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Abstract The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease.

Background: A standard treatment recommendation for third-line and subsequent treatments for advanced HER2-positive breast cancer is still missing, especially for low HER2 expression. Nevertheless, there is evidence that these patients might benefits from antibody-drug conjugates (ADCs) treatment. Therefore, this study aimed to evaluate the clinical efficacy, safety, and factors affecting efficacy of Disitamab Vedotin (RC48) for treating HER2-positive and HER2-low metastatic breast cancer (MBC) in the real-world setting. Methods: A retrospective study at five clinical sites was conducted in China, enrolling MBC patients treated with RC48 from July 01, 2021 and May 31, 2023. Patient demographics, treatment patterns, and adverse events (AEs) were recorded and analyzed. Results: A total of 154 patients were included: 104 (67.53%) patients with HER2-positive and 50 (32.47%) patients with HER2-low MBC. The median progression-free survival (mPFS) was 5.06 months. The objective response rate (ORR) and disease control rate (DCR) were 36.36% and 68.83%, respectively. HER2-positive patients exhibited a mPFS of 5.93 and an ORR of 41.35%. In contrast, patients with low-HER2 had a mPFS of 4.28 months and an ORR of 26.00%. The most common AEs included neutropenia (54.55%), increased AST (53.25%), leukopenia (51.95%), and fatigue (43.51%), mostly graded mild to moderate (grade 1-2). Conclusions: This extensive study in China demonstrated that RC48 has excellent therapeutic potential for both HER2-positive and HER2-low MBC with a favorable safety profile. The study also suggests that combination therapy significantly boosts efficacy beyond monotherapy, indicating a promising avenue for future ADC development. [ABSTRACT FROM AUTHOR]

Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications. [ABSTRACT FROM AUTHOR]

Sepsis‐induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti‐inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti‐inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β‐oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2‐DG, and fatty acid β‐oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1‐related markers (CD86, iNOS), the decrease of pro‐inflammatory factors (nitric oxide, IL‐1β, IL‐6, and TNF‐α), the upregulation of M2‐related markers (CD206, ARG‐1), the increase of immunomodulatory factors (IL‐4 and IL‐10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β‐oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis‐related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β‐oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2‐DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β‐oxidation in M2). [ABSTRACT FROM AUTHOR]

This study selected the five indicators of soil erosion, climate environment, geological hazards, biodiversity, and human disturbances and uses the entropy weight method to calculate the ecological sensitivity of the West Qinling Mountains from 2000 to 2020. The analysis produced a spatiotemporal distribution of ecological sensitivity over the 20-year period. An equal step size of 500 m was used to progressively increase the spatial scale from 500 m to 6 km. The optimal scale for the spatial differentiation of ecological sensitivity in the West Qinling Mountains was determined by analyzing the characteristics of changes at different scales, response mechanisms, and optimal parameters for geographical detector spatial scale identification. Based on this scale, the change in intensity and pattern and the influencing factors of ecological sensitivity were analyzed. The results show the following: (1) The 5.5 km spatial scale balances the requirements of accuracy, spatial heterogeneity, and data adequacy, making it the optimal scale for analyzing the spatiotemporal variation patterns of ecological sensitivity in the West Qinling Mountains. (2) From 2000 to 2020, the mean ecological sensitivity in the West Qinling Mountains exhibited a decreasing trend, indicating an improvement in the ecological environment. Spatially, the ecological sensitivity of the West Qinling Mountains showed a spatial distribution pattern of "low in the west and high in the east, low in the south and high in the north". During the study period, the ecological sensitivity in the West Qinling region remained generally stable, with no high-frequency changes observed. (3) Population density is the primary driving factor of spatial differentiation of ecological sensitivity in the West Qinling Mountains, while GDP serves as a secondary factor. Overall, socioeconomic factors have the most significant impact on ecological sensitivity. (4) Over 75% of the ecological sensitivity trends exhibit patterns of perennial unchanged and fluctuating unchanged trends, with areas of fluctuating increase smaller than areas of fluctuating decrease. Regions of perennial high sensitivity are primarily concentrated in the northeastern part of the West Qinling Mountains, while areas with increased fluctuation in ecological sensitivity are mainly located in the western and southern parts of the West Qinling Mountains. Future efforts should focus on these regions. [ABSTRACT FROM AUTHOR]

The aim of this article is to analyze the impact of land use changes on trade-offs/synergies of the ecosystem service in Gangu County, Gansu province, China, from 2000 to 2020, and intends to provide a reference for decision-making on regional ecological environment protection and restoration. We analyzed the land use changes in Gangu County with the dynamic degree of single land use. Changes in ecosystem service values (ESV) were analyzed using the equivalent factor method. The temporal and spatial distribution patterns of ecosystem service trade-offs/synergies were elaborated with the help of the correlation coefficient method and local autocorrelation analysis. The impact of land use change on trade-offs/synergies of ecosystem service was analyzed according to the ecological contribution rate of land use changing and the changing of land use area. The results showed that: (1) cultivated land and grassland were the dominant land use types in Gangu County, China; the largest increase in the dynamic degree of single land use was in construction land, followed by grassland, and the largest decrease in the dynamic degree of single land use was in unused land, followed by grassland. (2) Between 2000 and 2020, the ESV showed an upward trend; the regulating service provided the largest part of the ESV among the four first ecosystem service types. The medium ESV zone occupied the largest area, and the spatial distribution pattern of ESV was high in the south and low in the north of Gangu County, China. (3) The relationships of ecosystem services were dominated by synergistic and supplemented by trade-offs. The strongest synergistic relationship was expressed between EP and BP, then, between EP and AL. Meanwhile, the strongest trade-off relationship was carried out between BP and FP. During the 20 years, the relationship of ecosystem service showed a weak shift from mainly synergistic to trade-off temporally. Spatially, the synergistic relationship was dominated and concentrated in the central and southern parts of the study area. (4) The increase in the area of grassland and forest land were the root causes resulting in the increase of ESV in Gangu County. In the time dimension, land use change had the greatest impact on the trade-off synergistic relationship between FP and all other services. In the spatial dimension, land use change has little impact on trade-offs/synergies in the northern region and more in the central and southern regions of Gangu County. The results of this study can provide a scientific basis for improving the ecological environment and promoting sustainable development in Gangu County. At the same time, it will lay the foundation for the region to realize a win–win situation between economic development and ecological protection. [ABSTRACT FROM AUTHOR]

Cadmium (Cd), a prevalent environmental contaminant, exerts widespread toxic effects on human health through various biochemical and molecular mechanisms. This review encapsulates the primary pathways through which Cd inflicts damage, including oxidative stress induction, disruption of Ca2+ signaling, interference with cellular signaling pathways, and epigenetic modifications. By detailing the absorption, distribution, metabolism, and excretion (ADME) of Cd, alongside its interactions with cellular components such as mitochondria and DNA, this paper highlights the extensive damage caused by Cd2+ at the cellular and tissue levels. The role of Cd in inducing oxidative stress—a pivotal mechanism behind its toxicity—is discussed with emphasis on how it disrupts the balance between oxidants and antioxidants, leading to cellular damage and apoptosis. Additionally, the review covers Cd's impact on signaling pathways like Mitogen-Activated Protein Kinase (MAPK), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Tumor Protein 53 (p53) pathways, illustrating how its interference with these pathways contributes to pathological conditions and carcinogenesis. The epigenetic effects of Cd, including DNA methylation and histone modifications, are also explored to explain its long-term impact on gene expression and disease manifestation. This comprehensive analysis not only elucidates the mechanisms of Cd toxicity but also underscores the critical need for enhanced strategies to mitigate its public health implications. [ABSTRACT FROM AUTHOR]