Calcium overload in hepatocytes mediates the crosstalk and amplification loop with oxidative stress and severe inflammation that initiate pro-apoptotic and necrotic signaling pathways in acute liver injury (ALI). In this study, an N-acetylgalactosamine-modified amphiphilic dextran-silibinin conjugate (GalNAc-Dex-Sil) with ROS-sensitive phenylboronic acid (PBA) linkage was synthesized. The as-prepared amphiphilic polymer was self-assembled into GalNAc-Dex-Sil nanoparticles, which efficiently encapsulated the membrane-permeable calcium chelator BAPTA-AM (BA), achieving GalNAc-mediated hepatocyte-specific targeting and ROS-responsive release in injured hepatocytes through PBA cleavage. Accordingly, a single low-dose injection of formulation (BA: 150 μg·kg−1) significantly alleviated hepatocyte oxidative stress and inflammation, rescued dying hepatocytes, prevented further hepatocyte damage, and ultimately restored liver function in the ALI mouse model by 1) rapidly and effectively eliminating the overloaded calcium and scavenging excessive ROS via released BA to block the feed-forward vicious cycles of the cell damage, 2) inhibiting the inflammatory cascade by decreasing the expression of the key factor of the NF-κB/NLPR3 axis, 3) inhibiting the key branch of the mitochondrial apoptotic pathway (Cyt C/Bcl-2 family/caspase-3 axis) and death receptor pathway (TNFα/Caspase-8 axis), and 4) stabilizing hepatocyte membranes through the synergistic hepatoprotective effect of silibinin. Taken together, this formulation exhibited great potential as a potent and effective ALI treatment strategy. 

Ros-responsive dextran-phenylboronic acid-silibinin nanoparticles for targeting delivery of BAPTA-AM to effectively eliminate calcium overload-mediated inflammatory cascades and mitochondrial apoptosis: Alleviating acute liver injury

Hepatic macrophages represent a key cellular component of the liver and are essential for the progression of acute liver failure (ALF). We construct artificial apoptotic cells loaded with itaconic acid (AI-Cells), wherein the compositions of the synthetic plasma membrane and surface topology are rationally engineered. AI-Cells are predominantly localized to the liver and further transport to hepatic macrophages. Intravenous administration of AI-Cells modulates macrophage inflammation to protect the liver from acetaminophen-induced ALF. Mechanistically, AI-Cells act on caspase-1 to suppress NLRP3 inflammasome-mediated cleavage of pro-IL-1β into its active form in macrophages. Notably, AI-Cells specifically induce anti-inflammatory memory-like hepatic macrophages in ALF mice, which prevent constitutive overproduction of IL-1β when liver reinjury occurs. In light of AI-Cells' precise delivery and training of memory-like hepatic macrophages, they offer promising therapeutic potential in reversing ALF by finely controlling inflammatory responses and orchestrating liver homeostasis, which potentially affect the treatment of various types of liver failure. 

Artificial cells delivering itaconic acid induce anti-inflammatory memory-like macrophages to reverse acute liver failure and prevent reinjury

Acetaminophen overdose is a leading cause of acute liver failure (ALF). Despite the pivotal role of the inflammatory microenvironment in the progression of advanced acetaminophen-induced liver injury (AILI), a comprehensive understanding of the underlying cellular interactions and molecular mechanisms remains elusive. Mas is a G protein-coupled receptor highly expressed by myeloid cells; however, its role in the AILI microenvironment remains to be elucidated. A multidimensional approach, including single-cell RNA sequencing, spatial transcriptomics, and hour-long intravital imaging, is employed to characterize the microenvironment in Mas1 deficient mice at the systemic and cell-specific levels. The characteristic landscape of mouse AILI models involves reciprocal cellular communication among MYC+ CD63+ endothelial cells, MMP12+ macrophages, and monocytes, which is maintained by enhanced glycolysis and the NF-κB/TNF-α signaling pathway due to myeloid-Mas deficiency. Importantly, the pathogenic microenvironment is delineated in samples obtained from patients with ALF, demonstrating its clinical relevance. In summary, these findings greatly enhance the understanding of the microenvironment in advanced AILI and offer potential avenues for patient stratification and identification of novel therapeutic targets.

Myeloid-Mas Signaling Modulates Pathogenic Crosstalk among MYC+ CD63+ Endothelial Cells, MMP12+ Macrophages, and Monocytes in Acetaminophen-Induced Liver Injury.

Microorganisms are crucial components of freshwater ecosystems. Understanding the microbial community assembly processes and niche characteristics in freshwater ecosystems, which are poorly understood, is crucial for evaluating microbial ecological roles. The Yunnan Plateau lakes in China represent a freshwater ecosystem that is experiencing eutrophication due to anthropogenic activities. Here, variation in the assembly and niche characteristics of both prokaryotic and microeukaryotic communities was explored in Yunnan Plateau lakes across two seasons (dry season and rainy season) to determine the impacts of rainfall and environmental conditions on the microbial community and niche. The results showed that the environmental heterogeneity of the lakes decreased in the rainy season compared to the dry season. The microbial (bacterial and microeukaryotic) α-diversity significantly decreased during the rainy season. Deterministic processes were found to dominate microbial community assembly in both seasons. β-Diversity decomposition analysis revealed that microbial community compositional dissimilarities were dominated by species replacement processes. The co-occurrence networks indicated reduced species complexity for microbes and a destabilized network for prokaryotes prior to rainfall, while the opposite was found for microeukaryotes following rainfall. Microbial niche breadth decreased significantly in the rainy season. In addition, lower prokaryotic niche overlap, but greater microeukaryotic niche overlap, was observed after rainfall. Rainfall and environmental conditions significantly affected the microbial community assembly and niche characteristics. It can be concluded that rainfall and external pollutant input during the seasonal transition alter the lake environment, thereby regulating the microbial community and niche in these lakes. Our findings offer new insight into microbiota assembly and niche patterns in plateau lakes, further deepening the understanding of freshwater ecosystem functioning. 

Rainfall seasonality shapes microbial assembly and niche characteristics in Yunnan Plateau lakes, China

The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a significant population of macrophages (Mϕs) expressing ChAT and synthesizing acetylcholine in the resolution phase of acute peritonitis. Using Chat -GFP reporter mice, we observed marked upregulation of ChAT in monocyte-derived small peritoneal Mϕs (SmPMs) in response to Toll-like receptor agonists and bacterial infections. These SmPMs, phenotypically and transcriptionally distinct from tissue-resident large peritoneal macrophages, up-regulated ChAT expression through a MyD88-dependent pathway involving MAPK signaling. Notably, this process was attenuated by the TRIF-dependent TLR signaling pathway, and our tests with a range of neurotransmitters and cytokines failed to induce a similar response. Functionally, Chat deficiency in Mϕs led to significantly decreased peritoneal acetylcholine levels, reduced efferocytosis of apoptotic neutrophils, and a delayed resolution of peritonitis, which were reversible with exogenous ACh supplementation. Intriguingly, despite B lymphocytes being a notable ChAT-expressing population within the peritoneal cavity, Chat deletion in B cells did not significantly alter the resolution process. Collectively, these findings underscore the crucial role of Mϕ-derived acetylcholine in the resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation. 

Cholinergic macrophages promote the resolution of peritoneal inflammation

Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization

The water level of Lake Qinghai, the largest lake on the Qinghai-Tibetan Plateau, has increased continuously, at an average speed of 0.21 m per year since 2005, causing a rapid expansion of the lake area. We investigated the hydrological processes of Lake Qinghai and the surrounding watershed that have influenced water level and lake area from 1956 to 2019. Relationships among water level, climate change and human activities were also assessed. Water level and lake area were positively correlated with precipitation and runoff into the lake, and negatively correlated with evaporation. Climate change factors including precipitation and runoff were the primary causes of lake level change, whereas human activities, including variation in a human footprint index, land use, and grassland irrigation, were secondary factors. A time series model forecasted that from 2020 to 2050 water levels will increase further by 2.45 m. Although this increase in water level may have some benefits, such as reduced local desertification, the expansion of lake area will continue to flood low beaches, pasture lands, near shore infrastructure and roads, and impact tourism locations. However, continued water level rise may also have negative ecological effects, such as reduce habitat of seasonal birds and reduced water quality due to erosion and sediment resuspension in shallow nearshore lake areas. Local stakeholders, government authorities, and scientists should give greater attention to anticipated changes in water level, and further ecological studies and infrastructure adaptation measures should be implemented.

Recent water-level fluctuations, future trends and their eco-environmental impacts on Lake Qinghai.

Both phytoplankton and bacteria are fundamental organisms with key ecological functions in lake ecosystems. However, the mechanistic interactions through which phytoplankton community change and bacterial communities interact remain poorly understood. Here, the responses of bacterial communities to the community structure, resource-use efficiency (RUE), and community turnover of phytoplankton and microcystins (MCs) were investigated in Lake Dianchi, Lake Xingyun, and Lake Erhai of Southwestern China across two seasons (May and October 2020). Among phytoplankton, Cyanobacteria was the dominant species in all three lakes and attained greater dominance in October than in May due to variation in the RUE of nitrogen and phosphorus and environmental changes. The production of MCs, including MC_LR, MC_RR and MC_YR, was the result of the massive Cyanobacteria. Decreases in diversity and increases in heterogeneity were observed in the bacterial community structure. Nutrient levels, environmental factors and MCs (especially MC_YR) jointly affected the bacterial community in lakes, namely its diversity and community assembly. The cascading effects in lakes mediated by environmental conditions, phytoplankton community composition, RUE, community turnover, and MCs on bacterial communities were revealed in this study. These findings underscore the importance of relating phytoplankton community change and MCs to the bacterial community, which is fundamental for better understanding the lake ecosystem functioning and potential risks of MCs. 

Heterogeneous bacterial communities affected by phytoplankton community turnover and microcystins in plateau lakes of Southwestern China.

Antibiotics in the aquatic environment are of great concern as novel contaminants. In this study, we investigated the occurrence, distribution, potential sources, and risk assessment of antibiotics in an interconnected river–wetland–lake system. Thirty-three target antibiotics, including sulfonamides (SAs), macrolides (MLs), fluoroquinolones (FQs), tetracyclines (TCs), and chloramphenicol (CLs) belong to five common groups of antibiotics, were tested from water samples collected in the Panlong River, Xinghai Wetland, and Lake Dian (or Dianchi). Mass spectrophotometry was used to detect the target antibiotics, and the water quality parameters were measured in situ. We found four antibiotics, lincomycin (LIN), trimethoprim (TMP), sulfamethoxazole (SMX), and ofloxacin (OFL), with relatively low concentrations at the ng/L level, and detection rates among sample sites ranged from 42.3% to 76.9%, with maximum concentrations of 0.71 ng/L~5.53 ng/L. TMP was not detected in the Panlong River but appeared in the wetlands and Lake Dian. Midstream urban areas of the Panlong River showed the highest pollution among sites. Antibiotic concentrations were positively correlated with total nitrogen (TN) (p < 0.05) and showed some negative correlation with pH, salinity, and DO. According to the risk assessment, antibiotics in water do not pose a threat to human health and aquatic ecosystems, but a potentially harmful combined effect cannot be excluded. Our research offers a geographical summary of the distribution of antibiotics in urban river, wetland, and lake ecosystems in the plateau (PWL), which is important for predicting the distribution characteristics of antibiotics in the plateau water environment and establishing a standardized antibiotic monitoring and management system for the government.

Occurrence and Risk Assessment of Antibiotics in Urban River–Wetland–Lake Systems in Southwest China

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Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization

Recent water-level fluctuations, future trends and their eco-environmental impacts on Lake Qinghai.

Heterogeneous bacterial communities affected by phytoplankton community turnover and microcystins in plateau lakes of Southwestern China.

Occurrence and Risk Assessment of Antibiotics in Urban River–Wetland–Lake Systems in Southwest China