A new fossil species of Meliolinites Selkirk associated with Rhodoleia leaves from the Upper Pliocene of southwestern China.

Fossil epifoliar fungi are valuable indicators of paleoenvironment and paleoecology. The Meliolaceae, members of which typically inhabit the surface of living plants as biotrophs or pathogens, is one of the largest groups of epifoliar fungi. In this study, we report a novel fossil species of Meliolinites Selkirk (fossil Meliolaceae), Meliolinites tengchongensis, on the lower epidermis of compressed fossil Rhodoleia (Hamamelidaceae) leaves from the Upper Pliocene Mangbang Formation of Tengchong, Yunnan, southwestern China. Meliolinites tengchongensis is characterized by web-like, superficial, brown to dark brown, septate, and branching mycelia bearing 2-celled appressoria and unicellular phialides. The fungal colonies also include ellipsoidal, 5-celled, 4-septate ascospores and dark brown perithecia with suborbicular outline and verrucose surface. The well-preserved vegetative and reproductive organs help us to explore the potential disease process of the new fossil species. Besides, the presence of fungal remains indicates that the fungal taxon might have maintained its host preference since at least the Late Pliocene. Furthermore, the occurrence of both fossil fungi and their host plants in Tengchong indicate a subtropical-tropical, warm, and humid climate during the Late Pliocene, whereas the distribution pattern of the fungi on the host leaves suggests that Rhodoleia may have been a part of the middle-upper canopies in the Tengchong Late Pliocene multilayered forest.

Insulin-related traits and prostate cancer: A Mendelian randomization study.

Investigating the causal relationship between insulin secretion and prostate cancer (PCa) development is challenging due to the multifactorial nature of PCa, which complicates the isolation of the specific impact of insulin-related factors. We conducted a Mendelian randomization (MR) study to investigate the associations between insulin secretion-related traits and PCa. We used 36, 60, 56, 23, 48, and 49 single nucleotide polymorphisms (SNPs) as instrumental variables for fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals, individuals with diabetes, and individuals receiving exogenous insulin, respectively. These SNPs were selected from various genome-wide association studies. To clarify the causal relationship between insulin-related traits and PCa, we utilized a multivariable MR analysis to adjust for obesity and body fat percentage. Additionally, two-step Mendelian randomization was conducted to assess the role of insulin-like growth factor 1 (IGF-1) in the relationship between proinsulin and PCa. Two-sample MR analysis revealed strong associations between genetically predicted fasting insulin, insulin sensitivity, proinsulin, and proinsulin in nondiabetic individuals and the development of PCa. After adjustment for obesity and body fat percentage using multivariable MR analysis, proinsulin remained significantly associated with PCa, whereas other factors were not. Furthermore, two-step MR analysis demonstrated that proinsulin acts as a negative factor in prostate carcinogenesis, largely independent of IGF-1. This study provides evidence suggesting that proinsulin may act as a negative factor contributing to the development of PCa. Novel therapies targeting proinsulin may have potential benefits for PCa patients, potentially reducing the need for unnecessary surgical treatments.

FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC.

Older livers are more prone to hepatic ischaemia/reperfusion injury (HIRI), which severely limits their utilization in liver transplantation. The potential mechanism remains unclear. Here, we demonstrate older livers exhibit increased ferroptosis during HIRI. Inhibiting ferroptosis significantly attenuates older HIRI phenotypes. Mass spectrometry reveals that fat mass and obesity-associated gene (FTO) expression is downregulated in older livers, especially during HIRI. Overexpressing FTO improves older HIRI phenotypes by inhibiting ferroptosis. Mechanistically, acyl-CoA synthetase long chain family 4 (ACSL4) and transferrin receptor protein 1 (TFRC), two key positive contributors to ferroptosis, are FTO targets. For ameliorative effect, FTO requires the inhibition of Acsl4 and Tfrc mRNA stability in a m6A-dependent manner. Furthermore, we demonstrate nicotinamide mononucleotide can upregulate FTO demethylase activity, suppressing ferroptosis and decreasing older HIRI. Collectively, these findings reveal an FTO-ACSL4/TFRC regulatory pathway that contributes to the pathogenesis of older HIRI, providing insight into the clinical translation of strategies related to the demethylase activity of FTO to improve graft function after older donor liver transplantation.

Cross-species metabolomic profiling reveals phosphocholine-mediated liver protection from cold and ischemia/reperfusion.

Cold and ischemia/reperfusion (IR)-associated injuries are seemingly inevitable during liver transplantation and hepatectomy. As Syrian hamsters demonstrate intrinsic tolerance to transplantation-like stimuli, cross-species comparative metabolomic analyses were conducted with hamster, rat and donor liver samples to seek hepatic cold and IR-adaptive mechanisms. Lower hepatic phosphocholine contents were found in early graft-dysfunctioned recipients with virus-caused cirrhosis or high MELD scores (≥30). Choline/phosphocholine deficiency in cultured human THLE-2 hepatocytes and animal models weakened hepatocellular cold tolerance and recovery of glutathione and ATP production, which was rescued by phosphocholine supplements. Among the biological processes impacted by choline/phosphocholine deficiency, three lipid-related metabolic processes were downregulated, whilst phosphocholine elevated the expression of genes in methylation processes. Consistently, in THLE-2, phosphocholine enhanced the overall RNA m6A methylation, among which the transcript stability of Fatty acid desaturase 6 (FADS6) was improved. FADS6 functioned as a key phosphocholine effector in the production of polyunsaturated fatty acids, which may facilitate the hepatocellular recovery of energy and redox homeostasis. Thus, our study reveals the choline-phosphocholine metabolism and its downstream FADS6 functions in hepatic adaptation to cold and IR, which may inspire new strategies to monitor donor liver quality and improve recipient recovery from the LT process.

GDSL Lipase Gene HTA1 Negatively Regulates Heat Tolerance in Rice Seedlings by Regulating Reactive Oxygen Species Accumulation.

High temperature is a significant environmental stress that limits plant growth and agricultural productivity. GDSL lipase is a hydrolytic enzyme with a conserved GDSL sequence at the N-terminus, which has various biological functions, such as participating in plant growth, development, lipid metabolism, and stress resistance. However, little is known about the function of the GDSL lipase gene in the heat tolerance of rice. Here, we characterized a lipase family protein coding gene HTA1, which was significantly induced by high temperature in rice. Rice seedlings in which the mutant hta1 was knocked out showed enhanced heat tolerance, whereas the overexpressing HTA1 showed more sensitivity to heat stress. Under heat stress, hta1 could reduce plant membrane damage and reactive oxygen species (ROS) levels and elevate the activity of antioxidant enzymes. Moreover, real-time quantitative PCR (RT-qPCR) analysis showed that mutant hta1 significantly activated gene expression in antioxidant enzymes, heat response, and defense. In conclusion, our results suggest that HTA1 negatively regulates heat stress tolerance by modulating the ROS accumulation and the expression of heat-responsive and defense-related genes in rice seedlings. This research will provide a valuable resource for utilizing HTA1 to improve crop heat tolerance.

Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage.

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Transcriptomic Profiling of Two Rice Thermo-Sensitive Genic Male Sterile Lines with Contrasting Seed Storability after Artificial Accelerated Aging Treatment.

Seed storability has a significant impact on seed vitality and is a crucial genetic factor in maintaining seed value during storage. In this study, RNA sequencing was used to analyze the seed transcriptomes of two rice thermo-sensitive genic male sterile (TGMS) lines, S1146S (storage-tolerant) and SD26S (storage-susceptible), with 0 and 7 days of artificial accelerated aging treatment. In total, 2658 and 1523 differentially expressed genes (DEGs) were identified in S1146S and SD26S, respectively. Among these DEGs, 729 (G1) exhibited similar regulation patterns in both lines, while 1924 DEGs (G2) were specific to S1146S, 789 DEGs (G3) were specific to SD26S, and 5 DEGs (G4) were specific to contrary differential expression levels. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that "translation", "ribosome", "oxidative phosphorylation", "ATP-dependent activity", "intracellular protein transport", and "regulation of DNA-templated transcription" were significantly enriched during seed aging. Several genes, like Os01g0971400, Os01g0937200, Os03g0276500, Os05g0328632, and Os07g0214300, associated with seed storability were identified in G4. Core genes Os03g0100100 (OsPMEI12), Os03g0320900 (V2), Os02g0494000, Os02g0152800, and Os03g0710500 (OsBiP2) were identified in protein-protein interaction (PPI) networks. Seed vitality genes, MKKK62 (Os01g0699600), OsFbx352 (Os10g0127900), FSE6 (Os05g0540000), and RAmy3E (Os08g0473600), related to seed storability were identified. Overall, these results provide novel perspectives for studying the molecular response and related genes of different-storability rice TGMS lines under artificial aging conditions. They also provide new ideas for studying the storability of hybrid rice.

Stratifin promotes the malignant progression of HCC via binding and hyperactivating AKT signaling.

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with limited treatment options and poor prognosis. In this study, we reveal the pivotal role of Stratifin (SFN), also recognized as 14-3-3σ, in driving HCC progression. Our investigation underscores a substantial upregulation of SFN within HCC tissues, manifesting a significant association with worse prognostic outcomes among HCC patients. In vitro and in vivo experiments reveal that SFN overexpression significantly amplifies proliferation, mitigates sorafenib-induced effects on HCC cells, and enhances tumorigenesis. While SFN silencing exerts converse effects on HCC progression. Additionally, we unveil a critical interaction between SFN and AKT, where SFN boosts AKT kinase activity by disrupting the binding of PHLPP2 and AKT, thereby intensifying the malignant progression of HCC cells. In conclusion, this study identifies the oncogenic role of SFN and elucidates the regulatory mechanism of the SFN/AKT axis in HCC, which may provide valuable insights into the mechanisms of HCC progression and potential targets for therapeutic intervention.

Untargeted metabolomic analysis of the metabolites in roots of Pugionium cornutum seedlings under drought stress.

Pugionium cornutum is an annual or biennial xerophyte distributed in arid regions, with drought resistance properties. While previous studies have predominantly focused on the physiological changes of P. cornutum , the understanding of its metabolite variations remains limited. In this study, untargeted metabolomic technology was performed to analyse the change of metabolites in the roots of P. cornutum seedlings under drought stress. Our findings revealed that compared to the R1, the root water potential and the number of lateral roots increased, while the length of the tap root and fresh weight increased first and then decreased. In the R1-R2, a total of 45 differential metabolites (DMs) were identified, whereas in the R1-R3 82 DMs were observed. Subsequently, KEGG analysis revealed a significant enrichment of microbial metabolism in diverse environments and aminobenzoate degradation in the R1-R2, and phenylpropanoid biosynthesis, ubiquinone, and other terpenoid-quinone biosynthesis and isoquinoline alkaloid biosynthesis were significantly enriched in the R1-R3. The upregulation DMs, including L-arginosuccinate, L-tyrosine, p-coumarate, caffeate, ferulate, vanillin, coniferin, 5-aminopentanoate, 2-methylmaleate and 2-furoate in P. cornutum seedlings may play a crucial role in enhancing root growth and improving drought resistance. These findings provide a basis for future investigations into the underlying mechanisms of drought resistance in P. cornutum .

Values of prognostic nutritional index for predicting Kawasaki disease: a systematic review and meta-analysis.

Objective: This systematic review and meta-analysis aimed to evaluate the relationship between the prognostic nutritional index (PNI) and intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Kawasaki disease (KD). Methods: The relevant literature was searched on PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar up to August 5, 2023. A pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) were calculated to assess the predicted values of PNI in KD patients with IVIG resistance and CAL. Results: A total of 8 articles containing 10 studies involving 7,047 participants were included. The pooled results revealed a pooled sensitivity of 0.44 (0.25-0.65), a pooled specificity of 0.87 (0.73-0.94), a pooled PLR of 3.4 (2.0-5.9), a pooled NLR of 0.65 (0.48-0.87), a pooled DOR of 5.26 (2.76-10.02), and a pooled AUC of 0.75 (0.71-0.78) in the diagnosis of KD with CAL. The pooled results suggested that a pooled sensitivity was 0.69 (0.60-0.77), specificity was 0.76 (0.69-0.82), PLR was 2.9 (2.1-4.1), NLR was 0.40 (0.29-0.56), DOR was 7.27 (3.89-13.59), and AUC was 0.79 (0.75-0.82) in the diagnosis of KD with IVIG resistance. The combined results revealed the pooled sensitivity was 0.63 (0.58-0.67), specificity was 0.82 (0.80-0.83), PLR was 3.09 (1.06-8.98), NLR was 0.38 (0.07-2.02), DOR was 8.23 (0.81-83.16) in differentiating KD from febrile patients. These findings demonstrated low sensitivity and relatively high specificity of PNI for KD, KD-CAL, and IVIG-resistant KD. Conclusion: In conclusion, this study was the first systematic review and meta-analysis of the diagnostic value of PNI in KD with IVIG resistance and CAL. The results suggested that PNI could be used as biomarkers for distinguish KD, KD with CAL, and KD with IVIG resistance.

USP31 serves as a potential biomarker for predicting prognosis and immune responses for clear cell renal cell carcinoma via single-cell and bulk RNA-sequencing.

BACKGROUND: Currently, there is no research available on the prognosis, potential effect and therapeutic value of USP31 in clear cell renal cell carcinoma (ccRCC). To address this gap, the present study aimed to shed light on its potential roles and possible mechanisms in ccRCC. METHODS: R software was utilized to conduct bioinformatics analyses with the data derived from The Cancer Genome Atlas (i.e. KIRC) and Gene Expression Omnibus datasets. The expression of USP31 in ccRCC was validated by a PCR. The independent prognostic ability of USP31 was evaluated by Cox regression analysis. We conducted gene set enrichment analysis (GSEA) to explore the potential USP31-related pathways. We also discussed the relationships between USP31 and immunity, by predicting its possible upstream transcription factors (TFs) by ChEA3. RESULTS: In ccRCC, USP31 demonstrated a high level of expression and this increased expression was correlated with a poor prognosis (p < 0.05). Through univariate and multivariate Cox regression analysis, USP31 was identified as an independent prognostic factor for ccRCC (p < 0.05). Furthermore, eight USP31-related pathways were identified by GSEA (p < 0.05). Moreover, USP31 was found to be associated with microsatellite instability, tumor microenvironment, a variety of immune cells and immune checkpoints and immune infiltration (p < 0.05). Additionally, Patients with high USP31 expression in ccRCC were shown to have better curative effects after immunotherapy (p < 0.05). Finally, we found that AR, USF1, MXI1 and CLOCK could be the potential upstream TFs of USP31. CONCLUSIONS: USP31 could serve as a potential biomarker for predicting both prognosis and immune responses, revealing its potential mechanisms of TF-USP31 mRNA networks in ccRCC.

Single-cell immune profiling of mouse liver aging reveals Cxcl2+ macrophages recruit neutrophils to aggravate liver injury.

BACKGROUND AND AIMS: Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging. APPROACH AND RESULTS: We carried out single-cell RNA sequencing on mouse liver tissues at 4 different ages, namely, the newborn, suckling, young, and aged stages. The transcriptomic landscape, cellular classification, and intercellular communication were analyzed. We confirmed the findings by multiplex immunofluorescence staining, flow cytometry, in vitro functional experiments, and chimeric animal models. Nine subsets of 89,542 immune cells with unique properties were identified, of which Cxcl2+ macrophages within the monocyte/macrophage subset were preferentially enriched in the aged liver. Cxcl2+ macrophages presented a senescence-associated secretory phenotype and recruited neutrophils to the aged liver through the CXCL2-CXCR2 axis. Through the secretion of IL-1ß and TNF-α, Cxcl2+ macrophages stimulated neutrophil extracellular traps formation. Targeting the CXCL2-CXCR2 axis limited the neutrophils migration toward the liver and attenuated age-related liver injury. Moreover, the relationship between Cxcl2+ macrophages and neutrophils in age-related liver injury was further validated by human liver transplantation samples. CONCLUSIONS: This in-depth study illustrates that the mechanism of Cxcl2+ macrophage-driven neutrophil activation involves the CXCL2-CXCR2 axis and provides a potential therapeutic strategy for age-related liver injury.

Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Prone versus lateral position in acute hypoxemic respiratory failure patients with HFNO therapy: study protocol for a multicentre randomised controlled open-label trial.

BACKGROUND: High-flow nasal oxygen (HFNO) therapy is a leading treatment technique for acute hypoxemic respiratory failure (AHRF), but its treatment failure rate remains high. The awake prone position (APP) has been proven to increase oxygenation and reduce the endotracheal intubation rate in patients with COVID-19-induced AHRF. However, the APP is poorly tolerated in patients, and its performance in improving prognoses is controversial. The lateral position has a similar mechanism and effect to the prone position, but it is more tolerable than the prone position. Therefore, it is worth exploring whether the lateral position is better for awake patients with AHRF. METHODS: This is a protocol for a three-arm parallel-group multicentre randomised controlled open-label exploratory trial. A total of 583 patients from two hospitals in Chongqing, China, will be randomised to take the semi-recumbent position, lateral position, or prone position at a ratio of 1:1:1. Patients are all diagnosed with AHRF secondary to non-COVID-19 pneumonia or lung infection and receiving HFNO therapy. The primary outcome is ventilator-free days in 28 days. The secondary outcomes are the 28-day intubation rate, 28-day all-cause mortality, total position change time, the incidence of adverse events, number of hours using HFNO therapy, length of hospital and intensive care unit (ICU) stay, and others. We will conduct subgroup analyses on the arterial partial pressure of oxygen to the fraction of inspiration oxygen (PaO2/FiO2) ratio (> 200 mmHg or ≤ 200 mmHg), time from admission to intervention implementation (< 24 h or ≥ 24 h), position changing time, and different diagnoses. DISCUSSION: This trial will explore the prognostic effects of the APP with that of the lateral position in awake patients with non-COVID-19AHRF and compare the differences between them. To provide evidence for clinical decision-making and further research on position management. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry. The registration number is ChiCTR2200055822 . Registered on January 20, 2022.

Association of noncoding RNAs with Kawasaki disease: A meta-analysis based on the current evidences.

BACKGROUND: In recent years, many studies have focused on the relationship between noncoding RNAs (ncRNAs) and Kawasaki disease (KD). Studies have indicated that ncRNAs are associated with the occurrence and development of KD. Thus, we performed a systematic review and meta-analysis to investigate the diagnostic value of ncRNAs in KD patients. METHODS: We searched the PubMed, Web of Science, Embase and Cochrane Library, China National Knowledge Infrastructure, VIP, China Biology Medicine disc databases, and Wanfang databases until August 25, 2023 and screened all eligible studies focusing on the diagnostic performance of ncRNAs in KD patients. RESULTS: In total, 535 articles were found, and 28 articles were included in this systematic review and meta-analysis. The calculated area under the curve value was 0.880 (95% confidence intervals, 0.840-0.900). The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.790, 0.830, 4.610, and 0.260, respectively. The pooled diagnostic odds ratio was 17.890 (95% confidence intervals, 13.110-24.420), indicating a relatively good diagnostic performance of the ncRNAs for detecting KD. In addition, the diagnostic value of micro RNAs in KD was better than that of long noncoding RNAs and circular noncoding RNAs. A subgroup analysis by specimen indicated a better diagnostic value of ncRNAs in plasma and platelet than serum. The diagnostic accuracy of ncRNAs was better in febrile controls than in healthy control groups, indicating a relatively good accuracy in distinguishing KD patients from febrile diseases. CONCLUSIONS: This systematic review and meta-analysis demonstrated that ncRNAs could be used as novel biomarkers for detecting KD. More studies should be conducted in the future to verify the diagnostic values of ncRNAs in KD.

Artificial intelligence-based non-invasive tumor segmentation, grade stratification and prognosis prediction for clear-cell renal-cell carcinoma.

Due to the complicated histopathological characteristics of clear-cell renal-cell carcinoma (ccRCC), non-invasive prognosis before operative treatment is crucial in selecting the appropriate treatment. A total of 126 345 computerized tomography (CT) images from four independent patient cohorts were included for analysis in this study. We propose a V Bottleneck multi-resolution and focus-organ network (VB-MrFo-Net) using a cascade framework for deep learning analysis. The VB-MrFo-Net achieved better performance than VB-Net in tumor segmentation, with a Dice score of 0.87. The nuclear-grade prediction model performed best in the logistic regression classifier, with area under curve values from 0.782 to 0.746. Survival analysis revealed that our prediction model could significantly distinguish patients with high survival risk, with a hazard ratio (HR) of 2.49 [95% confidence interval (CI): 1.13-5.45, P = 0.023] in the General cohort. Excellent performance had also been verified in the Cancer Genome Atlas cohort, the Clinical Proteomic Tumor Analysis Consortium cohort, and the Kidney Tumor Segmentation Challenge cohort, with HRs of 2.77 (95%CI: 1.58-4.84, P = 0.0019), 3.83 (95%CI: 1.22-11.96, P = 0.029), and 2.80 (95%CI: 1.05-7.47, P = 0.025), respectively. In conclusion, we propose a novel VB-MrFo-Net for the renal tumor segmentation and automatic diagnosis of ccRCC. The risk stratification model could accurately distinguish patients with high tumor grade and high survival risk based on non-invasive CT images before surgical treatments, which could provide practical advice for deciding treatment options.

Liposomal Resveratrol Alleviates Platelet Storage Lesion via Antioxidation and the Physical Buffering Effect.

Platelet transfusion is essential in the treatment of platelet-related diseases and the prevention of bleeding in patients with surgical procedures. Platelet transfusion efficacy and shelf life are limited mainly by the development of platelet storage lesion (PSL). Mitigating PSL is the key to prolonging the platelet shelf life and reducing wastage. Excess intracellular reactive oxygen species (ROS) are one of the main factors causing PSL. In this study, we explored a nanomedicine strategy to improve the quality and functions of platelets in storage. Resveratrol (Res), a natural plant product, is known for its antioxidative effect. However, medical applications of Res are limited due to its low water solubility and stability. Therefore, we used a resveratrol-loaded liposomal system (Res-Lipo) to better utilize the antioxidant effect of the drug. This study aimed to evaluate the effect of Res-Lipo on platelet oxidative stress and alleviation of PSL during the storage time. Res-Lipo scavenged intracellular ROS and inhibited platelet apoptosis and activation during storage. Res-Lipo not only maintained mitochondrial function but also improved platelet aggregation in response to adenosine 5'-diphosphate. These results revealed that Res-Lipo ameliorated PSL and prolonged the platelet survival time in vivo. The strategy provides a potential method for extending the platelet storage time and might be considered a potential and safe additive to alleviate PSL.

Synergy of 5-aminolevulinate supplement and CX3CR1 suppression promotes liver regeneration via elevated IGF-1 signaling.

Inadequate remnant volume and regenerative ability of the liver pose life-threatening risks to patients after partial liver transplantation (PLT) or partial hepatectomy (PHx), while few clinical treatments focus on safely accelerating regeneration. Recently, we discovered that supplementing 5-aminolevulinate (5-ALA) improves liver cold adaptation and functional recovery, leading us to uncover a correlation between 5-ALA metabolic activities and post-PLT recovery. In a mouse 2/3 PHx model, 5-ALA supplements enhanced liver regeneration, promoting infiltration and polarization of anti-inflammatory macrophages via P53 signaling. Intriguingly, chemokine receptor CX3CR1 functions to counterbalance these effects. Genetic ablation or pharmacological inhibition of CX3CR1 (AZD8797; phase II trial candidate) augmented the macrophagic production of insulin-like growth factor 1 (IGF-1) and subsequent hepatocyte growth factor (HGF) production by hepatic stellate cells. Thus, short-term treatments with both 5-ALA and AZD8797 demonstrated pro-regeneration outcomes superior to 5-ALA-only treatments in mice after PHx. Overall, our findings may inspire safe and effective strategies to better treat PLT and PHx patients.

Combined inhibition of surface CD51 and γ-secretase-mediated CD51 cleavage improves therapeutic efficacy in experimental metastatic hepatocellular carcinoma.

BACKGROUND & AIMS: Integrin αv (ITGAV, CD51) is regarded as a key component in multiple stages of tumor progression. However, the clinical failure of cilengitide, a specific inhibitor targeting surface CD51, suggests the importance of yet-unknown mechanisms by which CD51 promotes tumor progression. METHODS: In this study, we used several hepatocellular carcinoma (HCC) cell lines and murine hepatoma cell lines. To investigate the role of CD51 on HCC progression, we used a 3D invasion assay and in vivo bioluminescence imaging. We used periostin-knockout transgenic mice to uncover the role of the tumor microenvironment on CD51 cleavage. Moreover, we used several clinically relevant HCC models, including patient-derived organoids and patient-derived xenografts, to evaluate the therapeutic efficacy of cilengitide in combination with the γ-secretase inhibitor LY3039478. RESULTS: We found that CD51 could undergo transmembrane cleavage by γ-secretase to produce a functional intracellular domain (CD51-ICD). The cleaved CD51-ICD facilitated HCC invasion and metastasis by promoting the transcription of oxidative phosphorylation-related genes. Furthermore, we identified cancer-associated fibroblast-derived periostin as the major driver of CD51 cleavage. Lastly, we showed that cilengitide-based therapy led to a dramatic therapeutic effect when supplemented with LY3039478 in both patient-derived organoid and xenograft models. CONCLUSIONS: In summary, we revealed previously unrecognized mechanisms by which CD51 is involved in HCC progression and uncovered the underlying cause of cilengitide treatment failure, as well as providing evidence supporting the translational prospects of combined CD51-targeted therapy in the clinic. IMPACT AND IMPLICATIONS: Integrin αv (CD51) is a widely recognized pro-tumoral molecule that plays a crucial role in various stages of tumor progression, making it a promising therapeutic target. However, despite early promising results, cilengitide, a specific antagonist of CD51, failed in a phase III clinical trial. This prompted further investigation into the underlying mechanisms of CD51's effects. This study reveals that the γ-secretase complex directly cleaves CD51 to produce an intracellular domain (CD51-ICD), which functions as a pro-tumoral transcriptional regulator and can bypass the inhibitory effects of cilengitide by entering the nucleus. Furthermore, the localization of CD51 in the nucleus is significantly associated with the prognosis of patients with HCC. These findings provide a theoretical basis for re-evaluating cilengitide in clinical settings and highlight the importance of identifying a more precise patient subpopulation for future clinical trials targeting CD51.