Collectin 11 has a pivotal role in host defense against kidney and bladder infection in mice.

The urinary tract is constantly exposed to microorganisms. Host defense mechanisms in protection from microbial colonization and development of urinary tract infections require better understanding to control kidney infection. Here we report that the lectin collectin 11 (CL-11), particularly kidney produced, has a pivotal role in host defense against uropathogen infection. CL-11 was found in mouse urine under normal and pathological conditions. Mice with global gene ablation of Colec11 had increased susceptibility to and severity of kidney and to an extent, bladder infection. Mice with kidney-specific Colec11 ablation exhibited a similar disease phenotype to that observed in global Colec11 deficient mice, indicating the importance of kidney produced CL-11 for protection against kidney and bladder infection. Conversely, intravesical or systemic administration of recombinant CL-11 reduced susceptibility to and severity of kidney and bladder infection. Mechanism analysis revealed that CL-11 can mediate several key innate defense mechanisms (agglutination, anti- adhesion, opsonophagocytosis), and limit local inflammatory responses to pathogens. Furthermore, CL-11-mediated innate defense mechanisms can act on clinically relevant microorganisms including multiple antibiotic resistant strains. CL-11 was detectable in eight of 24 urine samples from patients with urinary tract infections but not detectable in urine samples from ten healthy individuals. Thus, our findings demonstrate that CL-11 is a key factor of host defense mechanisms in kidney and bladder infection with therapeutic potential for human application.

Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

Bidirectional interaction between IL and 17A/IL-17RA pathway dysregulation and α-synuclein in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.

Site-specific quantification of Adenosine-to-Inosine RNA editing by Endonuclease-Mediated qPCR.

RNA molecules contain diverse modified nucleobases that play pivotal roles in numerous biological processes. Adenosine-to-inosine (A-to-I) RNA editing, one of the most prevalent RNA modifications in mammalian cells, is linked to a multitude of human diseases. To unveil the functions of A-to-I RNA editing, accurate quantification of inosine at specific sites is essential. In this study, we developed an endonuclease-mediated cleavage and real-time fluorescence quantitative PCR method for A-to-I RNA editing (EM-qPCR) to quantitatively analyze A-to-I RNA editing at a single site. By employing this method, we successfully quantified the levels of A-to-I RNA editing on various transfer RNA (tRNA) molecules at position 34 (I34) in mammalian cells with precision. Subsequently, this method was applied to tissues from sleep-deprived mice, revealing a notable alteration in the levels of I34 between sleep-deprived and control mice. The proposed method sets a precedent for the quantitative analysis of A-to-I RNA editing at specific sites, facilitating a deeper understanding of the biological implications of A-to-I RNA editing.

AHA Life's Essential 8 and new-onset CKD: a prospective cohort study from the UK Biobank.

BACKGROUND: The AHA has recently introduced a novel metric, Life's Essential 8, to assess cardiovascular health (CVH). Nevertheless, the association between varying levels of LE8 and the propensity for CKD is still unclear from a large prospective cohort. Our objective is to meticulously examine the relationship between LE8 and its associated susceptibilities to CKD. METHODS: A total of 251,825 participants free of CKD from the UK Biobank were included. Cardiovascular health was scored using LE8 and categorized as low, moderate, and high. Cox proportional hazard models were employed to evaluate the associations of LE8 scores with new-onset CKD. The genetic risk score for CKD was calculated by a weighted method. RESULTS: Over a median follow-up of 12.8 years, we meticulously documented 10,124 incident cases of CKD. Remarkably, an increased LE8 score correlated with a significant reduction of risk in new-onset CKD (high LE8 score vs. low LE8 score: HR = 0.300, 95% CI 0.270-0.330, p < 0.001; median LE8 score vs. low LE8 score: HR = 0.531, 95% CI 0.487-0.580, p < 0.001). This strong LE8-CKD association remained robust in extensive subgroup assessments and sensitivity analysis. Additionally, these noteworthy associations between LE8 scores and CKD remained unaffected by genetic predispositions to CKD. CONCLUSIONS: An elevated degree of CVH, as delineated by the discerning metric LE8, exhibited a pronounced and statistically significant correlation with a marked reduction in the likelihood of CKD occurrence.

Effect of urbanization and urban forests on water quality improvement in the Yangtze River Delta: A case study in Hangzhou, China.

In the context of rapid global urbanization, the sustainable development of ecosystems should be considered. Accordingly, the Planetary Boundaries theory posits that reducing the amount of nitrogen and phosphorus pollutants entering bodies of water is necessary as excess levels may harm the aquatic environment and reduce in water quality. Thus, based on the long-term monitoring data of representative urban rivers in the Yangtze River Delta region, we evaluated the nitrogen and phosphorus pollution of water bodies in different urbanization stages and further quantified the effect of urban forests on water quality improvement. The results showed that, with the continuous progression of urbanization, the proportion of impervious surface area increased, along with the levels of nitrogen and phosphorus pollution in water bodies. The critical period of water quality deterioration in urban rivers occurred during the medium urbanization level when the proportion of impervious surface area reached 55-65 %, and the probability of an abrupt increase in total nitrogen (TN) and total phosphorus (TP) concentration exceeded 95 %. However, increasing the area of urban forests during this period reduced TN pollution by 36.64 % and TP pollution by 49.03 %. The results of this study support the expansion of urban forests during the medium urbanization stage to improve water quality. Furthermore, our results provide a reference and theoretical basis for urban forest construction as a key aspect of the sustainable development of the urban ecosystem in the Yangtze River Delta and similar regions around world.

Improving diagnostic performance of rib fractures for the night shift in radiology department using a computer-aided diagnosis system based on deep learning: A clinical retrospective study.

OBJECTIVE: To investigate the application value of a computer-aided diagnosis (CAD) system based on deep learning (DL) of rib fractures for night shifts in radiology department. METHODS: Chest computed tomography (CT) images and structured reports were retrospectively selected from the picture archiving and communication system (PACS) for 2,332 blunt chest trauma patients. In all CT imaging examinations, two on-duty radiologists (radiologists I and II) completed reports using three different reading patterns namely, P1 = independent reading during the day shift; P2 = independent reading during the night shift; and P3 = reading with the aid of a CAD system as the concurrent reader during the night shift. The locations and types of rib fractures were documented for each reading. In this study, the reference standard for rib fractures was established by an expert group. Sensitivity and false positives per scan (FPS) were counted and compared among P1, P2, and P3. RESULTS: The reference standard verified 6,443 rib fractures in the 2,332 patients. The sensitivity of both radiologists decreased significantly in P2 compared to that in P1 (both p <  0.017). The sensitivities of both radiologists showed no statistical difference between P3 and P1 (both p >  0.017). Radiologist I's FPS increased significantly in P2 compared to P1 (p <  0.017). The FPS of radiologist I showed no statistically significant difference between P3 and P1 (p >  0.017). The FPS of Radiologist II showed no statistical difference among all three reading patterns (p >  0.05). CONCLUSIONS: DL-based CAD systems can be integrated into the workflow of radiology departments during the night shift to improve the diagnostic performance of CT rib fractures.

[Effects and mechanisms of total flavones of Abelmoschus manihot in attenuating diabetic tubulopathy by targeting endoplasmic reticulum stress-induced cell apoptosis].

Renal tubular injury in patients with diabetic kidney disease(DKD) may be accompanied by glomerular and microvascular diseases. It plays a critical role in the progression of renal damage in DKD, and is now known as diabetic tubulopathy(DT). To explore the multi-targeted therapeutic effects and pharmacological mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese medicine for treating kidney disease, in attenuating DT, the authors randomly divided all rats into four groups: a normal control group(normal group), a DT model group(model group), a DT model+TFA-treated group(TFA group) and a DT model+rosiglitazone(ROS)-treated group(ROS group). The DT rat model was established based on the DKD rat model by means of integrated measures. After successful modeling, the rats in the four groups were continuously given double-distilled water, TFA suspension, and ROS suspension, respectively by gavage every day. After 6 weeks of treatment, all rats were sacrificed, and the samples of their urine, blood, and kidneys were collected. The effects of TFA and ROS on various indicators related to urine and blood biochemistry, renal tubular injury, renal tubular epithelial cell apoptosis and endoplasmic reticulum stress(ERS), as well as the activation of the protein kinase R-like endoplasmic reticulum kinase(PERK)-eukaryotic translation initiation factor 2α(eIF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP) signaling pathway in the kidney of the DT model rats were investigated. The results indicated that hypertrophy of renal tubular epithelial cells, renal tubular hyperplasia and occlusion, as well as interstitial extracellular matrix and collagen deposition occurred in the DT model rats. Moreover, significant changes were found in the expression degree and the protein expression level of renal tubular injury markers. In addition, there was an abnormal increase in tubular urine proteins. After TFA or ROS treatment, urine protein, the characteristics of renal tubular injury, renal tubular epithelial cell apoptosis and ERS, as well as the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney of the DT model rats were improved to varying degrees. Therein, TFA was superior to ROS in affecting the pathological changes in renal tubule/interstitium. In short, with the DT model rats, this study demonstrated that TFA could attenuate DT by multiple targets through inhibiting renal tubular ERS-induced cell apoptosis in vivo, and its effect and mechanism were related to suppressing the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney. These findings provided preliminary pharmacological evidence for the application of TFA in the clinical treatment of DT.

Influences of Rapamycin on Retinal Ganglion Cells in Rats with Acute High Intraocular Pressure Through Regulating COX-2.

The study aimed to explore the influences of rapamycin on the retinal ganglion cells in rats with acute high intraocular pressure through regulating cyclooxygenase-2 (COX-2). 36 Sprague-Dawley rats were randomly assigned to the normal group (n=12), model group (n=12) and rapamycin group (n=12). The rats in the normal group were normally fed, those in the model group were prepared the model of acute high intraocular pressure and injected with normal saline, and those in the rapamycin group were given rapamycin. At 7 d after the operation, sampling was performed. The expressions of COX-2 and Caspase-3 were detected via immunohistochemistry, and their protein expressions were determined using Western blotting (WB). Quantitative polymerase chain reaction (qPCR) was conducted to measure the messenger ribonucleic acid (mRNA) expression levels, and cell apoptosis was evaluated using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) assay. The content of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) was determined via enzyme-linked immunosorbent assay (ELISA). Compared with those in the normal group, the positive expression levels rose substantially in the other two groups, and those in the rapamycin group were notably lower (p<0.05). The relative protein expression levels in the model group and rapamycin group were higher, and the rapamycin group exhibited remarkable decreases (p<0.05). In comparison with the normal group, the other two groups had considerably raised relative mRNA expression levels and those in the rapamycin group were lower (p<0.05). The cells in the model and rapamycin groups had a higher apoptosis rate, and the apoptosis rate of cells in the rapamycin group was lower (p<0.05). Compared with that in the normal group, the content of IL-6 and TNF-α was elevated in the other two groups and their content in the rapamycin group was lower. Rapamycin inhibits COX-2 to repress inflammation and apoptosis, thereby exerting a protective effect on the retinal ganglion cells in rats with acute high intraocular pressure.

Geranylgeranyl diphosphate synthase deficiency hyperactivates macrophages and aggravates lipopolysaccharide-induced acute lung injury.

Macrophage activation is a key contributing factor for excessive inflammatory responses of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Geranylgeranyl diphosphate synthase (GGPPS) plays a key role in the development of inflammatory diseases. Our group previously showed that GGPPS in alveolar epithelium have deleterious effects on acute lung injury induced by LPS or mechanical ventilation. Herein, we examined the role of GGPPS in modulating macrophage activation in ALI/ARDS. We found significant increased GGPPS expression in alveolar macrophages in patients with ARDS compared with healthy volunteers and in ALI mice induced by LPS. GGPPS-floxed control (GGPPSfl/fl) and myeloid-selective knockout (GGPPSfl/flLysMcre) mice were then generated. Interestingly, using an LPS-induced ALI mouse model, we showed that myeloid-specific GGPPS knockout significantly increased mortality, aggravated lung injury, and increased the accumulation of inflammatory cells, total protein, and inflammatory cytokines in BALF. In vitro, GGPPS deficiency upregulated the production of LPS-induced IL-6, IL-1ß, and TNF-α in alveolar macrophages, bone marrow-derived macrophages (BMDMs), and THP-1 cells. Mechanistically, GGPPS knockout increased phosphorylation and nuclear translocation of NF-κB p65 induced by LPS. In addition, GGPPS deficiency increased the level of GTP-Rac1, which was responsible for NF-κB activation. In conclusion, decreased expression of GGPPS in macrophages aggravates lung injury and inflammation in ARDS, at least partly by regulating Rac1-dependent NF-κB signaling. GGPPS in macrophages may represent a novel therapeutic target in ARDS.

Mefloquine as a dual inhibitor of glioblastoma angiogenesis and glioblastoma via disrupting lysosomal function.

Angiogenesis, the formation of new blood vessels from the pre-existing ones, is a hallmark characteristic of glioblastoma, making it an appealing target for treatment development. Given potent anti-cancer efficacy of mefloquine, FDA-approved anti-malarial drug, there is increasing interest in repurposing mefloquine for treatment of cancers, including glioblastoma. In line with these efforts, our work is the first to demonstrate that mefloquine is also an inhibitor of glioblastoma angiogenesis. Using glioblastoma microvascular endothelial cell (GMEC) isolated from glioblastoma patients, we show that mefloquine at clinically achievable concentration inhibits GMEC differentiation, capillary network formation, adhesion to Matrix, growth and survival. Mefloquine also inhibits growth and induces apoptosis in glioblastoma cells regardless of cellular origin and genetic background. We further show that mefloquine significantly inhibits glioblastoma growth but not formation, and this is associated with decreased glioblastoma angiogenesis in mice. Mechanistically, mefloquine disrupted lysosomal integrity and function in GMECs, leading to oxidative stress and lysosomal lipid damage. Rescue studies confirm that mefloquine acts on GMECs in a lysosomal disruption-dependent manner. Our findings demonstrate the anti-angiogenic activity of mefloquine via disrupting lysosomal function. The dual inhibitory role of mefloquine in glioblastoma angiogenesis and glioblastoma displays its advantage over other anti-cancer drugs for glioblastoma treatment. Our work also highlights the essential role of lysosome in both glioblastoma and its angiogenesis.

Lactated Ringer's solution versus normal saline in pediatric living-donor liver transplantation: A matched retrospective cohort study.

BACKGROUND: In pediatric living-donor liver transplantation, lactated Ringer's solution and normal saline are commonly used for intraoperative fluid management, but the comparative clinical outcomes remain uncertain. AIMS: To compare the effect between lactated Ringer's solution and normal saline for intraoperative volume replacement on clinical outcomes among pediatric living-donor liver transplantation patients. METHODS: This single-center, retrospective trial study enrolled children who received either lactated Ringer's solution or normal saline during living-donor liver transplantation between January 2010 and August 2016. The groups with comparable clinical characteristics were balanced by propensity score matching. The primary outcome was 90-day all-cause mortality, and the secondary outcomes included early allograft dysfunction, primary nonfunction, acute renal injury, and hospital-free days (days alive postdischarge within 30 days of liver transplantation). RESULTS: We included 333 pediatric patients who met the entry criteria for analysis. Propensity score matching identified 61 patients in each group. After matching, the lactated Ringer's solution group had a higher 90-day mortality rate than the normal saline group (11.5% vs. 0.0%). Early allograft dysfunction and primary nonfunction incidences were also more frequent in the lactated Ringer's solution group (19.7% and 11.5%, respectively) than in the normal saline group (3.3% and 0.0%, respectively). In the lactated Ringer's solution group, four (6.6%) recipients developed acute renal injury within 7 days postoperatively compared with three (4.9%) recipients in the normal saline group. Hospital-free days did not differ between groups (9 days [1-13] vs. 9 days [0-12]). CONCLUSIONS: For intraoperative fluid management in pediatric living-donor liver transplantation patients, lactated Ringer's solution administration was associated with a higher 90-day mortality rate than normal saline. This finding has important implications for selecting crystalloid in pediatric living-donor liver transplantation. Further randomized clinical trials in larger cohort are necessary to confirm this finding.

Publication Trends and Hot Spots in Femoroacetabular Impingement Research: A 20-Year Bibliometric Analysis.

BACKGROUND: Femoroacetabular impingement (FAI) has attracted increasing attention over the past few decades. We aim to evaluate FAI research and predict research hot spots quantitatively and qualitatively. METHODS: The publications in FAI research between 2000 and 2019 were assimilated from the Web of Science Core Collection of Clarivate Analytics. The retrieved data were evaluated by the bibliometric method. Software CiteSpace 5.7.R1, VOSviewer 1.6.15, and the Online Analysis Platform of Literature Metrology (http://bibliometric.com/) were used to analyze and identify the hot spots and trends in this field. RESULTS: A total of 2471 originals articles that fulfilled the study requirements were obtained. The number of manuscripts on FAI has experienced rapid growth, especially after 2009. The United States of America was the leading country for publication and to the collaboration network. FAI, osteoarthritis, hip arthroscopy, labral reconstruction, pathomorphology, outcome, rehabilitation, and joint cartilage are some of the high-frequency keywords in co-occurrence cluster analysis and cocited reference cluster analysis. Burst detection analysis of top keywords revealed that outcomes, instability, labral reconstruction, adolescent, and risk factor were newly emerged research hot spots. CONCLUSION: The understanding of FAI has been improved significantly during the past two decades. Present studies focused on identifying the optimal method to treat labral pathology, outcome assessment of either surgeries or conservative managements, and predicting midterm and long-term outcomes. Together these studies exert critical implications for decision-making and management for FAI.

Aldosterone enhances high phosphate-induced vascular calcification through inhibition of AMPK-mediated autophagy.

It remains unclear whether the necessity of calcified mellitus induced by high inorganic phosphate (Pi) is required and the roles of autophagy plays in aldosterone (Aldo)-enhanced vascular calcification (VC) and vascular smooth muscle cell (VSMC) osteogenic differentiation. In the present study, we found that Aldo enhanced VC both in vivo and in vitro only in the presence of high Pi, alongside with increased expression of VSMC osteogenic proteins (BMP2, Runx2 and OCN) and decreased expression of VSMC contractile proteins (α-SMA, SM22α and smoothelin). However, these effects were blocked by mineralocorticoid receptor inhibitor, spironolactone. In addition, the stimulatory effects of Aldo on VSMC calcification were further accelerated by the autophagy inhibitor, 3-MA, and were counteracted by the autophagy inducer, rapamycin. Moreover, inhibiting adenosine monophosphate-activated protein kinase (AMPK) by Compound C attenuated Aldo/MR-enhanced VC. These results suggested that Aldo facilitates high Pi-induced VSMC osteogenic phenotypic switch and calcification through MR-mediated signalling pathways that involve AMPK-dependent autophagy, which provided new insights into Aldo excess-associated VC in various settings.

1/2SH: A Simple, Accurate, and Reliable Method of Calculating the Hematoma Volume of Spontaneous Intracerebral Hemorrhage.

Background and Purpose- 1/2ABC has been used widely for assessing the volume of intracerebral hematoma. However, it is only suitable for calculating regular and small volume hematomas. Therefore, we re-explored the formula of hematoma volume to find a method that can calculate hematoma volumes accurately, reliably, and quickly. Methods- Computed tomography imaging data of 257 patients with intracerebral hemorrhage were collected. Hematoma volumes were estimated using 3-dimensional Slicer and 7 formulas (π/6ABC, 1/2ABC, 1/3ABC, 2/3SH, 1/2SH, π/6SH, and 2.5/6ABC). Taking the hematoma volumes measured by 3-dimensional Slicer as the reference standard, the accuracy and reliability of the 7 formulas were evaluated. Furthermore, the time needed to calculate hematoma volumes by the 1/2SH method was noted for further analysis. Results- (1) The accuracy of the 7 formulas based on the error analysis from the highest to the lowest was: π/6SH, 1/2SH, 2.5/6ABC, 1/3ABC, 1/2ABC, and π/6ABC or 2/3SH. According to concordance analysis and receiver operating characteristic curve analysis, the results from the highest to lowest were as follows: 1/2SH, π/6SH, 2.5/6ABC, 1/3ABC, 1/2ABC, 2/3SH, and π/6ABC. After categorizing cases according to size, shape, and location of hematoma, the results were almost the same as the results for overall accuracy evaluation in any subgroup. (2) Intraclass correlation coefficient (ICC) of 1/2SH in intra and inter-researcher were 0.998 and 0.989, respectively. For the formula π/6SH, intraclass correlation coefficient was the same as that of 1/2ABC. Kappa values of 1/2SH for intra- and inter-observer were 0.992 and 0.913, respectively. For π/6SH, kappa values of within- and between-reader were 0.984 and 0.904, respectively. (3) The average time taken to calculate hematoma volumes by 1/2SH was 74 seconds. Conclusions- The 1/2SH and π/6SH are accurate, reliable, and rapid methods for calculating hematoma volumes. The accuracy and reliability of 1/2SH were slightly higher than those of π/6SH.

Leonurine suppresses neuroinflammation through promoting oligodendrocyte maturation.

Focal inflammation and remyelination failure are major hallmarks of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we found that leonurine, a bioactive alkaloid, alleviated EAE disease severity along with reduced central nervous system inflammation and myelin damage. During the pathogenesis of EAE, leonurine dramatically suppressed the recruitment of encephalitogenic T cells into the central nervous system, whereas did not impair periphery immune responses and microglia activation. Mechanistically, leonurine protected mice against demyelination along with enhanced remyelination through promoting the maturation of oligodendrocytes in both EAE and cuprizone-induced demyelination mouse models. Moreover, we identified that the expression of demethylase jumonji domain-containing protein D3 was significantly enhanced upon treatment of leonurine, which suppressed the trimethylation of histone H3 lysine-27 and enhanced oligodendrocyte maturation accordingly. Collectively, our study identified the therapeutic effect of leonurine on EAE model, which potentially represents a promising therapeutic strategy for multiple sclerosis, even other demyelination disorders.

Inhibition of GGPPS1 attenuated LPS-induced acute lung injury and was associated with NLRP3 inflammasome suppression.

Inhibition of the mevalonate pathway using statins has been shown to be beneficial in the treatment of acute lung injury (ALI). Here, we investigated whether partial inhibition of this pathway by targeting geranylgeranyl pyrophosphate synthase large subunit 1 (GGPPS1), a catalase downstream of the mevalonate pathway, was effective at treating lung inflammation in ALI. Lipopolysaccharide (LPS) was intratracheally instilled to induce ALI in lung-specific GGPPS1-knockout and wild-type mice. Expression of GGPPS1 in lung tissues and alveolar epithelial cells was examined. The severity of lung injury and inflammation was determined in lung-specific GGPPS1 knockout and wild-type mice by measuring alveolar exudate, neutrophil infiltration, lung injury, and cell death. Change in global gene expression in response to GGPPS1 depletion was measured using mRNA microarray and verified in vivo and in vitro. We found that GGPPS1 levels increased significantly in lung tissues and alveolar epithelial cells in LPS-induced ALI mice. Compared with wild-type and simvastatin treated mice, the specific deletion of pulmonary GGPPS1 attenuated the severity of lung injury by inhibiting apoptosis of AECs. Furthermore, deletion of GGPPS1 inhibited LPS-induced inflammasome activation, in terms of IL-1ß release and pyroptosis, by downregulating NLRP3 expression. Finally, downregulation of GGPPS1 reduced the membrane expression of Ras-related protein Rab10 and Toll-like receptor 4 (TLR4) and inhibited the phosphonation of IκB. This effect might be attributed to the downregulation of GGPP levels. Our results suggested that inhibition of pulmonary GGPPS1 attenuated LPS-induced ALI predominantly by suppressing the NLRP3 inflammasome through Rab10-mediated TLR4 replenishment.

Geranylgeranyl diphosphate synthase deficiency aggravates lung fibrosis in mice by modulating TGF-ß1/BMP-4 signaling.

Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme that catalyzes the synthesis of geranylgeranyl pyrophosphate (GGPP). GGPPS is implicated in many disorders, but its role in idiopathic pulmonary fibrosis (IPF) remains unclear. This study aimed to investigate the role of GGPPS in IPF. We established bleomycin-induced lung injury in a lung-specific GGPPS-deficient mouse (GGPPS-/-) and detected GGPPS expression in lung tissues by Western blot and immunohistochemistry analysis. We found that GGPPS expression increased during lung injury and fibrosis in mice induced by bleomycin, and GGPPS deficiency augmented lung fibrosis. GGPPS deficiency activated lung fibroblast by facilitating transforming growth factor ß1 while antagonizing bone morphogenetic protein 4 signaling. Notably, the supplementation of exogenous GGPP mitigated lung fibrosis in GGPPS-/- mice induced by bleomycin. In conclusion, our findings suggest that GGPPS provides protection against pulmonary fibrosis and that the restoration of protein geranylgeranylation may benefit statin-induced lung injury.

Topotecan Alleviates Lipopolysaccharide-Mediated Acute Lung Injury Via the NF-κB Signaling Pathway.

BACKGROUND: The topoisomerase 1 (Top1) inhibitor has been reported to inhibit inflammatory genes induced by virus and protect mice from sepsis. Its role in acute lung injury (ALI) remains unknown. This study aimed to explore the effects of topotecan (TPT), a Top 1 inhibitor, in lipopolysaccharide (LPS)-ALI. MATERIALS AND METHODS: THP-1 cells were stimulated with LPS and then treated with or without TPT. Inflammatory cytokines expression was measured by ELISA. In vivo, we also detected the effect of TPT in LPS-induced ALI mouse model through hematoxylin-eosin staining of lung tissue and the quantification of total protein, total cell count, and cytokines in bronchoalveolar lavage fluid. To investigate the effect of TPT on transcriptome levels, microarray analyses were performed. KEGG analysis was applied to determine potential pathways modified by TPT. Microarray results were confirmed by real-time PCR and Western blot. RESULTS: TPT significantly decreased the expression of TNF-α and IL-1ß induced by LPS in THP-1 cells. In an LPS-induced ALI mouse model, TPT significantly attenuated lung injury and decreased the levels of total protein, total cell count, and inflammatory cytokine expression in bronchoalveolar lavage fluid. Microarray results showed that TPT significantly increased expression of 958 genes and decreased expression of 1400 genes in THP-1 cells upon LPS stimulation. KEGG analysis demonstrated that differentially expressed genes function in multiple signaling pathways, including the nuclear factor (NF)-κB signaling pathway. The downstream gene of NF-κB, including c-IAP1/2, c-FLIP, Bcl-2, IL-8, and VCAM-1, and the phosphorylation of NF-κB p105, p65, and IκB-α were significantly decreased after TPT administration in THP-1 cells. CONCLUSIONS: In conclusion, TPT attenuates LPS-induced ALI through inhibiting the NF-κB signaling pathway, suggesting that TPT might serve as a useful therapeutic for ALI. Thus, our study has provided new insight for current ALI treatment.