Distribution, toxicity load and risk assessment of heavy metals in the groundwater of Dhemaji, Assam, India.
Chemosphere
Metal contamination in drinking water has drawn attention since it gravely jeopardizes human health. This study was conducted in pre- and post-monsoon season in 2021 at Dhemaji, Assam, India. It characterized metal pollutants in groundwater, their distribution, possible sources, and evaluated the potential toxicity and associated health risk assessment. The seasonal mean concentration of Fe in both seasons is observed highest followed by Mn, Zn, Cu, As, and Ni. Furthermore, the metal concentrations during pre-monsoon are comparatively higher. The geogenic processes and agricultural practices are the major sources of groundwater metal contamination as evident from the statistical analysis. The different pollution indices viz. Heavy-metal Pollution Index (HPI), Heavy-metal Evaluation Index (HEI) and Degree of Contamination (Cd) suggested that groundwater is not suitable for drinking uses. The Heavy Metal Toxicity Load (HMTL) suggesting As, Co, Mn and Hg should be removed from the groundwater to ensure safety. Water pollution indices (WPI) suggest that Fe, Mn, As and Ni are the main pollution-causing metals in the study area which may be restored under the BIS and WHO limit by diluting the water. The human health risk has been calculated by carcinogenic and non-carcinogenic risk assessment. The non-carcinogenic risk for adults and children is within the threshold limit. The carcinogenic risk shows that continuous exposure of As and Ni may give rise to cancer among adults and children in the region. Therefore, comprehensive groundwater quality monitoring with well-planned treatment should be needed to provide safe and clean drinking water in the studied area.
10.1016/j.chemosphere.2024.141979
Comprehensive monitoring of contamination and ecological-health risk assessment of potentially harmful elements in surface water of Maroon-Jarahi sub-basin of the Persian Gulf, Iran.
Environmental geochemistry and health
The increase in heavy metal concentration in water bodies due to rapid industrial and socio-economic development significantly threatens ecological and human health. This study evaluated metal pollution and related risks to ecology and human health in the Maroon-Jarahi river sub-basin in the Persian Gulf and Oman Sea basin, southwest Iran, using various indicators. A total of 70 water samples were taken from the sampling sites in the Maroon, Allah, and Jarahi sub-basins and analyzed for nine heavy metals. According to the results, the mean concentration of metals in the sampling locations across the entire sub-basin of Maroon-Jarahi was observed as follows Iron (528.22 µg/L), zinc (292.62 µg/L), manganese (56.47 µg/L), copper (36.23 µg/L), chromium (11.78 µg/L), arsenic (7.09 µg/L), lead (3.43 µg/L), nickel (3.23 µg/L), and cadmium (1.38 µg/L). Most of the metals were detected at the highest concentration in the sub-basin of the Jarahi River. The Water Quality Index (WQI) index in the basin varied from 18.74 to 22.88, indicating well to excellent quality. However, the investigation of the pollution status at the monitoring stations, based on the classification of Degree of Contamination (CD) and Heavy Metal Pollution Index (HPI) indices, revealed that they are in the category of relatively high pollution (16 < CD < 32) to very high (32 ≤ CD), and in the low pollution category (HPI < 15) to high pollution (HPI < 30), respectively. According to the three sub-basins, the highest amount of WQI, HPI, and Cd was observed in the stations located in the sub-basins of the Jarahi River. The calculation of Heavy Metal Evaluation Index (HEI) also indicated that only 10% of the monitoring stations are in moderate pollution (10 < HEI < 20), while in other monitoring stations the HEI level is less than 10. The Potential ecological risk factors ( ) of an individual metal was obtained as follows: Cd (173.70) > As (131.99) > Zn (57.52) > Cu (55.39) > Ni (48.98) > Cr (21.57) > Pb (0.71), revealing that Cd and As are the main elements responsible for creating ecological risk in the studied area. The Maroon-Jarahi watershed included areas with ecological risks that ranged from low (PERI ≤ 150) to very high (PERI ≥ 600). HI and ILCR health indicators indicated that consumption and long-term contact with river water in the study area can cause potential risks to human health, especially children. Moreover, the findings, the highest level of pollution and health risk for both children and adults, considering both exposure routes, occurred in the Jarahi River sub-basin, suggesting that those who live in the vicinity of the Jarahi River are likely to face more adverse health effects. In addition, the findings of the evaluation of the relationship between land use patterns and water quality in the studied basin showed that agricultural lands acts as a main source of pollutants, but forest lands play an important role in the deposition of pollutants and the protection of water quality at the basin scale. In general, the results of pollution indicators, risk assessment, and statistical techniques suggest that the lower sub-basin, the Jarahi area, and the Shadegan wetland are the most polluted areas in the investigated sub-basin due to excessive discharge of agricultural runoff, industrialization, and rapid urbanization. Thus, special measures should be considered to reduce the risks of HMs pollution in the sub-basin of the Maroon-Jarahi watershed, especially its downstream and the impact of agricultural land use on water quality should be taken into consideration in basin management plans.
10.1007/s10653-024-02181-2
Remote sensing-based monitoring and evaluation of the basin-wise dynamics of terrestrial water and groundwater storage fluctuations.
Environmental monitoring and assessment
The recent dynamics of terrestrial water storage (TWS) and groundwater storage (GWS) fluctuations were investigated based on the Gravity Recovery And Climate Experiment (GRACE) observations over 25 basins of Türkiye. Coarse-resolution GRACE estimates were downscaled based on the Random Forest algorithm. The impacts of precipitation (P) and evapotranspiration (ET) on the variations of water storage were also assessed. The findings demonstrated good performance for the RF model in simulating finer resolution estimates of TWS. The results indicated a diminishing trend of TWS and its hydrologic components over all the basins from 2003 to 2020. The Doğu Akdeniz Basin with the annually decreasing TWS and GWS of [Formula: see text] and [Formula: see text] was the most critical basin of Türkiye. The least storage loss was observed in the Batı Karadeniz Basin with the annual TWS and GWS loss of [Formula: see text] and [Formula: see text], respectively. Based on the results, Türkiye has lost, on average, an estimated [Formula: see text] and [Formula: see text] of its TWS and GWS, respectively, which are equivalent to the total storage loss of [Formula: see text] and [Formula: see text] of TWS and GWS during the last 18 years. The results also indicated that P and ET interact differently with the variations of TWS and GWS. The net water flux was revealed to be partially correlated with the total water storage fluctuations, suggesting the governing role of other deriving forces particularly the anthropogenic factors in the spatiotemporal variations of Türkiye's water storage; therefore, a sector-specific analysis of the water storage variations is crucial for the country, particularly by concentrating more on the dynamics of GWS.
10.1007/s10661-023-11480-7
Evaluation and monitoring of the water quality of an Argentinian urban river applying multivariate statistics.
Environmental science and pollution research international
In this work, we present the water quality assessment of an urban river, the San Luis River, located in San Luis Province, Argentina. The San Luis River flows through two developing cities; hence, urban anthropic activities affect its water quality. The river was sampled spatially and temporally, evaluating ten physicochemical variables on each water sample. These data were used to calculate a Simplified Index of Water Quality in order to estimate river water quality and infer possible contamination sources. Data were statistically analyzed with the opensource software R, 4.1.0 version. Principal component analysis, cluster analysis, correlation matrices, and heatmap analysis were performed. Results indicated that water quality decreases in areas where anthropogenic activities take place. Robust inferential statistical analysis was performed, employing an alternative of multivariate analysis of variance (MANOVA), MANOVA.wide function. The most statistically relevant physicochemical variables associated with water quality decrease were used to develop a multiple linear regression model to estimate organic matter, reducing the variables necessary for continuous monitoring of the river and, hence, reducing costs. Given the limited information available in the region about the characteristics and recovery of this specific river category, the model developed is of vital importance since it can quickly detect anthropic alterations and contribute to the environmental management of the rivers. This model was also used to estimate organic matter at sites located in other similar rivers, obtaining satisfactory results.
10.1007/s11356-024-33205-0
Evaluation of water pollution monitoring for heavy metal contamination: A case study of Agodi Reservoir, Oyo State, Nigeria.
Environmental monitoring and assessment
Heavy metals affect the suitability of aquatic environment for all purposes; hence, this study evaluated heavy metal contamination in Agodi Reservoir Oyo State, Nigeria. Atomic Absorption Spectrophotometry was used to determine heavy metal concentrations. Heavy Metal Pollution Index (HPI), Water Quality Index (WQI), Pollution Index (PI), Comprehensive Pollution Index (CPI), Contamination Index (CI), Single-Factor Pollution Index (SFPI), Heavy metal Evaluation Index (HEI), and Human Health Risk Assessments (HRA) were used to determine the extent of heavy metal pollution and their impact on the aquatic environment. The order of heavy metal concentrations in both wet and dry seasons was Fe > Mn > Zn > Cu > Cd > Ni > Cr > Pb > Co and Mn > Fe > Zn > Cu > Co > Ni > Cd > Cr > Pb, respectively. WQI for both wet (3182.6) and dry (3649.5) seasons classified the reservoir as "unsuitable for aquatic life." Also, the CPI rated the reservoir to be "severely polluted" in both dry (311.2) and wet (268.7) seasons. Similarly, HEI (951.3 and 2059.7) and Cd (942.3 and 2050.7) rated the reservoir as "highly polluted" in wet and dry seasons, respectively. The Hazard Quotient (HQ ingestion) was in the order of Mn > Cu > Cd > Zn > Fe > Co > Ni > Cr > Pb in the dry season while the order was Cu > Mn > Cd > Fe > Zn > Ni > Pb > Co > Cr in the wet season. The HQ ingestion revealed that Cr (0.00), Ni (0.33; 022), and Pb (0.00; 0.06) were the only metals with HQ values lesser than 1 (HQ < 1) while the values of HQ (dermal) were less 1 (HQ < 1) indicating that there was no health risk in association with the domestic use of the water. The pollution level of the reservoir means that urgent attention is needed from different agencies for the conservation, management, and sustainable development of the reservoir.
10.1007/s10661-022-10326-y
Water Quality Evaluation and Pollution Source Apportionment of Surface Water in a Major City in Southeast China Using Multi-Statistical Analyses and Machine Learning Models.
International journal of environmental research and public health
The comprehensive evaluation of water quality and identification of potential pollution sources has become a hot research topic. In this study, 14 water quality parameters at 4 water quality monitoring stations on the M River of a city in southeast China were measured monthly for 10 years (2011-2020). Multiple statistical methods, the water quality index (WQI) model, machine learning (ML), and positive matrix factorisation (PMF) models were used to assess the overall condition of the river, select crucial water quality parameters, and identify potential pollution sources. The average WQI values of the four sites ranged from 68.31 to 77.16, with a clear trend of deterioration from upstream to downstream. A random forest-based WQI model (WQI model) was developed, and the results showed that Mn, Fe, faecal coliform, dissolved oxygen, and total nitrogen were selected as the top five important water quality parameters. Based on the results of the WQI and PMF models, the contributions of potential pollution sources to the variation in the WQI values were quantitatively assessed and ranked. These findings prove the effectiveness of ML in evaluating water quality, and improve our understanding of surface water quality, thus providing support for the formulation of water quality management strategies.
10.3390/ijerph20010881
Deep optimization of water quality index and positive matrix factorization models for water quality evaluation and pollution source apportionment using a random forest model.
Environmental pollution (Barking, Essex : 1987)
Effective evaluation of water quality and accurate quantification of pollution sources are essential for the sustainable use of water resources. Although water quality index (WQI) and positive matrix factorization (PMF) models have been proven to be applicable for surface water quality assessments and pollution source apportionments, these models still have potential for further development in today's data-driven, rapidly evolving technological era. This study coupled a machine learning technique, the random forest model, with WQI and PMF models to enhance their ability to analyze water pollution issues. Monitoring data of 12 water quality indicators from six sites along the Minjiang River from 2015 to 2020 were used to build a WQI model for determining the spatiotemporal water quality characteristics. Then, coupled with the random forest model, the importance of 12 indicators relative to the WQI was assessed. The total phosphorus (TP), total nitrogen (TN), chemical oxygen demand (COD), dissolved oxygen (DO), and five-day biochemical oxygen demand (BOD) were identified as the top five significant parameters influencing water quality in the region. The improved WQI model constructed based on key parameters enabled high-precision (R = 0.9696) water quality prediction. Furthermore, the feature importance of the indicators was used as weights to adjust the results of the PMF model, allowing for a more reasonable pollutant source apportionment and revealing potential driving factors of variations in water quality. The final contributions of pollution sources in descending order were agricultural activities (30.26%), domestic sewage (29.07%), industrial wastewater (26.25%), seasonal factors (6.45%), soil erosion (6.19%), and unidentified sources (1.78%). This study provides a new perspective for a comprehensive understanding of the water pollution characteristics of rivers, and offers valuable references for the development of targeted strategies for water quality improvement.
10.1016/j.envpol.2024.123771
A novel senolytic drug for pulmonary fibrosis: BTSA1 targets apoptosis of senescent myofibroblasts by activating BAX.
Aging cell
Idiopathic pulmonary fibrosis is a progressive and age-related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL-2 and BCL-XL, leading to BAX inactivation. We further showed that high levels of inactive BAX-mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (QVD-OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1-activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment.
10.1111/acel.14229
Spatial targeting of fibrosis-promoting macrophages with nanoscale metal-organic frameworks for idiopathic pulmonary fibrosis therapy.
Acta biomaterialia
Targeted delivery of therapeutic drugs to fibrosis-promoting macrophages (FPMs) holds promise as a challenging yet effective approach for the treatment of idiopathic pulmonary fibrosis (IPF). Here, nanocarriers composed of Mn-curcumin metal-organic frameworks (MOFs) were utilized to deliver the immune inhibitor BLZ-945 to the lungs, with the goal of depleting fibrosis-promoting macrophages (FPMs) from fibrotic lung tissues. FPM targeting was achieved by functionalizing the nanocarrier surface with an M2-like FPM binding peptide (M2pep). As a result, significant therapeutic benefits were observed through the successful depletion of approximately 80 % of the M2-like macrophages (FPMs) in a bleomycin-induced fibrosis mouse model treated with the designed M2-like FPM-targeting nanoparticle (referred to as M2NP-BLZ@Mn-Cur). Importantly, the released Mn2 and curcumin after the degradation of M2NP-BLZ@Mn-Cur accumulated in the fibrotic lung tissue, which can alleviate inflammation and oxidative stress reactions, thereby further improving IPF therapy. This study presents a novel strategy with promising prospects for molecular-targeted fibrosis therapy. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs)- based nanocarriers equipped with both fibrosis-promoting macrophage (FPM)-specific targeting ability and therapeutic drugs are appealing for pulmonary fibrosis treatment. Here, we prepared M2pep (an M2-like FPM binding peptide)-modified and BLZ945 (a small molecule inhibitor of CSF1/CSF-1R axis)-loaded Mn-curcumin MOF nanoparticles (M2NP-BLZ@Mn-Cur) for pulmonary fibrosis therapy. The functionalized M2NP-BLZ@Mn-Cur nanoparticles can be preferentially taken up by FPMs, resulting in their depletion from fibrotic lung tissues. In addition, Mnand curcumin released from the nanocarriers have anti-inflammation and immune regulation effects, which further enhance the antifibrotic effect of the nanoparticles.
10.1016/j.actbio.2023.12.006
SLC15A3 plays a crucial role in pulmonary fibrosis by regulating macrophage oxidative stress.
Cell death and differentiation
Idiopathic pulmonary fibrosis (IPF) is a fatal and irreversible disease with few effective treatments. Alveolar macrophages (AMs) are involved in the development of IPF from the initial stages due to direct exposure to air and respond to external oxidative damage (a major inducement of pulmonary fibrosis). Oxidative stress in AMs plays an indispensable role in promoting fibrosis development. The oligopeptide histidine transporter SLC15A3, mainly expressed on the lysosomal membrane of macrophages and highly expressed in the lung, has proved to be involved in innate immune and antiviral signaling pathways. In this study, we demonstrated that during bleomycin (BLM)- or radiation-induced pulmonary fibrosis, the recruitment of macrophages induced an increase of SLC15A3 in the lung, and the deficiency of SLC15A3 protected mice from pulmonary fibrosis and maintained the homeostasis of the pulmonary microenvironment. Mechanistically, deficiency of SLC15A3 resisted oxidative stress in macrophages, and SLC15A3 interacted with the scaffold protein p62 to regulate its expression and phosphorylation activation, thereby regulating p62-nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant stress pathway protein, which is related to the production of reactive oxygen species (ROS). Overall, our data provided a novel mechanism for targeting SLC15A3 to regulate oxidative stress in macrophages, supporting the therapeutic potential of inhibiting or silencing SLC15A3 for the precautions and treatment of pulmonary fibrosis.
10.1038/s41418-024-01266-w
Physalis Calyx seu Fructus inhibited pulmonary fibrosis through regulating Wnt/β-catenin signaling pathway.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Pulmonary fibrosis is a chronic and advancing interstitial lung disease, and there is an urgent need for novel agents for its therapy. Physalis Calyx seu Fructus (PCF) has been utilized in traditional Chinese medicine to treat respiratory disorders with a long history, however, the therapeutic effect and mechanism of PCF against pulmonary fibrosis are still unclear. PURPOSE:To assess therapeutic efficacy and underlying mechanism of 75 % ethanol extract of PCF (PCF-EtOH) against pulmonary fibrosis, as well as to discover active constituents in PCF. METHODS:A bleomycin-stimulated mice model was established to assess potential therapy of PCF-EtOH against pulmonary fibrosis in vivo. A lipopolysaccharide-induced inflammatory model in RAW 264.7 cells and a transforming growth factor β1-induced fibrosis model in MRC-5 cells were established to assess potential therapy and mechanisms of purified constituents in PCF-EtOH. UPLC-MS/MS analysis was adopted to ascertain the constituents of PCF-EtOH. Network pharmacology was employed to forecast targets of PCF against pulmonary fibrosis. RESULTS:PCF-EtOH ameliorated bleomycin-induced pulmonary fibrosis through repressing inflammatory response and extracellular matrix deposition. Meanwhile, PCF-EtOH inhibited Wnt/β-catenin pathway through decreasing β-catenin nuclear accumulation and promoting phosphorylation. Furthermore, withanolides and flavonoids were presumed to be main active compounds of PCF against pulmonary fibrosis based on the network pharmacology. Importantly, we found an extensive presence of withanolides in PCF-EtOH. Physapubescin, a typical withanolide in PCF-EtOH, inhibited the inflammatory response, extracellular matrix deposition, and Wnt/β-catenin pathway. Notably, physapubescin demonstrated a more potent antifibrotic effect than pirfenidone, a clinically approved antifibrotic drug, in the tested model. CONCLUSION:Withanolides and flavonoids are responsible for the inhibitory effect of PCF-EtOH against pulmonary fibrosis. Withanolides may represent a class of promising therapeutic agents against pulmonary fibrosis, and an in-depth exploration is warranted to validate this proposition.
10.1016/j.phymed.2024.155797
Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice.
Theranostics
Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated. We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and transgenic mice. macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis. We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages () significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway. NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.
10.7150/thno.94482
Silica aggravates pulmonary fibrosis through disrupting lung microbiota and amino acid metabolites.
The Science of the total environment
Silicosis, recognized as a severe global public health issue, is an irreversible pulmonary fibrosis caused by the long-term inhalation of silica particles. Given the intricate pathogenesis of silicosis, there is no effective intervention measure, which poses a severe threat to public health. Our previous study reported that dysbiosis of lung microbiota is associated with the development of pulmonary fibrosis, potentially involving the lipopolysaccharides/toll-like receptor 4 pathway. Similarly, the process of pulmonary fibrosis is accompanied by alterations in metabolic pathways. This study employed a combined approach of 16S rDNA sequencing and metabolomic analysis to investigate further the role of lung microbiota in silicosis delving deeper into the potential pathogenesis of silicosis. Silica exposure can lead to dysbiosis of the lung microbiota and the occurrence of pulmonary fibrosis, which was alleviated by a combination antibiotic intervention. Additionally, significant metabolic disturbances were found in silicosis, involving 85 differential metabolites among the three groups, which are mainly focused on amino acid metabolic pathways. The changed lung metabolites showed a substantial correlation with lung microbiota. The relative abundance of Pseudomonas negatively correlated with L-Aspartic acid, L-Glutamic acid, and L-Threonine levels. These results indicate that dysbiosis in pulmonary microbiota exacerbates silica-induced fibrosis through impacts on amino acid metabolism, providing new insights into the potential mechanisms and interventions of silicosis.
10.1016/j.scitotenv.2024.174028
CCT6A alleviates pulmonary fibrosis by inhibiting HIF-1α-mediated lactate production.
Journal of molecular cell biology
Idiopathic pulmonary fibrosis (IPF) is a lethal progressive fibrotic lung disease. The development of IPF involves different molecular and cellular processes, and recent studies indicate that lactate plays a significant role in promoting the progression of the disease. Nevertheless, the mechanism by which lactate metabolism is regulated and the downstream effects remain unclear. The molecular chaperone CCT6A performs multiple functions in a variety of biological processes. Our research has identified a potential association between CCT6A and serum lactate levels in IPF patients. Herein, we found that CCT6A was highly expressed in type 2 alveolar epithelial cells (AEC2s) of fibrotic lung tissues and correlated with disease severity. Lactate increases the accumulation of lipid droplets in epithelial cells. CCT6A inhibits lipid synthesis by blocking the production of lactate in AEC2s and alleviates bleomycin-induced pulmonary fibrosis in mice. In addition, our results revealed that CCT6A blocks HIF-1α-mediated lactate production by driving the VHL-dependent ubiquitination and degradation of HIF-1α and further inhibits lipid accumulation in fibrotic lungs. In conclusion, we propose that there is a pivotal regulatory role of CCT6A in lactate metabolism in pulmonary fibrosis, and strategies aimed at targeting these key molecules could represent potential therapeutic approaches for pulmonary fibrosis.
10.1093/jmcb/mjae021
Niclosamide - encapsulated lipid nanoparticles for the reversal of pulmonary fibrosis.
Materials today. Bio
Pulmonary fibrosis (PF) is a serious and progressive fibrotic interstitial lung disease that is possibly life-threatening and that is characterized by fibroblast accumulation and collagen deposition. Nintedanib and pirfenidone are currently the only two FDA-approved oral medicines for PF. Some drugs such as antihelminthic drug niclosamide (Ncl) have shown promising therapeutic potentials for PF treatment. Unfortunately, poor aqueous solubility problems obstruct clinical application of these drugs. Herein, we prepared Ncl-encapsulated lipid nanoparticles (Ncl-Lips) for pulmonary fibrosis therapy. A mouse model of pulmonary fibrosis induced by bleomycin (BLM) was generated to assess the effects of Ncl-Lips and the mechanisms of reversing fibrosis . Moreover, cell models treated with transforming growth factor β1 (TGFβ1) were used to investigate the mechanism through which Ncl-Lips inhibit fibrosis . These findings demonstrated that Ncl-Lips could alleviate fibrosis, consequently reversing the changes in the levels of the associated marker. Moreover, the results of the tissue distribution experiment showed that Ncl-Lips had aggregated in the lung. Additionally, Ncl-Lips improved the immune microenvironment in pulmonary fibrosis induced by BLM. Furthermore, Ncl-Lips suppressed the TGFβ1-induced activation of fibroblasts and epithelial-mesenchymal transition (EMT) in epithelial cells. Based on these results, we demonstrated that Ncl-Lips is an efficient strategy for reversing pulmonary fibrosis via drug-delivery.
10.1016/j.mtbio.2024.100980
Lung-Targeting Perylenediimide Nanocomposites for Efficient Therapy of Idiopathic Pulmonary Fibrosis.
Nano letters
Idiopathic pulmonary fibrosis, an idiopathic interstitial lung disease with high mortality, remains challenging to treat due to the lack of clinically approved lung-targeting drugs. Herein, we present PDIC-DPC, a perylenediimide derivative that exhibits superior lung-selective enrichment. PDIC-DPC forms nanocomposites with plasma proteins, including fibrinogen beta chain and vitronectin, which bind to pulmonary endothelial receptors for lung-specific accumulation. Moreover, PDIC-DPC significantly suppresses transforming growth factor beta1 and activates adenosine monophosphate-activated protein kinase. As a result, compared to existing therapeutic drugs, PDIC-DPC achieves superior therapeutic outcomes, evidenced by the lowest Ashcroft score, significantly improved pulmonary function, and an extended survival rate in a bleomycin-induced pulmonary fibrosis model. This study elucidates the lung-selective enrichment of assembled prodrug from biological perspectives and affords a platform enabling therapeutic efficiency on idiopathic pulmonary fibrosis.
10.1021/acs.nanolett.4c04089
The role of epithelial-mesenchymal transition in pulmonary fibrosis: lessons from idiopathic pulmonary fibrosis and COVID-19.
Cell communication and signaling : CCS
Despite the tremendous advancements in the knowledge of the pathophysiology and clinical aspects of SARS-CoV-2 infection, still many issues remain unanswered, especially in the long-term effects. Mounting evidence suggests that pulmonary fibrosis (PF) is one of the most severe complications associated with COVID-19. Therefore, understanding the molecular mechanisms behind its development is helpful to develop successful therapeutic strategies. Epithelial to mesenchymal transition (EMT) and its cell specific variants endothelial to mesenchymal transition (EndMT) and mesothelial to mesenchymal transition (MMT) are physio-pathologic cellular reprogramming processes induced by several infectious, inflammatory and biomechanical stimuli. Cells undergoing EMT acquire invasive, profibrogenic and proinflammatory activities by secreting several extracellular mediators. Their activity has been implicated in the pathogenesis of PF in a variety of lung disorders, including idiopathic pulmonary fibrosis (IPF) and COVID-19. Aim of this article is to provide an updated survey of the cellular and molecular mechanisms, with emphasis on EMT-related processes, implicated in the genesis of PF in IFP and COVID-19.
10.1186/s12964-024-01925-y
Mechanics-activated fibroblasts promote pulmonary group 2 innate lymphoid cell plasticity propelling silicosis progression.
Nature communications
Crystalline silica (CS) particle exposure leads to silicosis which is characterized as progressive fibrosis. Fibroblasts are vital effector cells in fibrogenesis. Emerging studies have identified immune sentinel roles for fibroblasts in chronic disease, while their immune-modulatory roles in silicosis remain unclear. Herein, we show that group 2 innate lymphoid cell (ILC2) conversion to ILC1s is closely involved in silicosis progression, which is mediated by activated fibroblasts via interleukin (IL)-18. Mechanistically, Notch3 signaling in mechanics-activated fibroblasts modulates IL-18 production via caspase 1 activity. The mouse-specific Notch3 knockout in fibroblasts retards pulmonary fibrosis progression that is linked to attenuated ILC conversion. Our results indicate that activated fibroblasts in silicotic lungs are regulators of ILC2-ILC1 conversion, associated with silicosis progression via the Notch3-IL-18 signaling axis. This finding broadens our understanding of immune-modulatory mechanisms in silicosis, and indicates potential therapeutic targets for lung fibrotic diseases.
10.1038/s41467-024-54174-5
Enhanced oxidative stress aggravates BLM-induced pulmonary fibrosis by promoting cellular senescence through enhancing NLRP3 activation.
Life sciences
AIMS:Idiopathic pulmonary fibrosis (IPF) is a disease associated with aging, where increased oxidative stress accelerates the progression of pulmonary fibrosis (PF). The specific mechanisms through which oxidative stress intensifies PF are still not fully understood. MATERIALS AND METHODS:In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-β-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess reactive oxygen species (ROS). KEY FINDINGS:Our findings revealed that heightened ROS production significantly exacerbated PF development in mice and increased collagen deposition in A549 cells. We also showed that cellular senescence was further intensified by the combined treatment of BSO with BLM or TGF-β, as indicated by the increased levels of p53 and p21, along with an increase in β-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-β combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-β. Inhibition of NLRP3 ameliorated the aging-related phenotype and reduced p53 and p21 expression. Furthermore, we showed that N-acetylcysteine (NAC) treatment significantly attenuated BLM or BLM plus BSO-enhanced PF in vivo. SIGNIFICANCE:Our study demonstrates that elevated ROS levels contribute to the development of PF via NLRP3-mediated cellular senescence. We also provide that targeting oxidative stress might be an effective strategy for treating PF.
10.1016/j.lfs.2024.123128
Updates on the controversial roles of regulatory lymphoid cells in idiopathic pulmonary fibrosis.
Frontiers in immunology
Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of pulmonary fibrosis, characterized by scar formation in the lung interstitium. Transforming growth factor beta (TGF-β) is known as a key mediator in the fibrotic process, acting on fibroblasts and mediating their proliferation and differentiation into myofibroblasts. Although the immune system is not considered responsible for the initiation of IPF, markers of tolerogenic immunity define the pro-fibrotic microenvironment in the lungs. In homeostatic conditions, regulatory T cells (Tregs) constitute the main lymphoid population responsible for maintaining peripheral tolerance. Similar to Tregs, regulatory B cells (Bregs) represent a recently described subset of B lymphocytes with immunosuppressive functions. In the context of IPF, numerous studies have suggested a role for Tregs in enhancing fibrosis, mainly via the secretion of TGF-β. In humans, most studies show increased percentages of Tregs associated with the severity of IPF, although their exact role remains unclear. In mice, the most commonly used model involves triggering acute lung inflammation with bleomycin, leading to a subsequent fibrotic process. Consequently, data are still conflicting, as Tregs may play a protective role during the inflammatory phase and a deleterious role during the fibrotic phase. Bregs have been less studied in the context of IPF, but their role appears to be protective in experimental models of lung fibrosis. This review presents the latest updates on studies exploring the implication of regulatory lymphoid cells in IPF and compares the different approaches to better understand the origins of conflicting findings.
10.3389/fimmu.2024.1466901
Engineering Macrophage-Derived Exosome to Deliver Pirfenidone: A Novel Approach to Combat Silicotic Pulmonary Fibrosis.
Advanced healthcare materials
Silicosis is a severe lung disease characterized by diffuse pulmonary fibrosis, for which there is currently no effective treatment. Pirfenidone (PFD) shows great antifibrotic potential but is clinically hindered by low bioavailability and gastrointestinal side effects. To address these limitations, this study develops a PFD delivery system (PFD-Exo) using J774A.1 macrophage-derived exosomes. Firstly, PFD is loaded via sonication, then PFD-Exo is characterized using Raman spectral imaging and UV absorption spectroscopy. Finally, in vitro and in vivo silicosis models are established to evaluate its antifibrotic effects. Results show that PFD-Exo outperforms free PFD in inhibiting TGF-β1-induced transdifferentiation of primary lung fibroblasts in vitro. In a mouse model of silicosis, PFD-Exo is found to be accumulated in the lungs following intratracheal administration and significantly ameliorates pulmonary inflammation and fibrosis while minimizing gastrointestinal side effects. Mechanistic studies reveal that PFD-Exo modulates the TGF-β signaling pathway by downregulating SMAD3 and upregulating SMAD7 and NOGGIN. In conclusion, this study provides the first evidence of macrophage-derived exosomes as an effective PFD delivery system for silicosis treatment and offers a promising strategy for other refractory pulmonary diseases.
10.1002/adhm.202403227