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Purpose The causal relationships between circulating adipokines and idiopathic pulmonary fibrosis (IPF) are yet to be established. We performed a two-sample Mendelian randomization (MR) study to investigate the causal roles of adipokines on IPF risk. Methods We analyzed the summary data from genome-wide association studies (GWAS), including adiponectin, leptin, resistin and monocyte chemoattractant protein-1 (MCP-1) and IPF. The inverse-variance weighted (IVW) method was considered as the major method and the MR-Egger, weighted median, simple mode and weighted mode were utilized as complementary methods. We also performed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test and leave-one-out analysis. Results The selected number of single nucleotide polymorphisms (SNPs) was 13 for adiponectin, 6 for leptin,12 for resistin, and 6 for MCP-1, respectively. The results showed a causal effect of the circulating adiponectin levels on the risk of IPF (OR 0.645, 95% CI 0.457-0.911, P = 0.013). However, we did not observe significant associations of genetic changes in serum leptin (OR 1.018, 95% CI 0.442-2.346, P = 0.967), resistin (OR 1.002, 95% CI 0.712-1.408, P = 0.993), and MCP-1 (OR 1.358, 95% CI 0.891-2.068, P = 0.155) with risk of developing IPF. There was no evidence of heterogeneity or horizontal pleiotropy. The sensitivity analyses confirmed that our results were stable and reliable. Conclusions The increase in serum adiponectin was associated causally with a decreased risk of developing IPF. There is no evidence to support a causal association between leptin, resistin or MCP-1 with risk of IPF. Further studies are needed to confirm our findings., Author(s): Dong Huang [sup.1] [sup.2], Linjing Gong [sup.1] [sup.2], Zhenru Wu [sup.2], Yujun Shi [sup.2], Zongan Liang [sup.1] Author Affiliations: (1) grid.13291.38, 0000 0001 0807 1581, Department of Respiratory and [...]

Purpose Pulmonary fibrosis is a life-threatening lung disorder. A comprehensive understanding of the pathophysiological changes in the development of pulmonary fibrosis will lead to new insights into its treatment. Methods We used a paraquat (PQ)-induced rhesus monkey model of pulmonary fibrosis to comprehensively investigate the process of pulmonary fibrosis development. Rhesus monkeys were orally administered PQ at concentrations of 25 mg/kg, 40 mg/kg, and 80 mg/kg. The dose was given once. Behavior and clinical data, such as PQ concentration, arterial oxygen saturation, biochemical evaluation, lung histopathology, and medical imaging, were continuously observed. Results Paraquat-exposed monkeys developed pulmonary fibrosis following an expected time course, especially at 25 mg/kg. CT images showed ground-glass lesions in the lung after 4 weeks, and pulmonary fibrosis persisted until the end of follow-up. Using pathological examination, the lung sustained collagen deposition and slight inflammatory cell infiltration. All rhesus monkeys had obvious inflammatory infiltration within 1 week according to the immunohistochemical results and the number of leukocytes in the blood. The CT results showed that pulmonary fibrosis had not formed, indicating that drugs with powerful anti-inflammatory ability are potential candidates for early pulmonary fibrosis treatment. Conclusion Our study describes the dynamic process of paraquat-induced pulmonary fibrosis in rhesus monkeys and provided a pathophysiological basis for the treatment of pulmonary fibrosis., Author(s): Mingyang Shao [sup.1], Sha Yang [sup.2], Aiyi Zheng [sup.2], Zhenru Wu [sup.1], Menglin Chen [sup.1], Rong Yao [sup.2], Yujun Shi [sup.1], Gen Chen [sup.3] Author Affiliations: (1) grid.13291.38, 0000 [...]

BackgroundAcute liver failure (ALF) is a complicated clinical syndrome associated with high mortality, with liver transplantation as the only treatment option. Treatment of mesenchymal stem cells has shown a potential therapeutic option for acute liver failure. However, the lack of random clinical trials and large non-human primate studies makes it necessary to assess the efficacy and safety in the clinic.MethodsWe treated the monkeys with peripheral delivery of human umbilical MSCs (hUC-MSCs) and investigated the role of hUC-MSCs in modulating the progress of acute liver failure.ResultsThe use of early peripheral infusion of human umbilical cord MSC infusion did not improve liver regeneration or modulate adaptive immunity. However, it significantly suppressed the hepatic aggregation and maturation of circulating monocytes and their IL-6 secretion, greatly improving liver histology, systemic homeostasis, and survival.ConclusionsOur study reveals the critical role of monocyte-derived IL-6 in initiating and accelerating acute liver failure and hUC-MSC treatment can disrupt the development of the inflammatory cascade by inhibiting monocyte activation. Early hUC-MSC treatment disrupts the development of the inflammatory cascade, indicating a potential clinical solution for acute liver failure.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers, usually diagnosed at an advanced stage. Metabolic reprogramming plays a significant role in HCC progression, probably related to immune evasion, yet the key gene is unclear. In this study, six metabolism‐related genes with prognostic implications were screened. Correlation analysis between the key genes and immune cell subtypes was conducted, and a prominent gene strongly associated with immunosuppression, SLC16A3, was identified. Overexpression of SLC16A3 is associated with the loss of T‐cell function and might lead to the upregulation of several immunosuppressive proteins. Gene function enrichment analysis showed genes correlated with SLC16A3 primarily involved in cell adhesion. Single‐cell analysis showed that the SLC16A3 gene was mainly expressed in macrophages, especially some tumour‐promoting macrophages. Further analysis of spatial transcriptome data indicated that SLC16A3 was enriched at the tumour invasion front. The mIHC revealed that patients with high SLC16A3 expression exhibited significantly reduced infiltration of GZMB+ cells. And SLC16A3 inhibitors significantly suppressed the proliferation of HCC, while simultaneously enhancing T‐cell cytotoxicity and reducing exhaustion. These results reveal the phenomenon of immune escape mediated by metabolic reprogramming and suggest that SLC16A3 may serve as a novel target for intervention. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is associated with high mortality, and a poor understanding of the underlying pathophysiology has resulted in a lack of effective treatments so far. Here, using an amatoxin-induced rhesus monkey model of ALF, we panoramically revealed the cellular and molecular events that lead to the development of ALF. The challenged monkeys with toxins underwent a typical course of ALF including severe hepatic injury, systemic inflammation and eventual death. Adaptive immune was not noticeably disturbed throughout the progress of ALF. A systematic examination of serum factors and cytokines revealed that IL-6 increase was the most rapid and drastic. Interestingly, we found that IL-6 was mainly produced by circulating monocytes. Furthermore, ablation of monocyte-derived IL-6 in mice decreased liver injury and systemic inflammation following chemical injection. Our findings reveal a critical role of circulating monocytes in initiating and accelerating ALF, indicating a potential therapeutic target in clinical treatment for ALF.

Microwave ablation is the most commonly used minimally invasive technique for thermal ablation of liver tumors, and accurate monitoring of the ablation area is crucial for evaluating treatment efficacy. While traditional imaging techniques play an important role in clinical monitoring, they still face several insurmountable challenges. Microwave-induced thermoacoustic imaging (TAI) has emerged as a promising modality for ablation detection due to its high resolution and deep imaging capabilities. To further enhance the effectiveness of TAI in ablation monitoring, we propose a technique based on thermoacoustic changes in backscattered energy (CBE) imaging. This method accurately delineates the liver ablation area by monitoring temperature variations before and after ablation. Experimental results show that thermoacoustic CBE imaging offers significant advantages over traditional TAI, achieving accuracies of 97.12% in ex vivo and 93.46% in in vivo experiments. Its superior resolution makes it an ideal choice for monitoring tissue damage during microwave ablation. [ABSTRACT FROM AUTHOR]

Background. Using a toxin‐induced lethal acute liver failure (ALF) monkey model, we have recently shown that early peripheral infusion of human umbilical cord mesenchymal stem cells (hUC‐MSCs) can alleviate liver damage and improve animal survival by suppressing the activation of circulating monocytes and the subsequent cytokine storm. Here, we explored whether the administration of hUC‐MSCs could still improve ALF when the cytokine storm is fully developed. Method. We treated ALF monkeys with peripheral delivery of hUC‐MSCs at 48 hr after toxin challenge. Liver indices, histology, imaging, and animal survival were recorded and analyzed. Results. In our cohort study, we conducted and demonstrated that the infusion of hUC‐MSCs significantly improved liver histology, effectively controlled inflammatory cytokine storms, and increased survival rates. Additionally, the administration of a higher dose of hUC‐MSCs (2 × 107/monkey) yielded superior outcomes compared to a lower dose (1 × 107/monkey). Conclusion. Treatment of hUC‐MSCs can significantly improve the pathological and survival outcomes of ALF even when the cytokine storm has been fully developed, indicating a promising clinical solution for ALF. [ABSTRACT FROM AUTHOR]