant cause of global morbidity and mortality. This study aims to elucidate the relationship between pyroptosis-related genes (PRGs) and COPD diagnosis in the context of immune infiltration, ultimately proposing a PRG-based diagnostic model for predicting COPD outcomes. Methods: Clinical data and PRGs of COPD patients were sourced from the GEO database. The "ConsensusClusterPlus" package was employed to generate molecular subtypes derived from PRGs that were identified through differential expression analysis and LASSO Cox analysis. A diagnostic signature including eight genes (CASP4, CASP5, ELANE, GPX4, NLRP1, GSDME, NOD1and IL18) was also constructed. Immune cell infiltration calculated by the ESTIMATE score, Stroma scores and Immune scores were also compared on the basis of pyroptosis-related molecular subtypes and the risk signature. We finally used qRT - PCR to detect the expression levels of eight genes in COPD patient and normal. Results: The diagnostic model, anchored on eight PRGs, underwent validation with an independent experimental cohort. The area under the receiver operating characteristic (ROC) curves (AUC) for the diagnostic model showcased values of 0.809, 0.765, and 0.956 for the GSE76925, GSE8545, and GSE5058 datasets, respectively. Distinct expression patterns and clinical attributes of PRGs were observed between the comparative groups, with functional analysis underscoring a disparity in immune-related functions between them. Conclusion: In this study, we developed a potential as diagnostic biomarkers for COPD and have a significant role in modulating the immune response. Such insights pave the way for novel diagnostic and therapeutic strategies for COPD.

Remote Health Management via WeChat to Improve the Quality of Life of Patients After PCI.

OBJECTIVES: The purpose of this research was to assess the effect of telehealth management via WeChat on improving the quality of life of patients after percutaneous coronary intervention (PCI). METHODS: In this study, we retrospectively collected the clinical data of 118 patients who underwent PCI and received remote health management from our hospital via WeChat from June 2021 to September 2021 (WeChat group). The clinical data of 114 patients who underwent PCI but did not receive remote health management from our hospital from September 2020 to December 2020 were also collected (conventional group). Anxiety, depression, and quality of life scale scores were compared between the 2 groups at 6 months postdischarge. RESULTS: Six months postdischarge, patients in the WeChat group had significantly lower Self-rating Anxiety Scale (SAS) (55.7 ± 7.2 vs 58.8 ± 6.4, P = .001) and Self-rating Depression Scale (SDS) (56.0 ± 5.9 vs 58.2 ± 6.2, P = .007) scores than did those in the conventional group. Compared to those in the conventional group, the patients in the WeChat group had significantly greater 6 months post-discharge The World Health Organization Quality of Life - BREF scores in the following domains: physical (14.3 ± 1.7 vs 13.1 ± 1.7, P < .001 psychological (15.2 ± 1.3 vs 13.5 ± 1.5, P < .001 social relationship (12.9 ± 1.7 vs 12.3 ± 1.8, P = .01) and environmental (12.7 ± 2.0 vs 12.0 ± 1.9, P = .006). CONCLUSION: The use of WeChat to carry out remote health management for patients who underwent PCI can be an effective way to provide high-quality hospital medical services to patients' families and can effectively alleviate patients' anxiety and depression and enhance their quality of life.

Disturbance of fetal growth by azithromycin through induction of ER stress in the placenta.

AIM: Azithromycin (AZM) is widely used to treat mycoplasma infection in pregnancy. However, there is no adequate evaluation of its side effect on the placenta. Here, by using human placental syncytiotrophoblasts and a mouse model, we investigated whether AZM use in pregnancy might adversely affect placental function and pregnancy outcome. RESULTS: Transcriptomic analysis of AZM-treated human placental syncytiotrophoblasts showed increased expression of ER stress-related genes and decreased expression of genes for hormone production and growth factor processing. Verification studies showed that AZM increased the abundance of ER stress mediators (phosphorylated eIF2α, ATF4 and CHOP), and decreased the abundance of enzymes involved in progesterone and estradiol synthesis (STS, CYP11A1 and CYP19A1) and IGFBP cleavage (PAPPA and ADAM12) in human placental syncytiotrophoblasts. Inhibition of ER stress blocked AZM-induced decreases in the expression of CYP19A1, CYP11A1, PAPPA and ADAM12, suggesting that the inhibition of AZM on those genes' expression was secondary to AZM-induced ER stress. Further mechanism study showed that increased ATF4 in ER stress might repressively interact with C/EBPα to suppresstheexpression ofthose genes including CEBPAitself. Mouse studies showed that AZM administration decreased fetal weights along with increased ER stress mediators and decreased levels of insulin-like growth factor, estrogen and progesterone in the maternal blood, which could be alleviated by inhibition of ER stress. INNOVATION AND CONCLUSION: These findings firstly support AZM, often used during pregnancy, may affect fetal growth by inhibiting crucial enzymes for estrogen and progesterone synthesis and disrupting crucial proteases for IGFBP cleavage via inducing ER stress in placental syncytiotrophoblasts.

Enhancing the catalytic activity of the MnNC catalyst by regulating the coordination environment.

The catalytic activity is largely determined by the coordination environment of the active sites. The catalytic activity of MnNC was much enhanced by the regulation of the coordination environment. The introduction of optimal epoxy to the vicinity of the Mn centers improved its half-wave potential by ∼300 mV.

PD-1/PD-L1 Provides Protective Role in Hypoxia-Induced Pulmonary Vascular Remodeling.

BACKGROUND: Hypoxia-induced pulmonary hypertension (HPH) is a T helper 17 cell response-driven disease, and PD-1 (programmed cell death 1)/PD-L1 (programmed cell death-ligand 1) inhibitor-associated pulmonary hypertension has been reported recently. This study is designed to explore whether the PD-1/PD-L1 pathway participates in HPH via regulating endothelial dysfunction and T helper 17 cell response. METHODS: Lung tissue samples were obtained from eligible patients. Western blotting, immunohistochemistry, and immunofluorescence techniques were used to assess protein expression, while immunoprecipitation was utilized to detect ubiquitination. HPH models were established in C57BL/6 WT (wild-type) and PD-1-/- mice, followed by treatment with PD-L1 recombinant protein. Adeno-associated virus vector delivery was used to upregulate PD-L1 in the endothelial cells. Endothelial cell function was assessed through assays for cell angiogenesis and adhesion. RESULTS: Expression of the PD-1/PD-L1 pathway was downregulated in patients with HPH and mouse models, with a notable decrease in PD-L1 expression in endothelial cells compared with the normoxia group. In comparison to WT mice, PD-1-/- mice exhibited a more severe HPH phenotype following exposure to hypoxia, However, administration of PD-L1 recombinant protein and overexpression of PD-L1 in lung endothelial cells mitigated HPH. In vitro, blockade of PD-L1 with a neutralizing antibody promoted endothelial cell angiogenesis, adhesion, and pyroptosis. Mechanistically, hypoxia downregulated PD-L1 protein expression through ubiquitination. Additionally, both in vivo and in vitro, PD-L1 inhibited T helper 17 cell response through the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathway in HPH. CONCLUSIONS: PD-1/PD-L1 plays a role in ameliorating HPH development by inhibiting T helper 17 cell response through the PI3K/AKT/mTOR pathway and improving endothelial dysfunction, suggesting a novel therapeutic indication for PD-1/PD-L1-based immunomodulatory therapies in the treatment of HPH.

Identification of an HLA-A*11:01-restricted neoepitope of mutant PIK3CA and its specific T cell receptors for cancer immunotherapy targeting hotspot driver mutations.

Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy.

Molecularly Tunable Heterostructured Co-Polymers Containing Electron-Deficient and -Rich Moieties for Visible-Light and Sacrificial-Agent-Free H2O2 Photosynthesis.

As an alternative to hydrogen peroxide (H2O2) production by complex anthraquinone oxidation process, photosynthesis of H2O2 from water and oxygen without sacrificial agents is highly demanded. Herein, a covalently connected molecular heterostructure is synthesized via sequential C-H arylation and Knoevenagel polymerization reactions for visible-light and sacrificial-agent-free H2O2 synthesis. The subsequent copolymerization of the electron-deficient benzodithiophene-4,8-dione (BTD) and the electron-rich biphenyl (B) and p-phenylenediacetonitrile (CN) not only expands the π-conjugated domain but also increases the molecular dipole moment, which largely promotes the separation and transfer of the photoinduced charge carriers. The optimal heterostructured BTDB-CN0.2 manifested an impressive photocatalytic H2O2 production rate of 1920 µmol g-1 h-1, which is 2.2 and 11.6 times that of BTDB and BTDCN. As revealed by the femtosecond transient absorption (fs-TA) and theoretical calculations, the linkage serves as a channel for the rapid transfer of photogenerated charge carriers, enhancing the photocatalytic efficiency. Further, in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) uncovers that the oxygen reduction reaction occurs through the step one-electron pathway and the mutual conversion between C=O and C-OH with the anchoring of H+ during the catalysis favored the formation of H2O2. This work provides a novel perspective for the design of efficient organic photocatalysts.

Dry environment on the expression of lacrimal gland S100A9, Anxa1, and Clu in rats via proteomics.

AIM: To investigate the underlying mechanism of dry environment (autumn dryness) affecting the lacrimal glands in rats. METHODS: Twenty Sprague-Dawley rats were randomly divided into two groups. The rats were fed in specific pathogen free environment as the control group (n=10), and the rats fed in dry environment as the dryness group (n=10). After 24d, lacrimal glands were collected from the rats. The tissues morphology was observed by hematoxylin-eosin (HE) staining. Tandem mass tags (TMT) quantitative proteomics analysis technology was used to screen the differential expressed proteins of lacrimal glands between the two groups, then bioinformatics analysis was performed. Further, the immunohistochemical (IHC) method was used to verify the target proteins. RESULTS: In dryness group, the lacrimal glands lobule atrophied, the glandular cavities enlarged, the sparse nuclear distribution and scattered inflammatory infiltration between the acinus were observed. The proteomics exhibited that a total of 195 up-regulated and 236 down-regulated differential expressed proteins screened from the lacrimal glands of rats. It was indicated that the biological processes (BP) of differential expressed proteins mainly included cell processes and single BP. The cellular compositions of differential expressed proteins mainly located in cells, organelles. The molecular functions of differential expressed proteins mainly included binding, catalytic activity. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the differential expressed proteins mainly involved lysosome, complement and coagulation cascade, and ribosome pathway. The IHC result verified that the up-regulated expression proteins of Protein S100A9 (S100A9), Annexin A1 (Anxa1), and Clusterin (Clu) in lacrimal glands of rats in dryness group were higher than control group. CONCLUSION: The up-regulated expression proteins of S100A9, Anxa1, and Clu may be the potential mechanisms of dry eye symptoms caused by dry environment. This study provides clues of dry environments causing eye-related diseases for further studies.

A Peel Test Method to Characterize the Decay Law of Prepreg Tape Tack at Different Temperatures.

The tack of prepreg is a key factor affecting the automatic tape laying process. During the manufacturing process of large composite parts, prepreg material may be stored at room temperature for several days, resulting in a decrease in its tack. In this study, a new tack test tool was designed, and the decay rate of prepreg tack at different temperatures was tested. We proposed a prepreg tack decay model, which assumes that the main factor in tack decay is the reduction in resin chain activity during storage. The maximum deviation between the model calculation results and the experimental results of the tack decay rate is 9.7%. This study also proposed a new statistical unit for prepreg tack, which can establish the relationship between the tack of prepreg and its remaining storage time and reduce prepreg management costs.

How to make full use of dental pulp stem cells: an optimized cell culture method based on explant technology.

Introduction: Dental pulp stem cells from humans possess self-renewal and versatile differentiation abilities. These cells, known as DPSC, are promising for tissue engineering due to their outstanding biological characteristics and ease of access without significant donor site trauma. Existing methods for isolating DPSC mainly include enzyme digestion and explant techniques. Compared with the enzymatic digestion technique, the outgrowth method is less prone to cell damage and loss during the operation, which is essential for DPSC with fewer tissue sources. Methods: In order to maximize the amount of stem cells harvested while reducing the cost of DPSC culture, the feasibility of the optimized explant technique was evaluated in this experiment. Cell morphology, minimum cell emergence time, the total amount of cells harvested, cell survival, and proliferative and differentiation capacity of DPSC obtained with different numbers of explant attachments (A1-A5) were evaluated. Results: There was a reduction in the survival rate of the cells in groups A2-A5, and the amount of harvested DPSC decreased in A3-A5 groups, but the DPSC harvested in groups A1-A4 had similar proliferative and differentiation abilities. However, starting from group A5, the survival rate, proliferation and differentiation ability of DPSC decreased significantly, and the adipogenic trend of the cells became more apparent, indicating that the cells had begun to enter the senescence state. Discussion: The results of our study demonstrated that the DPSC obtained by the optimized explant method up to 4 times had reliable biological properties and is available for tissue engineering.

Nanostructured, Biodoping-Activated Fungi-Modified Wood for Enhanced Cd2+ Removal: Performances and Insight on Adsorption Mechanisms.

Nanostructured activated carbon (AC) adsorbents derived from woody biomass have garnered attention for their potential usage to remove toxic substances from the environment due to their high specific surface area, superior micro/mesoporosity, and tunable surface chemistry profile. However, chemical dopants widely used to enhance the chemical reactivity with heavy metals would pollute the environment and conflict with the vision of a cleaner and sustainable environment. Herein, we report a facile, green, and sustainable approach using fungi modification combined with alkali activation to produce AC for heavy metal removal. The decayed wood-derived AC (DAC) exhibited a high specific surface area of 2098 m2/g, and the content of O and N functional groups was 18 and 2.24%, respectively. It showed remarkable adsorption capacity toward Cd2+ of 148.7 mg/g, which was much higher than most reported Cd2+ adsorbents. Such excellent adsorption capacity was primarily based on enhanced physical adsorption (pore filling, π-π) and chemical adsorption (functional group complexation, ion exchange, and precipitation). Additionally, the DAC showed rapid kinetics and remarkable applicability in both dynamic environments and actual water samples. These results suggest that decayed wood has excellent potential for efficient use in the removal of Cd2+ from wastewater. Furthermore, these results indicate that decayed wood can be cleanly produced into high efficiency heavy metal adsorbents to realize value-added utilization of decayed wood.

Spexin ameliorated obesity-related metabolic disorders through promoting white adipose browning mediated by JAK2-STAT3 pathway.

BACKGROUND: Spexin, a 14 amino acid peptide, has been reported to regulate obesity and its associated complications. However, little is known about the underlying molecular mechanism. Therefore, this study aimed to investigate the effects of spexin on obesity and explore the detailed molecular mechanisms in vivo and in vitro. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity, and mice fed a standard fat diet were used as controls. Then, these mice were treated with SPX or Vehicle by intraperitoneal injection for an additional 12 weeks, respectively. The metabolic profile, fat-browning specific markers and mitochondrial contents were detected. In vitro, 3T3-L1 cells were used to investigate the molecular mechanisms. RESULTS: After 12 weeks of treatment, SPX significantly decreased body weight, serum lipid levels, and improved insulin sensitivity in HFD-induced obese mice. Moreover, SPX was found to promote oxygen consumption in HFD mice, and it increased mitochondrial content as well as the expression of brown-specific markers in white adipose tissue (WAT) of HFD mice. These results were consistent with the increase in mitochondrial content and the expression of brown-specific markers in 3T3-L1 mature adipocytes. Of note, the spexin-mediated beneficial pro-browning actions were abolished by the JAK2/STAT3 pathway antagonists in mature 3T3-L1 cells. CONCLUSIONS: These data indicate that spexin ameliorates obesity-induced metabolic disorders by improving WAT browning via activation of the JAK2/STAT3 signaling pathway. Therefore, SPX may serve as a new therapeutic candidate for treating obesity.

D-A Conjugated Polymer/CdS S-Scheme Heterojunction with Enhanced Interfacial Charge Transfer for Efficient Photocatalytic Hydrogen Generation.

Owing to the improved charge separation and maximized redox capability of the system, Step-scheme (S-scheme) heterojunctions have garnered significant research attention for efficient photocatalysis of H2 evolution. In this work, an innovative linear donor-acceptor (D-A) conjugated polymer fluorene-alt-(benzo-thiophene-dione) (PFBTD) is coupled with the CdS nanosheets, forming the organic-inorganic S-scheme heterojunction. The CdS/PFBTD (CP) composite exhibits an impressed hydrogen production rate of 7.62 mmol g-1  h-1 without any co-catalysts, which is ≈14 times higher than pristine CdS. It is revealed that the outstanding photocatalytic performance is attributed to the formation of rapid electron transfer channels through the interfacial Cd─O bonding as evidenced by the density functional theory (DFT) calculations and in situ X-ray photoelectron spectroscopy (XPS) analysis. The charge transfer mechanism involved in S-scheme heterojunctions is further investigated through the photo-irradiated Kelvin probe force microscopy (KPFM) analysis. This work provides a new point of view on the mechanism of interfacial charge transfer and points out the direction of designing superior organic-inorganic S-scheme heterojunction photocatalysts.

Engineered exosomes and composite biomaterials for tissue regeneration.

Exosomes, which are small vesicles enclosed by a lipid bilayer and released by many cell types, are widely dispersed and have garnered increased attention in the field of regenerative medicine due to their ability to serve as indicators of diseases and agents with therapeutic potential. Exosomes play a crucial role in mediating intercellular communication through the transfer of many biomolecules, including proteins, lipids, RNA, and other molecular constituents, between cells. The targeted transport of proteins and nucleic acids to specific cells has the potential to enhance or impair specific biological functions. Exosomes have many applications, and they can be used alone or in combination with other therapeutic approaches. The examination of the unique attributes and many functions of these factors has emerged as a prominent field of study in the realm of biomedical research. This manuscript summarizes the origins and properties of exosomes, including their structural, biological, physical, and chemical aspects. This paper offers a complete examination of recent progress in tissue repair and regenerative medicine, emphasizing the possible implications of these methods in forthcoming tissue regeneration attempts.

Sex-Biased Expression and Response of microRNAs in Neurological Diseases and Neurotrauma.

Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and pathological factors that impact the sex disparity in neurological diseases. MicroRNAs (miRNAs) are a powerful class of gene expression regulator that are extensively involved in mediating biological pathways. Emerging evidence demonstrates that miRNAs play a crucial role in the sex dimorphism observed in various human diseases, including neurological diseases. Understanding the sex differences in miRNA expression and response is believed to have important implications for assessing the risk of neurological disease, defining therapeutic intervention strategies, and advancing both basic research and clinical investigations. However, there is limited research exploring the extent to which miRNAs contribute to the sex disparities observed in various neurological diseases. Here, we review the current state of knowledge related to the sexual dimorphism in miRNAs in neurological diseases and neurotrauma research. We also discuss how sex chromosomes may contribute to the miRNA sexual dimorphism phenomenon. We attempt to emphasize the significance of sexual dimorphism in miRNA biology in human diseases and to advocate a gender/sex-balanced science.

ADAMTS4 is a crucial proteolytic enzyme for versican cleavage in the amnion at parturition.

Hyalectan cleavage may play an important role in extracellular matrix remodeling. However, the proteolytic enzyme responsible for hyalectan degradation for fetal membrane rupture at parturition remains unknown. Here, we reveal that versican (VCAN) is the major hyalectan in the amnion, where its cleavage increases at parturition with spontaneous rupture of membrane. We further reveal that ADAMTS4 is a crucial proteolytic enzyme for VCAN cleavage in the amnion. Inflammatory factors may enhance VCAN cleavage by inducing ADAMTS4 expression and inhibiting ADAMTS4 endocytosis in amnion fibroblasts. In turn, versikine, the VCAN cleavage product, induces inflammatory factors in amnion fibroblasts, thereby forming a feedforward loop between inflammation and VCAN degradation. Mouse studies show that intra-amniotic injection of ADAMTS4 induces preterm birth along with increased VCAN degradation and proinflammatory factors abundance in the fetal membranes. Conclusively, there is enhanced VCAN cleavage by ADAMTS4 in the amnion at parturition, which can be reenforced by inflammation.

The cavitation characteristics of aerospace high-speed centrifugal pumps with different tip clearance.

This study investigates the Tip Clearance Cavitation (TCC) characteristics of three different Tip Clearances (TC) (0.4, 0.6, 0.8) and five inlet negative pressure conditions Pj = (- 20-60)kPa to improve the reliability of the aerospace high-speed centrifugal pump during in-orbit operation, based on the premise of good agreement between the TC 0.6 test curve and the simulation performance curve. Under negative pressure and high-speed conditions, the variation gradient of cavitation characteristics with various inlet negative pressures is non-linear and has a sudden change, but the trend becomes stable after the inlet negative pressure drops to a certain stage. The tip clearance cavitation characteristics vary from the blade surface cavitation characteristics due to the difference in forces on both sides. This study is a proper starting point for the design of aerospace power pumps.

Attenuation of palmitic acid-induced lysyl oxidase overexpression in the ovary contributes to the improvement of ovulation in obesity by metformin.

STUDY QUESTION: Does palmitic acid (PA), the most common saturated free fatty acid (FFA) in individuals with obesity, contribute to anovulation through upregulation of the collagen-crosslinking enzyme lysyl oxidase (LOX) in the ovary? SUMMARY ANSWER: Increased PA in individuals with obesity can cause LOX upregulation via the activation of hypoxia-inducible factor-1α (HIF-1α), resulting in abnormal collagen deposition in the ovary and anovulation, which can be ameliorated by metformin therapy. WHAT IS KNOWN ALREADY: The underlying cause of anovulation in individuals with obesity is poorly defined, and accumulating evidence indicates that hormonal disturbance, insulin resistance, and inflammation may all play a role in the development of ovulation disorders in individuals with obesity. However, it remains to be determined whether PA plays a role in the regulation of LOX expression, thus disrupting ovarian extracellular matrix (ECM) remodelling in the ovary and resulting in impaired ovulation in individuals with obesity. STUDY DESIGN SIZE DURATION: PA concentration and LOX protein abundance and activity in follicular fluid and ovarian tissue were compared between control (n = 21) subjects, patients with obesity with ovulation (n = 22), and patients with obesity with anovulation (n = 16). The effect of PA on LOX protein expression, and the underlying mechanism, was examined in primary human granulosa cells in vitro. The improvements in obesity conditions induced by LOX inhibition combined with metformin were investigated in a high-fat diet-induced obese rat model. PARTICIPANTS/MATERIALS SETTING METHODS: The abundance of PA concentration and LOX activity was measured via a LOX activity assay and ELISA, respectively. The effect of PA on LOX protein expression was examined in the presence or absence of inhibitors of signalling molecules and siRNA-mediated knockdown of the putative transcription factor. Chromatin immunoprecipitation assays were subsequently conducted to further identify the responsible transcription factor. The role of metformin in the treatment of anovulation by LOX inhibition was investigated in a high-fat diet (HFD)-induced obese rat model. The numbers of retrieved total oocytes and metaphase II oocytes were recorded upon ovarian stimulation. Masson's trichrome staining was used to measure the total collagen content, and immunohistochemical staining and western blotting were used to measure LOX, HIF-1α, and collagen I and IV in the ovary. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly increased FFA, LOX, and collagen abundance were observed in the ovaries of obese women with anovulation, compared to healthy controls or obese women with ovulation. In a HFD-induced obese rat model, metformin corrected the distortion of ovarian morphology by decreasing LOX and collagen protein abundance in the ovary and improving oestrous cyclicity and ovulation. PA increased LOX expression via the activation of HIF-1α in human granulosa cells, which was attenuated by metformin. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Several other saturated and polyunsaturated FFAs, such as stearic acid and arachidonic acid, are also increased in the blood of individuals with obesity, and increased levels of other FFAs may also contribute to the development of anovulation in individuals with obesity, which needs to be further verified in the future. WIDER IMPLICATIONS OF THE FINDINGS: Elevated PA in individuals with obesity can cause LOX dysregulation via activation of HIF-1α, resulting in abnormal collagen deposition in the ovary and anovulation. This dysregulation can be ameliorated by metformin therapy through its local effect on ECM remodelling in the ovary, which is independent of its systemic effect on insulin sensitivity and chronic inflammation. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the National Natural Science Foundation of China (grant numbers 82101730, 82130046, and 31900598) and Innovative Research Team of High-level local Universities in Shanghai (SHSMU-ZLCX20210201). All the authors declare no conflicts of interest in relation to this work.

Elafibranor emerged as a potential chemotherapeutic drug for non-muscle invasive bladder cancer.

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 µM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.