Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response.

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10Q144K mutation in EEECs resulted in aberrant SIGLEC-10 protein expression and promoted progestin resistance by interacting with estrogen receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity.

BACKGROUND: Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms. METHODS: Neonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells. RESULTS: Repeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005. CONCLUSIONS: Our findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

Baicalin attenuates neuronal damage associated with SDH activation and PDK2-PDH axis dysfunction in early reperfusion.

BACKGROUND: Energy deficiency and oxidative stress are interconnected during ischemia/reperfusion (I/R) and serve as potential targets for the treatment of cerebral ischemic stroke. Baicalin is a neuroprotective antioxidant, but the underlying mechanisms are not fully revealed. PURPOSE: This study explored whether and how baicalin rescued neurons against ischemia/reperfusion (I/R) attack by focusing on the regulation of neuronal pyruvate dehydrogenase kinase 2 (PDK2)-pyruvate dehydrogenase (PDH) axis implicated with succinate dehydrogenase (SDH)-mediated oxidative stress. STUDY DESIGN: The effect of the tested drug was explored in vitro and in vivo with the model of oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion/reperfusion (MCAO/R), respectively. METHODS: Neuronal damage was evaluated according to cell viability, infarct area, and Nissl staining. Protein levels were measured by western blotting and immunofluorescence. Gene expression was investigated by RT-qPCR. Mitochondrial status was also estimated by fluorescence probe labeling. RESULTS: SDH activation-induced excessive production of reactive oxygen species (ROS) changed the protein expression of Lon protease 1 (LonP1) and hypoxia-inducible factor-1ɑ (HIF-1ɑ) in the early stage of I/R, leading to an upregulation of PDK2 and a decrease in PDH activity in neurons and cerebral cortices. Treatment with baicalin prevented these alterations and ameliorated neuronal ATP production and survival. CONCLUSION: Baicalin improves the function of the neuronal PDK2-PDH axis via suppression of SDH-mediated oxidative stress, revealing a new signaling pathway as a promising target under I/R conditions and the potential role of baicalin in the treatment of acute ischemic stroke.

Elucidation of the Anti-Lung Cancer Mechanism of Xiao'ai Jiedu Prescription Based on Network Pharmacology and Molecular Docking.

Objective: Network pharmacology is an emerging discipline that applies computational methods to understand drug actions and interactions with multiple molecular targets. Xiao'ai Jiedu is a valued traditional Chinese medicine preparation for which the mechanism of action is not yet established. This study aims to explore the mechanism of Xiao'ai Jiedu in treating lung cancer through network pharmacology. Methods: First, the Traditional Chinese Medicine Systems Pharmacology (TCMSP) data platform was used to analyze the target treatment results of different medicinal materials in Mr. Zhou's cancer prescriptions. Then, functional enrichment analysis was performed to conduct a secondary analysis of the dissemination of cancer biological and pharmacological information in the human body. The Cancer Genome Atlas (TCGA) was used to obtain several cancer-aggressive target groups, and their transcription RNA was extracted for collection. The CIBERSORT evaluation method was used to conduct a Spearman correlation analysis on the data processing results. Then the matching degree between the experimental cells and the principle of drug treatment was analyzed to improve the statistical analysis. Results: Pharmacology research results showed that the network can accurately eliminate cancer detoxification targeted target correlation set, and through the data interpretation found that four different gene transcription have significant influence on lung cancer. The findings also confirmed that the degree of immune cell infiltration has a key role in lung cancer The study summarizes the active ingredients and their targets and mechanisms of action of the elimination of Xiao'ai Jiedu formula for the treatment of lung cancer. Conclusion: Network pharmacology can carry on the processing of the data, find the key to conform to the goal of research data, and the corresponding results are obtained, and the development of network pharmacology is not limited to, the study of lung cancer.

circRNA_8521 promotes Senecavirus A infection by sponging miRNA-324 to regulate LC3A.

Senecavirus A (SVA) causes outbreaks of vesicular disease in pigs, which imposes a considerable economic burden on the pork industry. As current SVA prevention measures are ineffective, new strategies for controlling SVA are urgently needed. Circular (circ)RNA is a newly characterized class of widely expressed, endogenous regulatory RNAs, which have been implicated in viral infection; however, whether circRNAs regulate SVA infection remains unknown. To investigate the influence of circRNAs on SVA infection in porcine kidney 15 (PK-15) cells, RNA sequencing technology was used to analyze the circRNA expression profiles of SVA-infected and uninfected PK-15 cells, the interactions between circRNAs, miRNAs, and mRNAs potentially implicated in SVA infection were predicted using bioinformatics tools. The prediction accuracy was verified using quantitative real-time (qRT)-PCR, Western blotting, as well as dual-luciferase reporter and RNA pull-down assays. The results showed that 67 circRNAs were differentially expressed as a result of SVA infection. We found that circ_8521 was significantly upregulated in SVA-infected PK-15 cells and promoted SVA infection. circ_8521 interacted with miR-324. miR-324 bound to LC3A mRNA which inhibited the expression of LC3A. Knockdown of LC3A inhibited SVA infection. However, circ_8521 promoted the expression of LC3A by binding to miR-324, thereby promoting SVA infection. We demonstrated that circ_8521 functioned as an endogenous miR-324 sponge to sequester miR-324, which promoted LC3A expression and ultimately SVA infection.

Hypoxia preconditioning of human amniotic mesenchymal stem cells enhances proliferation and migration and promotes their homing via the HGF/C-MET signaling axis to augment the repair of acute liver failure.

BACKGROUND: Transplantation of mesenchymal stem cells (MSCs) is a newly developed strategy for treating acute liver failure (ALF). Nonetheless, the low survival rate of MSCs after transplantation and their poor homing to damaged tissues limit the clinical application of MSCs. The research assessed whether hypoxic preconditioning (HPC) can improve the biological activity of human amniotic mesenchymal stem cells (hA-MSCs), promote their homing ability to the liver of mice with ALF, and influence liver tissue repair. METHODS: Flow cytometry, CCK8, Transwell, and Western blotting assays were conducted to assess the effects of hypoxic preconditioning on the phenotype, proliferation, and migration of hA-MSCs and the changes in the c-Met and CXCR4 gene expression levels were studied. To evaluate the effects of the transplantation of hypoxic preconditioning of hA-MSCs on the homing and repair of D-galactosamine (D-GalN)/LPS-induced ALF, the mechanism was elucidated by adding c-Met, CXCR4-specific blockers (SU11274 and AMD3100). RESULTS: After hypoxia pretreatment (1% oxygen volume fraction), hA-MSCs maintained the morphological characteristics of adherence and vortex colony growth and showed high CD44, CD90, and CD105 and low CD31, CD34, and CD45 expression levels. Hypoxic preconditioning of hA-MSCs significantly increased their proliferation and migration and highly expressed the c-Met and CXCR4 genes. In vivo and in vitro, this migration-promoting effect was suppressed by the c-Met specific blocker SU11274. In the acute liver failure mouse model, the HGF expression level was considerably elevated in the liver than that in the serum, lungs and kidneys. The transplantation of hypoxic preconditioned hA-MSCs introduced a remarkable improvement in the liver function and survival rate of mice with ALF and enhanced the anti-apoptosis ability of liver cells. The anti-apoptotic enhancing effect of hypoxic preconditioning was suppressed by the c-Met specific blocker SU11274. Hypoxic hA-MSCs administration was observed to have considerably increased the fluorescent cells in the liver than that recorded after administering normal oxygen-hA-MSCs. The number of hepatic fluorescent cells decreased remarkably after adding the c-Met inhibitor SU11274, compared to that recorded after hypoxic pretreatment, whereas the effect of c-Met inhibitor SU11274 on normal oxygen-hA-MSCs was not significant. CONCLUSIONS: Hypoxic preconditioning depicted no impact on the morphology and phenotype features of the human amniotic mesenchymal stem cells, but it can promote their proliferation, migration, anti-apoptotic effect, and homing rate and improve the repair of acute liver failure, which might be mediated by the HGF/c-Met signaling axis.

Dominant Solvent-Separated Ion Pairs in Electrolytes Enable Superhigh Conductivity for Fast-Charging and Low-Temperature Lithium Ion Batteries.

The low ionic conductivities of aprotic electrolytes hinder the development of extreme fast charging technologies and applications at low temperatures for lithium-ion batteries (LIBs). Herein, we present an electrolyte with LiFSI in acetone (DMK). In DMK electrolytes, the solvation number is three, and solvent-separated ion pairs (SSIPs) are the dominant structure, which is largely different from other linear aprotic electrolytes where salts primarily exist as contact ion pairs (CIPs). With incompact solvation structures due to the weak solvation ability of DMK with Li+, the ionic conductivity reaches 45 mS/cm at room temperature. The percentage of SSIPs increases as temperatures decrease in DMK electrolytes, which is totally different from the carbonate-based electrolytes but greatly beneficial to low-temperature ionic conductivity. With the appropriate addition of VC and FEC, DMK-based electrolytes still exhibit a superhigh ionic conductivity. Even at -40 °C, the ionic conductivity is greater than 10 mS/cm. With DMK-based electrolytes, LIBs with thick LiFePO4 electrodes can be cycled at high rates and at low temperatures.

Pharmacokinetics of Ziyuglycoside I and Ziyuglycoside II in Rat Plasma by UPLC-MS/MS.

Ziyuglycoside I and ziyuglycoside II are important active components of Sanguisorba officinalis L., which have excellent pharmacological effects, such as antioxidant and anticancer effects. However, the bioavailability of ziyuglycoside I and ziyuglycoside II has not been reported. This work aims to establish a UPLC-MS/MS method to study the pharmacokinetics of ziyuglycoside I and ziyuglycoside II in rats under different administration routes (intragastric and intravenous administration) and to calculate the bioavailability. The concentration of ziyuglycoside I and ziyuglycoside II in rat plasma in the range of 2-2000 ng/mL showed a good linear relationship (r > 0.99). The intra-day accuracies of ziyuglycoside I and ziyuglycoside II ranged from 87% to 110%, and the inter-day accuracies ranged from 97% to 109%. The intra-day precision was less than 15% and the inter-day precision was less than 14%. The matrix effects ranged from 88% to 113%. The recoveries were all above 84%. The developed UPLC-MS/MS method for the determination of ziyuglycoside I and ziyuglycoside II in rat plasma was applied to pharmacokinetics. The bioavailability of ziyuglycoside I and ziyuglycoside II was measured at 2.6% and 4.6%, respectively.

Effect of Potentilla anserina L. powder on gel properties and volatile flavor characteristics of silver carp surimi.

BACKGROUND: Potentilla anserina L. is rich in various nutrients, active ingredients and unique flavor, comprising a natural nutrition and health food. However, its application in aquatic food has been rarely reported. Therefore, the effects of Potentilla anserina L. powder (PAP) on gel properties and volatile flavor profile of silver carp surimi were investigated. RESULTS: The gel strength and water-holding capacity of the surimi gels were significantly improved (P < 0.05), and the whiteness and cooking loss of all the samples decreased slightly with the increase in PAP content. The addition of PAP shortened the relaxation time (T2 ) of the surimi gels and converted some of the free water into immobile or bound water, which resulted in a better immobilization of water in the surimi. Scanning electron microscopy images demonstrated that the network of surimi gels with PAP added was denser and had a smoother surface compared to the control. Volatile components (VCs) analysis showed that 33 VCs were identified in the surimi gel samples with different additions of PAP, among which aldehydes, alcohols and esters were the major VCs, accounting for more than 50% of the VCs in the surimi gels. PAP addition reduced the fishy and rancid flavor compounds in surimi gels, such as 1-propanol, 1-octen-3-ol, etc., and promoted the production of aldehydes, alcohols, esters and other flavor substances. CONCLUSION: These results of the present study provide theoretical support for the investigation and development of new nutrient-health-flavored surimi products. © 2024 Society of Chemical Industry.

Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation.

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

Carbon dots and covalent organic frameworks based FRET immunosensor for sensitive detection of Escherichia coli O157:H7.

The combination of carbon dots (CDs) with covalent organic frameworks (COFs) was used to design an innovative sensor based on fluorescence resonance energy transfer (FRET) for the detection of Escherichia coli O157:H7 (E. coli O157:H7) in food samples. Carbon dots were used as fluorescence donors, covalent organic frameworks as fluorescence acceptors. The antibody (Ab) specific to E. coli O157:H7 was used to form a CD-Ab-COF immunosensor by linking CDs and COFs. The antibody was specifically bound with E. coli O157:H7, which caused the connection between CDs and COFs to be interrupted, and the carbon dots exhibited fluorescence restoration. The sensor exhibited a linear detection range spanning from 0 to 106 CFU/mL, with the limit of detection (LOD) of 7 CFU/mL. The analytical performance of the developed immunosensor was evaluated using spiked food samples with different concentrations of E. coli O157:H7, validating the capability of assessing risks in food testing.

Pursuing Impactful Quantitative Proteomics Using QC-Channels in Every Spectrum and Trend-Design in Experiment.

False changes discovered by quantitative proteomics reduce the trust of biologists in proteomics and limit the applications of proteomics to unlock biological mechanisms, which suppresses the application of proteomics techniques in the pharmaceutical industry more than it does in academic research. To remove false changes that arise during LC-MS/MS data acquisition, we evaluated the contributions of peptide abundance and number of unique peptides on reproducibility. Lower abundance and only one unique peptide have a higher risk of generating a higher coefficient of variation (CV), resulting in less accurate quantification. However, the abundance of peptides in samples is not adjustable and discarding proteins quantified by only one unique peptide is not a choice either. Indeed, a large percentage of proteins are accurately quantified by only one unique peptide. Therefore, to improve the calculations of the CV, we leverage a new function in PEAKS called QC-channels which enables technical replicates of each spectrum to be evaluated prior to calculation of the CV. While the QC-channels function in PEAKS significantly reduced the false quantification, random false changes still exist due to known or unknown reasons. To address this challenge, we present the idea of Trend-design to track trend changes rather than changes from two points to remove false quantifications and reveal consequential changes responding to a treatment or condition. The idea was confirmed by molecules with different affinity and dose in the current study. The combination of QC-channels and Trend-design enables a more impactful quantitative proteomics to allow unlocking biological mechanisms using proteomics.

HIV coinfection exacerbates HBV-induced liver fibrogenesis through a HIF-1α- and TGF-ß1-dependent pathway.

BACKGROUND & AIMS: Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-ß1 signaling. METHODS: The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice. RESULTS: We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-ß1 (TGF-ß1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-ß1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-ß1-induced fibrogenesis. CONCLUSIONS: Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-ß1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection. IMPACT AND IMPLICATIONS: HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-ß1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.

Whole-transcriptome sequencing reveals a melanin-related ceRNA regulatory network in the breast muscle of Xichuan black-bone chicken.

The economic losses incurred due to reduced muscle pigmentation highlight the crucial role of melanin-based coloration in the meat of black-bone chickens. Melanogenesis in the breast muscle of black-bone chickens is currently poorly understood in terms of molecular mechanisms. This study employed whole-transcriptome sequencing to analyze black and white breast muscle samples from black-bone chickens, leading to the identification of 367 differentially expressed (DE) mRNAs, 48 DElncRNAs, 104 DEcircRNAs, and 112 DEmiRNAs involved in melanin deposition. Based on these findings, a competitive endogenous RNA (ceRNA) network was developed to better understand the complex mechanisms of melanin deposition. Furthermore, our analysis revealed key DEmRNAs (TYR, DCT, EDNRB, MLPH and OCA2) regulated by DEmiRNAs (gga-miR-140-5p, gga-miR-1682, gga-miR-3529, gga-miR-499-3p, novel-m0012-3p, gga-miR-200b-5p, gga-miR-203a, gga-miR-6651-5p, gga-miR-7455-3p, gga-miR-31-5p, miR-140-x, miR-455-x, novel-m0065-3p, gga-miR-29b-1-5p, miR-455-y, novel-m0085-3p, and gga-miR-196-1-3p). These DEmiRNAs competitively interacted with DElncRNAs including MSTRG.2609.2, MSTRG.4185.1, LOC112530666, LOC112533366, LOC771030, LOC107054724, LOC121107411, LOC100859072, LOC101750037, LOC121108550, LOC121109224, LOC121110876, and LOC101749016, as well as DEcircRNAs, such as novel_circ_000158, novel_circ_000623, novel_001518, and novel_circ_003596. The findings from this study provide insight into the mechanisms that regulate lncRNA, circRNA, miRNA, and mRNA expression in chicken melanin deposition.

Three-Step Depletion Strategy of Glutathione: Tunable Metal-Organic-Framework-Engineered Nanozymes for Driving Oxidative/Nitrative Stress to Maximize Ferroptosis Therapy.

Ferroptosis is a novel type of nonapoptotic programmed cell death involving the accumulation of lipid peroxidation (LPO) to a lethal threshold. Herein, we propose tunable zeolitic imidazolate framework (ZIFs)-engineered biodegradable nanozymes for ferroptosis mediated by both reactive oxygen species (ROS) and nitrogen species (RNS). l-Arginine is utilized as an exogenous nitric oxide donor and loaded into hollow ZIFs@MnO2 artificial nanozymes, which are formed by etching ZIFs with potassium permanganate and simultaneously generating a MnO2 shell in situ. The constructed nanozymes with multienzyme-like activities including peroxidase, oxidase, and catalase can release satisfactory ROS and RNS through a cascade reaction, consequently promoting the accumulation of LPO. Furthermore, it can improve the efficiency of ferroptosis through a three-step strategy of glutathione (GSH) depletion; that is, the outer MnO2 layer consumes GSH under slightly acidic conditions and RNS downregulates SLC7A11 and glutathione reductase, thus directly inhibiting GSH biosynthesis and indirectly preventing GSH regeneration.

Amphiphilic Janus nanoparticles for nitric oxide synergistic photodynamic eradication of MRSA biofilms.

Biofilms pose significant threats to public health by causing persistent clinical infections. The development of innovative antibacterial approaches for eliminating biofilms is an urgent necessity. In this study, we developed amphiphilic Janus nanoparticles (JNPs), loaded with hydrophobic chlorin e6 (Ce6) and hydrophilic S-nitrosoglutathione (GSNO), denoted as Ce6-PDA/CaP-GSNO, with the aim to effectively eradicate biofilms and combat methicillin-resistant Staphylococcus aureus (MRSA) infections through nitric oxide (NO) synergistic photodynamic therapy (PDT). Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration ability, efficiently reaching the acidic inner layers, which triggered the rapid release of GSNO, resulting in the generation of an abundant supply of NO. NO not only exhibited potent bactericidal activity but also effectively lowered the GSH level of the biofilm, leading to enhanced efficacy of Ce6. Additionally, the interaction between NO and reactive oxygen species (ROS) resulted in the generation of reactive nitrogen species (RNS), further enhancing PDT efficacy both in vitro and in vivo. In summary, Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration capacity and effective reduction of the GSH level in the biofilms, leading to enhanced PDT efficacy at low photosensitizer doses and laser intensities, thereby minimizing adverse effects on normal tissues. These findings highlight the promising potential of our approach for combating biofilm-related infections.

PKCiota Inhibits the Ferroptosis of Esophageal Cancer Cells via Suppressing USP14-Mediated Autophagic Degradation of GPX4.

Esophageal squamous cell carcinoma (ESCC) is one of the most frequent malignant tumors, and the mechanisms underlying the anti-ferroptosis of esophageal cancer cells are still largely unclear. This study aims to explore the roles of amplified protein kinase C iota (PKCiota) in the ferroptosis of ESCC cells. Cell viability, colony formation, MDA assay, Western blotting, co-IP, PLA, and RNA-seq technologies are used to reveal the roles and mechanisms underlying the PKCiota-induced resistance of ESCC cells to ferroptosis. We showed here that PKCiota was amplified and overexpressed in ESCC and decreased during RSL3-induced ferroptosis of ESCC cells. PKCiota interacted with GPX4 and the deubiquitinase USP14 and improved the protein stability of GPX4 by suppressing the USP14-mediated autophagy-lysosomal degradation pathway. PKCiota was negatively regulated by miR-145-5p, which decreased in esophageal cancer, and also regulated by USP14 and GPX4 by a positive feedback loop. PKCiota silencing and miR-145-5p overexpression suppressed tumor growth of ESCC cells in vivo, respectively; even a combination of silencing PKCiota and RSL3 treatment showed more vital suppressive roles on tumor growth than silencing PKCiota alone. Both PKCiota silencing and miR-145-5p overexpression sensitized ESCC cells to RSL3-induced ferroptosis. These results unveiled that amplified and overexpressed PKCiota induced the resistance of ESCC cells to ferroptosis by suppressing the USP14-mediated autophagic degradation of GPX4. Patients with PKCiota/USP14/GPX4 pathway activation might be sensitive to GPX4-targeted ferroptosis-based therapy.

An update of predictive biomarkers related to WEE1 inhibition in cancer therapy.

PURPOSE: WEE1 is a crucial kinase involved in the regulation of G2/M checkpoint within the cell cycle. This article aims to comprehensively review the existing knowledge on the implication of WEE1 as a therapeutic target in tumor progression and drug resistance. Furthermore, we summarize the current predictive biomarkers employed to treat cancer with WEE1 inhibitors. METHODS: A systematic review of the literature was conducted to analyze the association between WEE1 inhibition and cancer progression, including tumor advancement and drug resistance. Special attention was paid to the identification and utilization of predictive biomarkers related to therapeutic response to WEE1 inhibitors. RESULTS: The review highlights the intricate involvement of WEE1 in tumor progression and drug resistance. It synthesizes the current knowledge on predictive biomarkers employed in WEE1 inhibitor treatments, offering insights into their prognostic significance. Notably, the article elucidates the potential for precision medicine by understanding these biomarkers in the context of tumor treatment outcomes. CONCLUSION: WEE1 plays a pivotal role in tumor progression and is a promising therapeutic target. Distinguishing patients that would benefit from WEE1 inhibition will be a major direction of future research.

Impacts of UV radiation on Bacillus biocontrol agents and their resistance mechanisms.

Bacillus biocontrol agent(s) BCA(s) such as Bacillus cereus, Bacillus thuringiensis and Bacillus subtilis have been widely applied to control insects' pests of plants and pathogenic microbes, improve plant growth, and facilitate their resistance to environmental stresses. In the last decade, researchers have shown that, the application of Bacillus biocontrol agent(s) BCA(s) optimized agricultural production yield, and reduced disease risks in some crops. However, these bacteria encountered various abiotic stresses, among which ultraviolet (UV) radiation severely decrease their efficiency. Researchers have identified several strategies by which Bacillus biocontrol agents resist the negative effects of UV radiation, including transcriptional response, UV mutagenesis, biochemical and artificial means (addition of protective agents). These strategies are governed by distinct pathways, triggered by UV radiation. Herein, the impact of UV radiation on Bacillus biocontrol agent(s) BCA(s) and their mechanisms of resistance were discussed.