Dual-Parasitic Effect Enables Highly Reversible Zn Metal Anode for Ultralong 25,000 Cycles Aqueous Zinc-Ion Batteries.

The use of electrolyte additives is an efficient approach to mitigating undesirable side reactions and dendrites. However, the existing electrolyte additives do not effectively regulate both the chaotic diffusion of Zn2+ and the decomposition of H2O simultaneously. Herein, a dual-parasitic method is introduced to address the aforementioned issues by incorporating 1-ethyl-3-methylimidazolium trifluoromethanesulfonate ([EMIm]OTf) as cosolvent into the Zn(OTf)2 electrolyte. Specifically, the OTf- anion is parasitic in the solvent sheath of Zn2+ to decrease the number of active H2O. Additionally, the EMIm+ cation can construct an electrostatic shield layer and a hybrid organic/inorganic solid electrolyte interface layer to optimize the deposition behavior of Zn2+. This results in a Zn anode with a reversible cycle life of 3000 h, the longest cycle life of full cells (25,000 cycles), and an extremely high initial capacity (4.5 mA h cm-2), providing a promising electrolyte solution for practical applications of rechargeable aqueous zinc-ion batteries.

Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways.

This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe2+, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.

Advancements and Prospects of Genome-Wide Association Studies (GWAS) in Maize.

Genome-wide association studies (GWAS) have emerged as a powerful tool for unraveling intricate genotype-phenotype association across various species. Maize (Zea mays L.), renowned for its extensive genetic diversity and rapid linkage disequilibrium (LD), stands as an exemplary candidate for GWAS. In maize, GWAS has made significant advancements by pinpointing numerous genetic loci and potential genes associated with complex traits, including responses to both abiotic and biotic stress. These discoveries hold the promise of enhancing adaptability and yield through effective breeding strategies. Nevertheless, the impact of environmental stress on crop growth and yield is evident in various agronomic traits. Therefore, understanding the complex genetic basis of these traits becomes paramount. This review delves into current and future prospectives aimed at yield, quality, and environmental stress resilience in maize and also addresses the challenges encountered during genomic selection and molecular breeding, all facilitated by the utilization of GWAS. Furthermore, the integration of omics, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, and phenomics has enriched our understanding of intricate traits in maize, thereby enhancing environmental stress tolerance and boosting maize production. Collectively, these insights not only advance our understanding of the genetic mechanism regulating complex traits but also propel the utilization of marker-assisted selection in maize molecular breeding programs, where GWAS plays a pivotal role. Therefore, GWAS provides robust support for delving into the genetic mechanism underlying complex traits in maize and enhancing breeding strategies.

Computational analysis of 5-fluorouracil anti-tumor activity in colon cancer using a mechanistic pharmacokinetic/pharmacodynamic model.

5-Fluorouracil (5-FU) is a standard chemotherapeutic agent to treat solid cancers such as breast, colon, head, and neck. Computational modeling plays an essential role in predicting the outcome of chemotherapy and developing optimal dosing strategies. We developed an integrated mechanistic pharmacokinetics/pharmacodynamics (PK/PD) model examining the influence of 5-FU, as an S-phase specific double-strand break (DSB)-inducing agent, on tumor proliferation. The proposed mechanistic PK/PD model simulates the dynamics of critical intermediate components and provides the accurate tumor response prediction. The integrated model is composed of PK, cellular, and tumor growth inhibition (TGI) sub-models, quantitatively capturing the essential drug-related physiological processes. In the cellular model, thymidylate synthase (TS) inhibition, resultant deoxynucleoside triphosphate (dNTP) pool imbalance, and DSB induction are considered, as well as 5-FU incorporation into RNA and DNA. The amount of 5-FU anabolites and DSBs were modeled to drive the kinetics of the pharmacological tumor response. Model parameters were estimated by fitting to literature data. Our simulation results successfully describe the kinetics of the intermediates regulating the 5-FU cytotoxic events and the pattern of tumor suppression. The comprehensive model simulated the tumor volume change under various dose regimens, and its generalizability was attested by comparing it with literature data. The potential causes of the tumor resistance to 5-FU are also investigated through Monte Carlo analysis. The simulation of various dosage regimens helps quantify the relationship between treatment protocols and chemotherapy potency, which will lead to the development of efficacy optimization.

Photodynamic therapy improves the outcome of immune checkpoint inhibitors via remodelling anti-tumour immunity in patients with gastric cancer.

BACKGROUND: Photodynamic therapy (PDT) plays an immunoregulatory role in tumours. Here, we conducted a retrospective patient analysis to evaluate the effectiveness of PDT plus immune checkpoint inhibitors (ICIs) in gastric cancer. Further, we performed a dynamic analysis of gastric cancer patients receiving PDT to clarify its effects on anti-tumour immunity. METHODS: Forty ICI-treated patients that received PDT or not were retrospectively analysed. Five patients with gastric adenocarcinoma were enrolled for sample collection before and after PDT. Single-cell RNA/T cell receptor (TCR) sequencing, flow cytometry and histological exanimation were used to analyse the collected specimens. RESULTS: Patients in PDT group had a significantly better OS after ICI treatment than those in No PDT group. Single-cell analysis identified ten cell types in gastric cancer tissues and four sub-populations of T cells. Immune cell infiltration increased in the tumours after PDT and the circular immune cells showed consistent alterations. TCR analysis revealed a specific clonal expansion after PDT in cytotoxic T lymphocytes (CTL), but a constriction in Tregs. The B2M gene is upregulated in tumour cells after PDT and is associated with immune cell infiltration. Several pathways involving the positive regulation of immunity were enriched in tumour cells in the post-PDT group. The interactions following PDT were increased between tumour cells and effector cells but decreased between Tregs and other immune cells. Some co-stimulatory signaling emerged, whereas co-inhibitory signaling disappeared in intercellular communication after PDT. CONCLUSIONS: PDT elicits an anti-tumour response through various mechanisms and is promising as an adjuvant to enhance ICI benefit.

Mapping of dwarfing QTL of Ari1327, a semi-dwarf mutant of upland cotton.

BACKGROUND: Upland Cotton (Gossypium hirsutum L.) has few cotton varieties suitable for mechanical harvesting. The plant height of the cultivar is one of the key features that need to modify. Hence, this study was planned to locate the QTL for plant height in a 60Co γ treated upland cotton semi-dwarf mutant Ari1327. RESULTS: Interestingly, bulk segregant analysis (BSA) and genotyping by sequencing (GBS) methods exhibited that candidate QTL was co-located in the region of 5.80-9.66 Mb at D01 chromosome in two F2 populations. Using three InDel markers to genotype a population of 1241 individuals confirmed that the offspring's phenotype is consistent with the genotype. Comparative analysis of RNA-seq between the mutant and wild variety exhibited that Gh_D01G0592 was identified as the source of dwarfness from 200 genes. In addition, it was also revealed that the appropriate use of partial separation markers in QTL mapping can escalate linkage information. CONCLUSIONS: Overwhelmingly, the results will provide the basis to reveal the function of candidate genes and the utilization of excellent dwarf genetic resources in the future.

MSCs cell fates in murine acute liver injury and chronic liver fibrosis induced by carbon tetrachloride.

Mesenchymal stem cells (MSCs) therapy has shown potential benefits in multiple diseases. However, their clinic performance is not as satisfactory as expected. This study aimed to provide an alternative explanation by comparing MSCs' fates in different liver diseases. The distribution and therapeutic effects of hMSCs were investigated in acute liver injury (ALI) and chronic liver fibrosis (CLF) mice models, respectively. The two models were induced by single or repeated injection of carbon tetrachloride (CCl4) separately. The increase of hMSCs exposure in the liver (AUCliver 0-72 h) were more significant in ALI than in CLF (177.1% vs. 96.2%). In the ALI model, the hMSCs exposures in the lung (AUClung 0-72 h) increased by nearly 50% while decreased by 60.7% in CLF. The efficacy satellite study indicated that hMSCs could significantly ameliorate liver injury in ALI, but its effects in CLF were limited. In the ALI, suppressed Natural Killer (NK) cell activities were observed, while NK cell activities were increased in CLF. The depletion of NK cells could increase hMSCs exposure in mice. For mice MSC (mMSCs), their cell fates in ALI were very similar to hMSCs in ALI: mMSCs' exposure in the liver and lung increased in ALI. In conclusion, our study revealed the distinct cell pharmacokinetic patterns of MSCs in ALI and CLF mice, which might be at least partially attributed to the different NK cell activities in the two liver diseases. This finding provided a novel insight into the varied MSCs' therapeutic efficacy in the clinic. Significance Statement Currently, there is little knowledge about the PK behavior of cell products like MSCs. This study was the first time investigating the influence of liver diseases on cell fates and efficacies of MSCs and the underneath rationale. The exposure was distinct between two representative liver disease models, which directly linked with the therapeutic performance that MSCs achieved. The difference could be attributed to the NK cells-mediated MSCs clearance.

Radiomics-based prediction of response to immune checkpoint inhibitor treatment for solid cancers using computed tomography: a real-world study of two centers.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent an approved treatment for various cancers; however, only a small proportion of the population is responsive to such treatment. We aimed to develop and validate a plain CT-based tool for predicting the response to ICI treatment among cancer patients. METHODS: Data for patients with solid cancers treated with ICIs at two centers from October 2019 to October 2021 were randomly divided into training and validation sets. Radiomic features were extracted from pretreatment CT images of the tumor of interest. After feature selection, a radiomics signature was constructed based on the least absolute shrinkage and selection operator regression model, and the signature and clinical factors were incorporated into a radiomics nomogram. Model performance was evaluated using the training and validation sets. The Kaplan-Meier method was used to visualize associations with survival. RESULTS: Data for 122 and 30 patients were included in the training and validation sets, respectively. Both the radiomics signature (radscore) and nomogram exhibited good discrimination of response status, with areas under the curve (AUC) of 0.790 and 0.814 for the training set and 0.831 and 0.847 for the validation set, respectively. The calibration evaluation indicated goodness-of-fit for both models, while the decision curves indicated that clinical application was favorable. Both models were associated with the overall survival of patients in the validation set. CONCLUSIONS: We developed a radiomics model for early prediction of the response to ICI treatment. This model may aid in identifying the patients most likely to benefit from immunotherapy.

Define Mesenchymal Stem Cell from Its Fate: Biodisposition of Human Mesenchymal Stem Cells in Normal and Concanavalin A-Induced Liver Injury Mice.

The pharmaceutical industry and clinical trials have been revolutionized mesenchymal stem cell-based therapeutics. However, the pharmacokinetics of transplanted cells has been little characterized in their target tissues under healthy or disease condition. A quantitative polymerase chain reaction analytical method with matrix effect was developed to track the biodistribution of human mesenchymal stem cells in normal mice and those with Concanavalin A (Con A)-induced liver injury. Mesenchymal stem/stromal cell (MSC) disposition in blood and different organs were compared, and relevant pharmacokinetic parameters were calculated. Human MSCs (hMSCs) and mouse MSCs (mMSCs) displayed a very similar pharmacokinetic profile in all tested doses: about 95% of the detected hMSCs accumulated in the lung and 3% in the liver, and almost negligible cells were detected in other tissues. A significant double peak of hMSC concentration emerged in the lung within 1-2 hours after intravenous injection, as with mMSCs. Prazosin, a vasodilator, could eliminate the second peak in the lung and increase its Cmax and area under the concentration-time curve (AUC) by 10% in the first 2 hours. The injury caused by Con A was significantly reduced by hMSCs, and the Cmax and AUC0-8 (AUC from time 0 to 8 hours) of cells in the injured liver decreased by 54 and 50%, respectively. The Cmax and AUC would be improved with the alleviation of congestion through the administration of heparin. The study provides a novel insight into the pharmacokinetics of exogenous MSCs in normal and Con A-induced liver injury mice, which provides a framework for optimizing cell transplantation. SIGNIFICANCE STATEMENT: Mesenchymal stem/stromal cells (MSCs) are known for their potential as regenerative therapies in treating several diseases, but an insufficient understanding of the pharmacokinetics of MSCs restricts their future application. The current study was the first to elucidate the pharmacokinetics and possible factors, including dosage, species, and derived sources, in a systematic way. The study further revealed that Concanavalin A-induced liver injury significantly prevented cells from entering the injury site, which could be reversed by the diminished congestion achieved by heparin.

Genome-wide association and transcriptome analysis of root color-related genes in Gossypium arboreum L.

MAIN CONCLUSION: The significant number loci and candidate genes of root color in Gossypium arboreum are identified and provide a theoretical basis of root color for cotton. A stimulating phenomenon was observed on the 4th day of sowing in the root color of some G. arboreum accessions that turned red. To disclose the genetic mechanisms of root color formation via genome and transcript levels, we identified the significant number of SNPs and candidate genes that are related to root color through genome-wide association study (GWAS) and RNAseq analysis in G. arboreum. Initially, 215 no. of G. arboreum accessions was collected, and the colors of root on the 4th, 6th and 9th day of germination were recorded. The GWAS demonstrated that 225 significant SNPs and 47 candidate genes have been identified totally. The strongest signal SNP A04_91824 could greatly distinguish the root color with most "C" allele accessions have displayed white and "T" allele accessions displayed red. RNAseq was performed on accessions having the white and red root, and results revealed that 12 and 138 DEGs were detected on 2nd and 4th day, respectively. ACD6, UFGT, and LYM2 were the most related genes of root color, later, verified by qRT-PCR. The mature zone of red and the white roots was observed by the histological section method, and results shown that cells were more closely arranged in the white root, and both average cell length and cell width were longer in the red root. This study will be helpful to cotton breeders for utilization of several elite genes and related SNPs related to root color, in addition to find linkage with economically important traits of interests.

A facile method for vancomycin C-terminus functionalization and derivatization through hydrazide.

Over 60-year clinical use of vancomycin led to the emergence of vancomycin-resistant bacteria and threatened our health. To combat vancomycin-resistant strains, numerous vancomycin analogues were developed, such as Telavancin, Oritavancin and Dalbavancin. Extra structures embedded on C-terminus has been proved to be an effective strategy to promote antibacterial activity of vancomycin against vancomycin-resistant strains. Here, we reported a facile strategy, inspired by native chemical ligation, for vancomycin C-terminus functionalization and derivatization. The introduction of C-terminal hydrazide on vancomycin not only provided us an accessible method for C-terminus functionalization through carbonyl azide and thioester, also acted as an efficient site for vancomycin structure modifications. Based on hydrazide-vancomycin, we effectively conjugated cysteine and cysteine containing peptides onto vancomycin C-terminus, and two fluorescent FITC-vancomycin were prepared through Cys-Maleimide conjugation. Meanwhile, we introduced lipophilic structures onto vancomycin C-terminus via the hydrazide moiety. The obtained vancomycin derivatives were evaluated against both Gram-positive and negative bacteria strains.

MicroRNA-146a negatively regulates IL-33 in activated group 2 innate lymphoid cells by inhibiting IRAK1 and TRAF6.

Type II innate lymphoid cells (ILC2) play a very important role in the pathogenesis of allergic asthma. This study aims to investigate whether miR-146a inhibition of asthma is related with interleukin (IL)-33 signaling path way in ILC2 and the underlying mechanisms. Asthma mice model was induced by ovalbumin. miRNA146a mimics was administrated to asthma mice or transfected to activated ILC2 purified from asthma mice lung. RT-PCR was used to detect miRNA146a level in lung tissue and ILC2. IL-5 and IL-13 levels in culture supernatant were detected by flow cytometry. Interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6), signal transducer and activator of transcription 1 (STAT1) protein expression levels were detected by western blot. miR-146a directly inhibited ILC2 function and suppressed ILC2 proliferation both in vivo and in vitro. During stimulation of ILC2, miR-146a expression gradually increased with a decrease of cell proliferation. Modulation of ILC2 function by miR-146a may depend on IL-33/interleukin 1 receptor-like 1 (IL1RL1 or ST2) signaling through inhibiting IRAK1 and TRAF6.miR-146a can inhibit IRAK1 and TRAF6, downstream molecules of ST2 signal pathway, thereby negatively regulate IL-33/ST2-activated ILC2 to inhibit asthma. Targeting miR-146 maybe a novel strategy for the treatment of allergic asthma.

Combination of TLR agonist and miR146a mimics attenuates ovalbumin-induced asthma.

BACKGROUND: microRNA-146a has been reported to be a regulator in the process of attenuating asthma by inhibiting Toll-like receptor 2 (TLR2) pathway. This study aimed to investigate how miR146a-inhibitor affect the symptom of asthma and the underlying mechanisms. METHODS: Ovalbumin (OVA)-induced allergic asthma mice model was established by intraperitoneal injection with 20 µg of OVA. Total cells and differential inflammatory cells in bronchoalveolar lavage fluid were counted by flow cytometry. The expression levels of molecules and cytokines in TLR2 signaling pathway were detected by Q-PCR and ELISA. RESULTS: miR146a-inhibitor attenuated OVA-induced allergic asthma by increasing Th1 cytokines in OVA-induced allergic asthma model, and the treatment of miR146a-inhibitor can reduce the inflammation caused by asthma, followed by the down-regulation of IL-5 and IL-13 in sorted ILC2. The inhibition of miR-146a significantly reduced symptoms of asthma model with TLR2-related molecules being up-regulated. CONCLUSION: It was found that miR-146a is an important regulator in OVA-induced allergic asthma model, which can relieve symptoms of asthma through regulating TLR2 pathway. These findings provide a theoretical basis for solving asthma in clinical treatment.

Intestinal Transporter-Associated Drug Absorption and Toxicity.

Oral drug administration is the most favorable route of drug administration in the clinic. Intestinal transporters have been shown to play a significant role in the rate and extent of drug absorption of some, but not all, drug molecules. Due to the heterogeneous expression of multiple transporters along the intestine, the preferential absorption sites for drugs may vary significantly. In this chapter, we aim to summarize the current research on the expression, localization, function, and regulation of human intestinal transporters implicated in altering the absorption of low to medium molecular weight drug molecules. The role played by bile acid transport proteins (e.g., ASBT and OST-α/ß) is included in the discussion. The synergistic action of intestinal drug metabolism and transport is also discussed. Despite the complicated regulatory factors, the biopharmaceutics drug disposition classification system (BDDCS) put forward by Wu and Benet may help us better predict the effect of transporters on drug absorption. The drug-induced toxicity in the intestine, which may result from drug-drug interaction, gut microbiota, and bile salt toxicity, is also discussed.

miR-146a Mimics Attenuate Allergic Airway Inflammation by Impacted Group 2 Innate Lymphoid Cells in an Ovalbumin-Induced Asthma Mouse Model.

BACKGROUND: The prevalence of allergic asthma has increased dramatically. Previous studies have found that the microRNA 146a (miR-146a) expression in asthma inhibits cell proliferation and promotes apoptosis of bronchial smooth muscle cells. We aimed to investigate the effect of miR-146a mimics on ovalbumin (OVA)-induced asthma in a mouse model. METHODS: Inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) was measured by flow cytometry. Levels of OVA-specific immunoglobulin E (IgE) in serum and cytokines in BALF were examined by enzyme-linked immunosorbent assay. For monitoring the airway, the Penh value (% baseline) was measured using a whole-body plethysmograph. RESULTS: In OVA-induced asthmatic mice, miR-146a significantly suppressed the infiltration of inflammatory cells in BALF and decreased the levels of OVA-specific IgE and T helper 2 cell type cytokines. In addition, miR-146a inhibited the OVA-induced airway hyperresponsiveness and the group 2 innate lymphoid cell responses. Moreover, the effects of miR-146a mimics were dependent on interleukin 33 stimulation. CONCLUSIONS: Our results suggest that miR-146a mimics might serve as an attractive candidate for further preclinical studies as an anti-inflammatory treatment of asthma.

The role of TWIST1 in epithelial-mesenchymal transition and cancers.

TWIST1 is a basic helix-loop-helix (bHLH) transcription factor which plays essential and pivotal roles in multiple stages of embryonic development, and significantly contributes to tumor metastasis, even tumor initiation and primary tumor growth. It is well recognized that TWIST1 is overexpressed in a variety of tumors. Overexpression of TWIST1 induces epithelial-mesenchymal transition (EMT), a key process in the metastases formation of cancer. TWIST1 also promotes the formation of cancer stem cells and facilitates the process of tumorigenesis. Numerous studies have shown that targeting TWIST1 or TWIST1-related molecules significantly inhibits tumor growth, restricts tumor metastasis, reverses drug resistance, and thus improves the survival of cancer patients. Therefore, it is important to provide a better understanding of the context-dependent regulation of TWIST1 in each individual epithelial tumor, which might reveal new therapeutic targets in cancer treatment.

The growth arrest-specific transcript 5 (GAS5): a pivotal tumor suppressor long noncoding RNA in human cancers.

Long noncoding RNAs (lncRNAs), which refer to a group of RNAs with length more than 200 nucleotides and limited protein-coding potential, play a widespread role in regulating biological processes, such as cell differentiation, proliferation, apoptosis, and migration. LncRNAs are dysregulated in multiple cancers, playing an either oncogenic or tumor-suppressive role. LncRNA GAS5 is a recently identified tumor suppressor involved in several cancers, like breast cancer, prostate cancer, lung cancer, and colorectal cancer. The low-expression pattern confers tumor cells elevated capacity of proliferation and predicts poorer prognosis. Existing studies mirror that lncRNA GAS5 promises to be a novel diagnostic biomarker, therapy target, as well as prognostic biomarker. In this review, we will summarize the current knowledge about this vital lncRNA, from its discovery, characteristics, and biological function to molecular mechanism in various neoplasms.

Chloroquine inhibits tumor growth and angiogenesis in malignant pleural effusion.

Malignant pleural effusion (MPE) is associated with a poor prognosis in lung cancer. Currently, no effective cure exists for MPE. Chloroquine (CQ) has been demonstrated to induce vascular normalization and inhibit tumor growth. The aim of this study was to assess whether CQ affects MPE. The xenografts mice were divided into normal saline (NS), CQ, or bevacizumab (BE) group. Tumor growth and microvascular density (MVD) were monitored. We explored the effect of CQ on the proliferation, survival, and proangiogenic signaling of tumor cells in vitro. We further evaluated the effects of CQ on the viability, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). A chicken chorioallantoic membrane (CAM) model was used to elucidate the effects of CQ on angiogenesis. Finally, an MPE mouse model were treated by CQ, BE, or NS. The volume of pleural effusion, tumor foci, and MVD was evaluated. CQ therapy group exhibited decreased tumor volume, tumor weight, and MVD in the mouse xenografts. CQ inhibited the proliferation of the tumor cells. However, the expression of vascular endothelial growth factor was not affected. Additionally, CQ inhibited the proliferation, migration, and tube formation of HUVECs and also restrained angiogenesis in the CAM. Western blot showed that CQ might suppress angiogenesis by downregulating p-Akt, Jagged1, and Ang2 in HUVECs. In MPE mice, the volume of the pleural effusion, the number of pleural tumor foci, and the MVD were significantly reduced in the CQ group. Our work demonstrated that CQ played the role of an efficient treatment for MPE.

AhR-STAT3-HO-1/COX-2 signalling pathway may restrict ferroptosis and improve hMSC accumulation and efficacy in mouse liver.

BACKGROUND AND PURPOSE: The low efficacy of mesenchymal stem cells (MSCs) has restricted their application in the treatment of liver disease. Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate damage to the liver microenvironment. Here, we have investigated the contribution of liver ferroptosis to the elimination and effectiveness of human MSC (hMSC). Furthermore, potential links between liver ferroptosis and aryl hydrocarbon receptors (AhR) were explored. EXPERIMENTAL APPROACH: Two mouse models, iron supplement-induced hepatic ferroptosis and hepatic ischaemia/reperfusion (I/R) injury, were used to identify effects of ferroptosis on hMSC pharmacokinetics (PK)/pharmacodynamics (PD). KEY RESULTS: AhR inhibition attenuated hepatic ferroptosis and improved survival of hMSCs. hMSC viability was decreased by iron supplementation or serum from I/R mice. The AhR antagonist CH223191 reversed iron overload and oxidative stress induced by ferroptosis and increased hMSC concentration and efficacy in mouse models. Effects of CH223191 were greater than those of deferoxamine, a conventional ferroptosis inhibitor. Transcriptomic results suggested that the AhR-signal transducer and activator of transcription 3 (STAT3)-haem oxygenase 1/COX-2 signalling pathway is critical to this process. These results were confirmed in a mouse model of hepatic I/R injury. In mice pre-treated with CH223191, hMSC exhibited more potent protective effects, linked to decreased hepatic ferroptosis. CONCLUSION AND IMPLICATIONS: Our findings showed that ferroptosis was a critical factor in determining the fate of hMSCs. Inhibition of AhR decreased hepatic ferroptosis, thereby increasing survival and therapeutic effects of hMSCs in mouse models of liver disease.

The "Heater" of "Cold" Tumors-Blocking IL-6.

The resolution of inflammation is not simply the end of the inflammatory response but rather a complex process that involves various cells, inflammatory factors, and specialized proresolving mediators following the occurrence of inflammation. Once inflammation cannot be cleared by the body, malignant tumors may be induced. Among them, IL-6, as an immunosuppressive factor, activates a variety of signal transduction pathways and induces tumorigenesis. Monitoring IL-6 can be used for the diagnosis, efficacy evaluation and prognosis of tumor patients. In terms of treatment, improving the efficacy of targeted and immunotherapy remains a major challenge. Blocking IL-6 and its mediated signaling pathways can regulate the tumor immune microenvironment and enhance immunotherapy responses by activating immune cells. Even transform "cold" tumors that are difficult to respond to immunotherapy into immunogenic "hot" tumors, acting as a "heater" for "cold" tumors, restarting the tumor immune cycle, and reducing immunotherapy-related toxic reactions and drug resistance. In clinical practice, the combined application of IL-6 inhibition with targeted therapy and immunotherapy may produce synergistic results. Nevertheless, additional clinical trials are imperative to further validate the safety and efficacy of this therapeutic approach.