Tumor-Tailored Ionizable Lipid Nanoparticles Facilitate IL-12 Circular RNA Delivery for Enhanced Lung Cancer Immunotherapy.

The advancement of message RNA (mRNA) -based immunotherapies for cancer is highly dependent on the effective delivery of RNA (Ribonucleic) payloads using ionizable lipid nanoparticles (LNPs). However, the clinical application of these therapies is hindered by variable mRNA expression among different cancer types and the risk of systemic toxicity. The transient expression profile of mRNA further complicates this issue, necessitating frequent dosing and thus increasing the potential for adverse effects. Addressing these challenges, a high-throughput combinatorial method is utilized to synthesize and screen LNPs that efficiently deliver circular RNA (circRNA) to lung tumors. The lead LNP, H1L1A1B3, demonstrates a fourfold increase in circRNA transfection efficiency in lung cancer cells over ALC-0315, the industry-standard LNPs, while providing potent immune activation. A single intratumoral injection of H1L1A1B3 LNPs, loaded with circRNA encoding interleukin-12 (IL-12), induces a robust immune response in a Lewis lung carcinoma model, leading to marked tumor regression. Immunological profiling of treated tumors reveals substantial increments in CD45+ leukocytes and enhances infiltration of CD8+ T cells, underscoring the ability of H1L1A1B3 LNPs to modulate the tumor microenvironment favorably. These results highlight the potential of tailored LNP platforms to advance RNA drug delivery for cancer therapy, broadening the prospects for RNA immunotherapeutics.

Cardiac tissue model of immune-induced dysfunction reveals the role of free mitochondrial DNA and the therapeutic effects of exosomes.

Despite tremendous progress in the development of mature heart-on-a-chip models, human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip with circulating immune cells to model severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute myocarditis. We observed hallmarks of coronavirus disease (COVID-19)-induced myocardial inflammation, as the presence of immune cells augmented the secretion of proinflammatory cytokines, triggered progressive impairment of contractile function, and altered intracellular calcium transients. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the heart-on-a-chip and then validated in COVID-19 patients with low left ventricular ejection fraction, demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation-induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2-induced myocardial inflammation, we established that administration of endothelial cell-derived exosomes effectively rescued the contractile deficit, normalized calcium handling, elevated the contraction force, and reduced the ccf-mtDNA and cytokine release via Toll-like receptor-nuclear factor κB signaling axis.

Molecular insights into the microbial degradation of sediment-derived DOM in a macrophyte-dominated lake under aerobic and hypoxic conditions.

The mineralization of dissolved organic matter (DOM) in sediments is an important factor leading to the eutrophication of macrophyte-dominated lakes. However, the changes in the molecular characteristics of sediment-derived DOM during microbial degradation in macrophyte-dominated lakes are not well understood. In this study, the microbial degradation process of sediment-derived DOM in Lake Caohai under aerobic and hypoxic conditions was investigated using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and metagenomics. The results revealed that the microbial degradation of sediment-derived DOM in macrophyte-dominated lakes was more intense under aerobic conditions. The microorganisms mainly metabolized the protein-like substances in the macrophyte-dominated lakes, and the carbohydrate-active enzyme genes and protein/lipid-like degradation genes played key roles in sediment-derived DOM degradation. Organic compounds with high H/C ratios such as lipids, carbohydrates, and protein/lipid-like compounds were preferentially removed by microorganisms during microbial degradation. Meanwhile, there was an increase in the abundance of organic molecular formula with a high aromaticity such as tannins and unsaturated hydrocarbons with low molecular weight and low double bond equivalent. In addition, aerobic/hypoxic environments can alter microbial metabolic pathways of sediment-derived DOM by affecting the relative abundance of microbial communities (e.g., Gemmatimonadetes and Acidobacteria) and functional genes (e.g., ABC.PE.P1 and ABC.PE.P) in macrophyte-dominated lakes. The abundances of lipids, unsaturated hydrocarbons, and protein compounds in aerobic environments decreased by 58 %, 50 %, and 44 %, respectively, compared to in hypoxic environments under microbial degradation. The results of this study deepen our understanding of DOM biodegradation in macrophyte-dominated lakes under different redox environments and provide new insights into nutrients releases from sediment and continuing eutrophication in macrophyte-dominated lakes.

Corn stigma ameliorates hyperglycemia in zebrafish and GK rats of type 2 diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornstigma (CS), derived from the stigma and style of gramineous plant Zeamays. The medicinal use of CS can be traced back to DianNanMateriaMedica. LingnanMedicinalPlantsCompendium records its effectiveness in ameliorating diabetes. Diabetes is a metabolic disorder characterized by hyperglycemia and the consequent chronic complications of kidney, heart, brain and other organs, which pose a significant threat to human health. CS has shown great potential in relieving hyperglycemia associated with diabetes. However, the mechanism of CS in treating diabetes remains unclear. AIM OF THE STUDY: To explore the pathogenesis of diabetes and the mechanism of CS improving hyperglycemia in diabetes. MATERIALS AND METHODS: We measured apigenin and luteolin contents in CS by UPLC/MS/MS method. Selecting Wistar rats as normal group, and GK rats as model group. For rats, we detected glucose and lipid metabolism indicators, including GHb, AST, ALT, U-Glu, UA, U-TP, U-ALB, and ACR after treatment. For zebrafish, we utilized alloxan and sucrose to establish the diabetes model. Measuring zebrafish blood glucose is employed to evaluate the hypoglycemic capability of CS. In order to explore the mechanism of CS in treating diabetes, we sequenced the transcriptome of zebrafish, compared differentially expressed genes of normal, diabetic, and CS-treated group, and validated multiple enrichment pathways by PCR. RESULTS: CS can improve blood glucose levels in both GK rats and diabetic zebrafish. For rats, CS partially restored glucose and lipid metabolism indicators. Transcriptome data from zebrafish showed a close correlation with steroid biosynthesis. The RNA-Sequencing was consistent with PCR results, indicating that CS downregulated gene (fdft1,lss,cyp51) expression concerned with steroid biosynthesis pathway in the diabetes model. CONCLUSION: CS effectively improved blood glucose levels, regulated glucose and lipid metabolism by suppressing gene expression in steroid biosynthesis pathway, and ameliorated hyperglycemia. Our research provides valuable insights for CS in the treatment of diabetes, and proposes a new strategy for selecting clinical medications for diabetes.

Combinatorial design of ionizable lipid nanoparticles for muscle-selective mRNA delivery with minimized off-target effects.

Ionizable lipid nanoparticles (LNPs) pivotal to the success of COVID-19 mRNA (messenger RNA) vaccines hold substantial promise for expanding the landscape of mRNA-based therapies. Nevertheless, the risk of mRNA delivery to off-target tissues highlights the necessity for LNPs with enhanced tissue selectivity. The intricate nature of biological systems and inadequate knowledge of lipid structure-activity relationships emphasize the significance of high-throughput methods to produce chemically diverse lipid libraries for mRNA delivery screening. Here, we introduce a streamlined approach for the rapid design and synthesis of combinatorial libraries of biodegradable ionizable lipids. This led to the identification of iso-A11B5C1, an ionizable lipid uniquely apt for muscle-specific mRNA delivery. It manifested high transfection efficiencies in muscle tissues, while significantly diminishing off-targeting in organs like the liver and spleen. Moreover, iso-A11B5C1 also exhibited reduced mRNA transfection potency in lymph nodes and antigen-presenting cells, prompting investigation into the influence of direct immune cell transfection via LNPs on mRNA vaccine effectiveness. In comparison with SM-102, while iso-A11B5C1's limited immune transfection attenuated its ability to elicit humoral immunity, it remained highly effective in triggering cellular immune responses after intramuscular administration, which is further corroborated by its strong therapeutic performance as cancer vaccine in a melanoma model. Collectively, our study not only enriches the high-throughput toolkit for generating tissue-specific ionizable lipids but also encourages a reassessment of prevailing paradigms in mRNA vaccine design. This study encourages rethinking of mRNA vaccine design principles, suggesting that achieving high immune cell transfection might not be the sole criterion for developing effective mRNA vaccines.

Spatial variation of soil phosphorus in the water level fluctuation zone of the Three Gorges Reservoir: Coupling effects of elevation and artificial restoration.

The water level fluctuation zone (WLFZ) is a distinctive and important component of the reservoir ecosystem. Due to periodic inundation, the fraction, spatial distribution, and chemical reactivity of soil phosphorus (P) within the WLFZ can potentially impact the loading of P into reservoir waters. However, a detailed study of this subject is lacking. In this study, the soil P in the WLFZ of the Three Gorges Reservoir, China, was examined using a combination of chemical sequential extraction, 31P NMR, and adsorption experiments. The results of chemical sequential extraction showed that HCl-Pi constituted the largest P pool among all P forms, with a mean concentration of 338 mg/kg. The content of HCl-Pi decreased significantly toward the dam, while the content of Res-P decreased in the opposite direction. The highest contents of most P forms and total P were observed at an elevation of 160 m. 31P NMR measurements showed that NaOH-EDTA Pi detectable in WLFZ soils at 145 m, 160 m, and 175 m elevation consisted mainly of orthophosphate and pyrophosphate, while NaOH-EDTA Po contained phosphate monoesters and phosphate diesters, accounting for 1.4 % to 46.2 % of NaOH-EDTA TP. Adsorption experiments showed that soil P in the WLFZ was a potential P source for reservoir waters, with chemisorption being the dominant mechanism of P sequestration. The adsorption equilibrium concentration of WLFZ soil was lower at higher elevations (>170 m) compared to lower elevations (<150 m), exhibiting a decrease in the average maximum adsorption from 271 mg/kg to 192 mg/kg. Statistical analysis suggested that Ca and Fe content, particle size, elevation, and artificial restoration were key factors affecting the fraction and content of soil P in the WLFZ. Our findings contribute to an improved understanding of the behavior of soil P in the WLFZ of large reservoirs and its potential contribution to the reservoir waters.

Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the role of free mitochondrial DNA and therapeutic effects of endothelial exosomes.

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis. Briefly, we observed hallmarks of COVID-19-induced myocardial inflammation in the heart-on-a-chip model, as the presence of immune cells augmented the expression levels of proinflammatory cytokines, triggered progressive impairment of contractile function and altered intracellular calcium transient activities. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the in vitro heart-on-a-chip model and then validated in COVID-19 patients with low left ventricular ejection fraction (LVEF), demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2 induced myocardial inflammation, we established that administration of human umbilical vein-derived EVs effectively rescued the contractile deficit, normalized intracellular calcium handling, elevated the contraction force and reduced the ccf- mtDNA and chemokine release via TLR-NF-kB signaling axis.

External Application of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Hyaluronic Acid Gel Repairs Foot Wounds of Types I and II Diabetic Rats Through Paracrine Action Mode.

Diabetic foot ulcer (DFU) is a main diabetic complication with unmet treatment needs. This study applied human umbilical cord-derived mesenchymal stem cells-hyaluronic acid (hucMSCs-HA) gel to treat DFU in a noninvasive external way and investigated its paracrine action and mechanism. In this study, after analyzing the physical and biological properties of HA gel, hucMSCs-HA gel was applied in 2 in vivo models (types I and II DFU), and a molecular mechanism was investigated. To evaluate the paracrine action of hucMSCs, hucMSCs-conditional medium (MSC-CM) was collected to treat 1 in vivo model (type I DFU) and 2 in vitro models (high glucose (HG)-injured human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs)). The results indicated that HA gel with a porous microstructure underwent over 90% degradation and swelled to the maximum value within 48 h. In vivo, hucMSCs-HA gel accelerated wound healing of DFU rats by improving re-epithelialization, collagen deposition, and angiogenesis, in which a paracrine action of hucMSCs was confirmed and the phosphorylation of p38, ERK1/2, JNK, and Akt was increased. In vitro, MSC-CM improved cell viability, wound healing, migration, tube formation, cell senescence, and abnormal expressions (TNF-α, IL-1ß, IL-6, ET-1, p16 genes, and PCNA protein) of HUVECs, also improved cell viability, wound healing, antioxidant stress, and abnormal expressions (COL1, COL3, COL4, SOD1, SOD2 genes, and PCNA protein) of HSFs. Summarily, noninvasive external application of hucMSCs-HA gel shows great perspective against DFU and exerts wound healing effects through the MAPK and Akt pathways-mediated paracrine mechanism.

Application of two-dimension, high-resolution evidences to reveal the biogeochemical process patterns of trace metals in reservoir sediments.

Pollutions of trace metals (TMs) in reservoirs are blooming due to TMs were trapped efficiently in reservoir sediments by dams. Despite the mobilization of TMs in sediments have been well-documented, the patterns of biogeochemical processes occurred in sediments remain poorly understanding. Herein, a deep reservoir was selected to investigate the patterns of TMs biogeochemical processes in sediments by using high-resolution ZrO-Chelex-AgI diffusive gradient in thin films technique (HR-ZCA DGT) and the laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). 2-dimension high-resolution (2D-HR) images showed significant differential spatial enrichment of TMs (V, Mn, Fe, Co, Zn and Sb) in sediments, indicating strong heterogeneity in sediments. Correlations of TMs within microniches (diameter < 1 mm) in horizontal were usually different even contrast with that in vertical profile, suggesting distinct biogeochemical process patterns occurred in vertical vs. in horizontal. Further analyses from 2D-HR images showed the distributions of TMs in microniches reflected their mobilization that was driven by microenvironmental conditions. In contrast, distributions in sediment vertical profile recorded the diagenesis in different deposition depth. The diagenesis in sediment vertical is continuously accumulated by the discrete, microniches mobilization of TMs in horizontal. Collectively, our findings evidenced that 2D-HR data is an update complement to 1-dimension data for better interpret the biogeochemical process patterns of TMs in sediments, that have implication for water management to metals pollution in reservoir ecosystems.

Relationship between anthropogenic factors and freshwater quality in Hainan Province, south China.

Water resource security directly or indirectly affects the development of society, economy, and the environment, and is of massive significance for regional sustainable development. This study addresses whether anthropogenic activities, especially from tourism, significantly affect the freshwater quality in Hainan Province, China. The freshwater quality in Hainan Province was generally good in 2012 to 2015 (at level II, GB3838-2002). Agriculture, fishery, animal husbandry, and chemical oxygen demand discharge mainly affect freshwater quality in the Nandu and Changhua rivers. Water quality in Wanquan River is more susceptible to tourism in comparison with the Nandu and Changhua rivers. DO content in the Wanquan River fluctuated greatly. It remains necessary to closely monitor negative changes in water quality due to increasing tourism, especially in Wanquan River and eastern Hainan Province. The developed radial basis function neural network shows that the changes in water quality are predicted accurately in comparison with experimental values in the present study. Our results suggested that current anthropogenic factors had a modest effect on water quality on Hainan Island, while tourism had a perceptible effect in eastern Hainan. Our findings provide a reference for the interplay of water quality, people's livelihood, and economic development (tourism and port construction) in Hainan Province.

Suspended phosphorus sustains algal blooms in a dissolved phosphorus-depleted lake.

The expansion of algal bloom in surface waters is a global problem in the freshwater ecosystem. Differential reactivity of organic phosphorus (Po) compounds from organic debris, suspended particulate matter (SPM), and sediment towards hydrolysis can dictate the extent of supply often limited inorganic P (Pi) for algal growth, thereby controlling the extent of bloom. Here, we combined solution P-31 nuclear magnetic resonance (31P NMR), sequential extraction, enzymatic hydrolysis, and 16S rRNA measurements to characterize speciation and biogeochemical cycling of P in Lake Erhai, China. Lower ratios of diester-P/monoester-P in SPM in January (mean 0.09) and July (0.14) than that in April (0.29) reflected the higher degree of diester-P remineralization in cold and warm months. Both H2O-Pi and Po were significantly higher in SPM (mean 1580 mg ·kg-1 and 1618 mg ·kg-1) than those in sediment (mean 8 mg ·kg-1 and 387 mg ·kg-1). In addition, results from enzymatic hydrolysis experiments demonstrated that 61% Po in SPM and 58% in sediment in the H2O, NaHCO3, and NaOH extracts could be hydrolyzed. These results suggested that H2O-Pi and Po from SPM were the primarily bioavailable P sources for algae. Changes of Pi contents (particularly H2O-Pi) in algae and alkaline phosphatase activity (APA) during the observation periods were likely to be controlled by the strategies of P uptake and utilization of algae. P remobilization/remineralization from SPM likely resulted from algae and bacteria (e.g., Pseudomonas). Collectively, these results provide important insights that SPM P could sustain the algal blooms even if the dissolved P was depleted in the water column.

Intravenous injection of human umbilical cord-derived mesenchymal stem cells ameliorates not only blood glucose but also nephrotic complication of diabetic rats through autophagy-mediated anti-senescent mechanism.

BACKGROUND: Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus, which is characterized by early occurrence of albuminuria and end-stage glomerulosclerosis. Senescence and autophagy of podocytes play an important role in DN development. Human umbilical cord-derived mesenchymal stem cells (hucMSCs) have potential in the treatment of diabetes and its complications. However, the role of hucMSCs in the treatment of DN and the underlying mechanism remain unclear. METHODS: In vivo, a streptozotocin-induced diabetic male Sprague Dawley rat model was established to determine the renoprotective effect of hucMSCs on DN by biochemical analysis, histopathology, and immunohistochemical staining of renal tissues. And the distribution of hucMSCs in various organs in rats within 168 h was analyzed. In vitro, CCK8 assay, wound healing assay, and ß-galactosidase staining were conducted to detect the beneficial effects of hucMSCs on high glucose-induced rat podocytes. Real-time PCR and western blot assays were applied to explore the mechanism of action of hucMSCs. RESULTS: The in vivo data revealed that hucMSCs were distributed into kidneys and significantly protected kidneys from diabetic damage. The in vitro data indicated that hucMSCs improved cell viability, wound healing, senescence of the high glucose-damaged rat podocytes through a paracrine action mode. Besides, the altered expressions of senescence-associated genes (p16, p53, and p21) and autophagy-associated genes (Beclin-1, p62, and LC3) were improved by hucMSCs. Mechanistically, hucMSCs protected high glucose-induced injury in rat podocytes by activating autophagy and attenuating senescence through the AMPK/mTOR pathway. CONCLUSIONS: In conclusion, hucMSCs might be a promising therapeutic strategy for the clinical treatment of DN-induced renal damages.

Antimony isotope fractionation and the key controls in the soil profiles of an antimony smelting area.

The controlling factors of antimony migration and transformation in soil profiles are still unclear. Antimony isotopes might be a useful tool to trace it. In this paper, antimony isotopic compositions of plant and smelter-derived samples, and two soil profiles were measured for the first time. The δ123Sb values of the surface and bottom layers of the two soil profiles varied in 0.23‰-1.19‰ and 0.58‰-0.66‰, respectively, while δ123Sb of the smelter-derived samples varied in 0.29‰-0.38‰. The results show that the antimony isotopic compositions in the soil profiles are affected by post-depositional biogeochemical processes. The enrichment and loss of light isotopes at 0-10 cm and 10-40 cm layers of the contrasted soil profile may be controlled by plant uptake process. The loss and enrichment of heavy isotopes in the 0-10 cm and 10-25 cm layers of the antimony from smelting source in the polluted soil profile may be controlled by the adsorption process, while the enrichment of light isotopes in the 25-80 cm layer may be related to the reductive dissolution process. The conclusion emphasizes that the promotion of the Sb isotope fractionation mechanism will play a crucial role in understanding the migration and transformation behaviors of Sb in soil systems.

Extensive abundances and characteristics of microplastic pollution in the karst hyporheic zones of urban rivers.

Cities are potential areas for microplastic pollution due to large-scale production and the use of plastic products. The karst ecosystem in southwestern China is fragile, and pollutants are more likely to be transported over long distance, resulting in higher pollution risks. Understanding the abundance and composition of microplastics in karst urban water systems is crucial for microplastic pollution management in a karst region. This study investigates the abundances and characteristics of microplastics typically found in river sediments in 10 cities in karst regions of Southwest China. The results show that the abundance of microplastics in sediments ranged from 800 items·kg-1 to 4400 items·kg-1, with an average of 2273 ± 775 items·kg-1 (n = 30), indicating high abundance. Polyamide (PA) was the most common plastic polymer types in all sediment samples. The abundance of microplastics in the downstream (2527 ± 698 items·kg-1) was higher than that in the midstream (2350 ± 999 items·kg-1) and upstream areas (1943 ± 370 items·kg-1), indicating a gradual accumulation effect in the karst water systems. Microplastic abundance in cities (2119 ± 838 items·kg-1) was lower than in counties (2427 ± 671 items·kg-1). No significant correlation was found between microplastic abundance in rivers of urban areas and the level of regional population and economy, but significantly negatively correlated with the efficiency of urban sewage treatment. The results obtained from this study provided insights into the management of microplastic pollution in urban river of a karst region.

Sedimentary records of polycyclic aromatic hydrocarbons from three enclosed lakes in China: Response to energy structure and economic development.

Historical polycyclic aromatic hydrocarbon (PAH) pollution was explored through the sedimentary records of three lakes: Huguangyan Maar Lake (HGY) in South China, Mayinghai Lake (MYH) in North China, and Sihailongwan Lake (SHLW) in Northeast China. In these three lakes, the PAH concentrations in sediments are still rising, showing the different trend to lakes in developed countries. PAH pollution in South China occurred from 1850, much earlier than the increases since 1980 observed in North and Northeast China. The temporal trends of PAH concentrations in lake sediments are highly correlated with local economic development. Spatially, although the region where HGY is located has the highest gross domestic product, higher fluxes of PAHs were found in MYH sediments, indicating that atmospheric PAH pollution in North China might be more serious, and that PAH pollution is not fully correlated with economic development. Source analysis suggested that the PAHs in lake sediments are mainly derived from oil leaks, coal and biomass combustion, vehicle emissions, and diagenesis. Positive matrix factorization (PMF) model revealed that the contribution of vehicle emissions and coal combustion to PAHs has increased significantly in the past 40 years. Benzo(a)pyrene equivalent (BaPE) in the surface sediments of MYH and SHLW were similar and higher than in HGY. In HGY, vehicle emissions posed the highest toxic risk, followed by coal combustion. However, in MYH, the toxicity risk of vehicle emissions was close to that of coal and biomass combustion due to the highly developed coal industry in Shanxi Province. In SHLW, the contribution of fossil fuel combustion to BaPE was significantly higher than that of biomass combustion. This study provides important information for understanding PAH pollution affected by anthropogenic activities in the Anthropocene and provides a scientific basis for formulating PAH pollution control strategies.

Identification of six hub genes and two key pathways in two rat renal fibrosis models based on bioinformatics and RNA-seq transcriptome analyses.

Renal fibrosis (RF) is the common pathological manifestation and central treatment target of multiple chronic kidney diseases with high morbidity and mortality. Currently, the molecular mechanisms underlying RF remain poorly understood, and exploration of RF-related hub targets and pathways is urgently needed. In this study, two classical RF rat models (adenine and UUO) were established and evaluated by HE, Masson and immunohistochemical staining. To clear molecular mechanisms of RF, differentially expressed genes (DEGs) were identified using RNA-Seq analysis, hub targets and pathways were screened by bioinformatics (functional enrichment analyses, PPI network, and co-expression analysis), the screening results were verified by qRT-PCR, and potential drugs of RF were predicted by network pharmacology and molecular docking. The results illustrated that renal structures were severely damaged and fibrotic in adenine- and UUO-induced models, as evidenced by collagen deposition, enhanced expressions of biomarkers (TGF-ß1 and α-SMA), reduction of E-cadherin biomarker, and severe renal function changes (significantly decreased UTP, CREA, Ccr, and ALB levels and increased UUN and BUN levels), etc. 1189 and 1253 RF-related DEGs were screened in the adenine and UUO models, respectively. Two key pathways (AGE-RAGE and NOD-like receptor) and their hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) were identified by PPI networks, co-expressed relationships, and qRT-PCR verification. Furthermore, various reported herbal ingredients (curcumin, resveratrol, honokiol, etc.) were considered as important drug candidates due to the strong binding affinity with these hub targets. Overall, this study mainly identified two key RF-related pathways (AGE-RAGE and NOD-like receptor), screened hub targets (Tgfb1, Col1a1, Nlrc4, Casp4, Trpm2, and Il18) that involved inflammation, ECM formation, myofibroblasts generation, and pyroptosis, etc., and provided referable drug candidates (curcumin, resveratrol, honokiol, etc.) in basic research and clinical treatment of RF.

Fuel from within: Can suspended phosphorus maintain algal blooms in Lake Dianchi.

Extensive algal bloom in the surface water is a pressing issue in Lake Dianchi that causes lake restoration to be difficult owing to complex and variable phosphorus (P) sources in the water column. P released from algae, suspended particles (SS), and sediment can provide sustainable P sources for algal blooms. However, little is known regarding the dynamic of P speciation in these substances from different sources. In this study, solution 31P nuclear magnetic resonance (31P NMR) and chemical sequential extraction were employed to identify P speciation in algae, SS, and sediment during different periods. Results showed that dissolved inorganic P (Pi) directly accumulated in algae in the form of orthophosphate (ortho-P) and pyrophosphate (pyro-P). Algae preferentially utilized Pi, followed by organic P (Po) in the water column when the Pi was insufficient during growth and reproduction. The 31P NMR spectra demonstrated that ortho-P, orthophosphate monoesters (mono-P), orthophosphate diesters (diester-P), and pyro-P dominated the P compounds across the samples tested. Increasing remineralization of SS mono-P driven by intense alkaline phosphatase activities was caused by increasing P needs of algae and pressure of P supply in the water column. The higher ratios of diester-P to mono-P in sediment (mean 0.55) than those in algae (mean 0.07) and SS (mean 0.11 in surface water, 0.14 in bottom water) suggested that the degradation and regeneration occurred within these P compounds during or after sedimentation. Pi content in algae during growth and reproduction was controlled by its P absorption and utilization strategies. Results of this study provide insights into the dynamic cycling of P in algae, SS, and sediment, explaining the reason for algal blooms in the surface water with low concentrations of dissolved P.

Effects of cascade dams on the occurrence and distribution of microplastics in surface sediments of Wujiang river basin, Southwestern China.

The influence of cascade dams on the migration of microplastics (MPs) was conducted by analyzing the spatial distribution of MPs in sediments of the Wujiang river basin (Wujiang river basin) in Southwest China. The results showed that the abundance of MPs in Wujiang river basin sediments ranged from 310 to 2620 items/kg dw (mean: 1354 items/kg dw, a high level compared with aquatic sediments worldwide). The main chemical components of these MPs were polypropylene and polyethylene. High abundance of MPs in tributary sediments suggested that tributary inputs contributed to the main stream and reservoirs. Statistical analysis showed that gross domestic product (GDP) and the basin area of cascade reservoirs, rather than hydraulic retention time and reservoir age, were the dominating factors in the distribution of MPs in the Wujiang river basin. The accumulation of MPs in cascade reservoirs implied the interception effect of cascade dams. The rapid development of cascade dam systems and the interception effect of dams should be taken into account when predicting the flux of MPs from rivers to the ocean. Heavy metals found on the surface of the MPs showed the compound pollution of MPs and heavy metals in dammed rivers and cascade reservoirs. Our results deepen the understanding of the migration of MPs in rivers alongside intensive cascade hydropower development.

Human umbilical cord-derived mesenchymal stem cells not only ameliorate blood glucose but also protect vascular endothelium from diabetic damage through a paracrine mechanism mediated by MAPK/ERK signaling.

BACKGROUND: Endothelial damage is an initial step of macro- and micro-vasculature dysfunctions in diabetic patients, accounting for a high incidence of diabetic vascular complications, such as atherosclerosis, nephropathy, retinopathy, and neuropathy. However, clinic lacks effective therapeutics targeting diabetic vascular complications. In field of regenerative medicine, mesenchymal stem cells, such as human umbilical cord-derived MSCs (hucMSCs), have great potential in treating tissue damage. METHODS: To determine whether hucMSCs infusion could repair diabetic vascular endothelial damage and how it works, this study conducted in vivo experiment on streptozotocin-induced diabetic rat model to test body weight, fasting blood glucose (FBG), serum ICAM-1 and VCAM-1 levels, histopathology and immunohistochemical staining of aorta segments. In vitro experiment was further conducted to determine the effects of hucMSCs on diabetic vascular endothelial damage, applying assays of resazurin staining, MTT cell viability, wound healing, transwell migration, and matrigel tube formation on human umbilical vein endothelial cells (HUVECs). RNA sequencing (RNAseq) and molecular experiment were conducted to clarify the mechanism of hucMSCs. RESULTS: The in vivo data revealed that hucMSCs partially restore the alterations of body weight, FBG, serum ICAM-1 and VCAM-1 levels, histopathology of aorta and reversed the abnormal phosphorylation of ERK in diabetic rats. By using the conditioned medium of hucMSCs (MSC-CM), the in vitro data revealed that hucMSCs improved cell viability, wound healing, migration and angiogenesis of the high glucose-damaged HUVECs through a paracrine action mode, and the altered gene expressions of IL-6, TNF-α, ICAM-1, VCAM-1, BAX, P16, P53 and ET-1 were significantly restored by MSC-CM. RNAseq incorporated with real-time PCR and Western blot results clarified that high glucose activated MAPK/ERK signaling in HUVECs, while MSC-CM reversed the abnormal phosphorylation of ERK and overexpressions of MKNK2, ERBB3, MYC and DUSP5 in MAPK/ERK signaling pathway. CONCLUSIONS: HucMSCs not only ameliorated blood glucose but also protected vascular endothelium from diabetic damage, in which MAPK/ERK signaling mediated its molecular mechanism of paracrine action. Our findings provided novel knowledge of hucMSCs in the treatment of diabetes and suggested a prospective strategy for the clinical treatment of diabetic vascular complications.

Experimental and modeling evidence of hydroxyl radical production in iron electrocoagulation as a new mechanism for contaminant transformation in bicarbonate electrolyte.

Iron electrocoagulation is designed for sustainable high-efficiency and high-flexibility water purification applications. Recent advances reported that hydroxyl radicals (•OH)-based oxidative transformation of organic contaminants can occur in iron electrocoagulation. However, there is still a lack of mechanistic understanding the production of •OH in bicarbonate electrolyte, which presents a critical knowledge gap in the optimization of iron electrocoagulation technology towards practical application. Combined with contaminant degradation, radical quenching experiments, and spectroscopic techniques, we found that •OH was produced at rate of 16.1 µM∙h - 1 during 30-mA iron electrocoagulation in bicarbonate electrolyte through activation of O2 by Fe(II) under pH-neutral conditions. High yield of •OH occurred at pH 8.5, likely due to high adsorbed Fe(II) that can activate O2 to enhance •OH production. Mössbauer and X-ray photoelectron spectroscopy measurements substantiated that Fe(II)-adsorbed lepidocrocite was the dominant solid Fe(II) species at pH 8.5. A process-based kinetic modeling was developed to describe the dynamic of •OH production, Fe(II) oxidation, and contaminant degradation processes in iron electrocoagulation. Findings of this study extend the functionality of electrocoagulation from phase separation to •OH-based advanced oxidation process, which provides a new perspective for the development of electrocoagulation-based next generation sustainable water purification technology.