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The delivery of biomolecules by extracellular vesicles (EVs) derived from endothelial progenitor cells (EPCs) has been proven to ameliorate sepsis, yet the therapeutic mechanism remains to be elucidated. Taurine upregulated gene 1 ( TUG1 ) is a long noncoding RNA (lncRNA) that is downregulated in sepsis. The current study was designed to explore the role of EPCs derived EVs transmitting TUG1 in macrophage polarization and macrophage-mediated inflammation in a cecal ligation and puncture (CLP)-induced sepsis mouse model. TUG1 was underexpressed in CLP-induced sepsis, and its reexpression induced anti-inflammatory macrophage polarization and suppressed macrophage-medicated inflammatory injury to the pulmonary vascular endothelium. EPCs derived EVs transmitted TUG1 to promote M2 macrophage polarization. Luciferase, RIP, and RNA pull-down assays showed that TUG1 could competitively bind to microRNA-9-5p (miR-9-5p) to upregulate the expression of sirtuin 1 (SIRT1). Furthermore, EPCs derived EVs transmitted TUG1 to promote M2 macrophage polarization through the impairment of miR-9-5p-dependent SIRT1 inhibition. Finally, EPCs derived EVs carrying TUG1 were verified to ameliorate sepsis-induced organ damage in the murine model. In summary, EPCs derived EVs transmit TUG1 to attenuate sepsis via macrophage M2 polarization. This study also highlights the proinflammatory mechanism associated with miR-9-5p-mediated inhibition of SIRT1, which contributes to a more comprehensive understanding of the pathogenesis of sepsis.

As the Pamir Plateau is known as the “Water Tower of Central Asia”, accurate precipitation dataset is essential for the study of climate and hydrology in this region. Based on the monthly precipitation observations from 268 meteorological stations in the Eastern Pamir Plateau (EPP) during the April-to-September warm season of 2010–2024, this paper comprehensively evaluates the applicability of eight multi-source precipitation datasets in complex terrains by using statistical indicators, constructs a skill-weighted ensemble mean dataset (Skill-Ens), and analyzes the elevation-dependent characteristics of precipitation in the EPP. The research findings are as follows: (1) The warm-season precipitation in the EPP shows a significant elevation-dependent feature, with the maximum precipitation altitude (MPA) in the range of 2400–2800 m. Precipitation is reduced above this elevation range, but a second MPA may appear in the glacier area above 4000 m. (2) Among the studied eight datasets, the first-generation Chinese Global Land-surface Reanalysis (CRA40/Land) performs the best overall. A long-term (1979–2020) high-resolution (1/30°) precipitation dataset for the Third Pole region (TPHiPr) can most accurately capture the elevation-dependent characteristics of precipitation, while the satellite datasets are relatively poor in this respect. (3) The skill-weighted ensemble mean dataset (Skill-Ens) constructed in this study can significantly improve precipitation estimation (DISO = 0.35), especially in the MPA region, and can accurately depict the elevation-dependent characteristics of precipitation as well (CC = 0.92). In a word, this paper provides the applicable options for precipitation data in complex terrain areas. With the Skill-Ens, the limitation of the individual dataset has been compensated for, which is of significant application value in improving the accuracy of hydrological simulations in high-elevation mountainous areas.

Extreme high-temperature events pose huge threats on human health and ecological environment. Central Asia (CA), located in an arid region, experiences frequent occurrences of extreme high-temperature events with regional discrepancy. However, it is unknown to what extent the distribution of summer extreme high-temperature events over CA can be predicted. This study aims to investigate the dynamic origins of summer distribution of extreme high-temperature days (EHDs) over CA and estimate the predictability using Predictable Mode Analysis (PMA). Based on daily maximum temperature data from 1980 to 2010, two major EOF (Empirical Orthogonal Function) modes of EHDs over CA are identified. The first mode exhibits a homogeneous positive pattern, which is associated with a barotropic anticyclonic anomaly that covers the entire CA. The second mode features a meridional dipole pattern, corresponding to a north to south see-saw geopotential height anomaly pattern in CA. Based on the understanding of the simultaneous physical factors and tracing lower boundary anomalous forcing in the previous season, two physical predictors are selected for each principal component (PC), and a set of Physics-based Empirical (P-E) models is established. The temporal correlation coefficient (TCC) skill between observed and predicted PC1 (PC2) is 0.60 (0.74) during the independent forecast period (2010–2021). According to the criteria of PMA, the first two modes can be considered as predictable modes. If predictable modes can be perfectly predicted, 64.8% of the total observed variability of EHDs over CA is potentially predictable. Using the predicted values of the first two PCs and the corresponding observed EOF patterns, the predicted distribution of EHDs can be reconstructed. During the independent forecast period, the areal averaged TCC skill can reach 0.44, providing a reference for actual predictability.

Emerging evidences demonstrate the involvement of gut microbiota in the progression of chronic kidney disease (CKD) and CKD-associated complications including cardiovascular disease (CVD) and intestinal dysfunction. In this review, we discuss the interactions between the gut, kidney and heart in CKD state, and elucidate the significant role of intestinal microbiota in the gut-kidney-heart axis hypothesis for the pathophysiological mechanisms of these diseases, during which process mitochondria may serve as a potential therapeutic target. Dysregulation of this axis will lead to a vicious circle, contributing to CKD progression. Recent studies suggest novel therapies targeting gut microbiota in the gut-kidney-heart axis, including dietary intervention, probiotics, prebiotics, genetically engineered bacteria, fecal microbiota transplantation, bacterial metabolites modulation, antibiotics, conventional drugs and traditional Chinese medicine. Further, the identification of specific microbial communities and their corresponding pathophysiological metabolites and the illumination of the gut-kidney-heart axis may contribute to innovative basic research, clinical trials and therapeutic strategies against CKD progression and uremic complications in CKD patients.

A reliable precipitation dataset with high spatial resolution is essential for climate research in the Tarim Basin. This study evaluated the performances of four models, namely a random forest (RF), a long short-term memory network (LSTM), a support vector machine (SVM), and a feedforward neural network (FNN). FNN, which was found to be superior to the other models, was used to integrate eight precipitation datasets spanning from 1990 to 2022 across the Tarim Basin, resulting in a new monthly high-resolution (0.1°) precipitation dataset named MoHiPr-TB. This dataset was subsequently bias-corrected by the China Land Data Assimilation System version 2.0 (CLDAS2.0). Validation results indicate that the corrected MoHiPr-TB not only accurately reflects the spatial distribution of precipitation but also effectively simulates its intensity and interannual and seasonal variations. Moreover, MoHiPr-TB is capable of detecting the precipitation–elevation relationship in the Pamir Plateau, where precipitation initially increases and then decreases with elevation, as well as the synchronous variation of precipitation and elevation in the Tianshan region. Collectively, this study delivers a high-accuracy precipitation dataset for the Tarim Basin, which is anticipated to have extensive applications in meteorological, hydrological, and ecological research.

The etiology of acute lung injury (ALI) is not clear, and the treatment of ALI presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of ALI and to define the target gene of Tanreqing (TRQ), which is a traditional Chinese medicine formula composed of five medicines, scutellaria baicalensis, bear bile powder, goat horn powder, honeysuckle and forsythia. Macrophage activation plays a critical role in many pathophysiological processes, such as inflammation. Although the regulation of macrophage activation has been extensively investigated, there is little knowledge of the role of long noncoding RNAs (lncRNAs) in this process. In this study, we found that lncRNA-SNHG1 expression is distinctly regulated in differently activated macrophages in that it is upregulated in LPS. LncRNA-SNHG1 knockdown attenuates LPS-induced M1 macrophage activation. The SNHG1 promoter was bound by NF-κB subunit p65, indicative of SNHG1 being a direct transcriptional target of LPS-induced NF-κB activation. SNHG1 acts as a proinflammatory driver that leads to the production of inflammatory cytokines and the activation of macrophages and cytokine storms by physically interacting with high-mobility group box 1 (HMGB1) in ALI. TRQ inhibited NF-κB signaling activation and binding of NF-κB to the SNHG1 promoter. In conclusion, this study defined TRQ target genes, which can be further elucidated as mechanism(s) of TRQ action, and provides insight into the molecular pathogenesis of ALI. The lncRNA-SNHG1/HMGB1 axis is an ideal therapeutic for ALI treatment.

Background Renal fibrosis represents the final common pathological manifestation of chronic kidney disease (CKD), yet the underlying mechanism remains elusive, and there is still a lack of effective targeted therapeutic strategy. Although previous research indicated that repressor element 1-silencing transcription factor (REST) contributed to acute kidney injury (AKI) in renal tubular epithelial cells (RTECs), its specific contribution to renal fibrosis and associated mechanisms remains largely unexplored. Methods Renal biopsies from CKD patients were collected to evaluate the expression of REST. Kidney-specific Rest conditional knockout (Cdh16 - Cre/ Rest flox/flox ) mice were generated and employed unilateral ureter obstruction (UUO) models to investigate the role of REST in renal fibrosis. RNA sequencing was performed to elucidate the mechanism. Mitochondrial function was evaluated by transmission electron microscopy (TEM), reactive oxygen species (ROS), oxygen consumption rates (OCR), extracellular acidifcation rate (ECAR) and adenosine triphosphate (ATP). The severity of renal fibrosis was assessed through Western blot, immunofluorescent staining and immumohistochemical staining. Bioinformatic prediction, dual luciferase reporter gene assay, point mutation and chromatin immunoprecipitation (ChIP) assay were utilized to clarify the molecular mechanism. Results REST was significantly up-regulated in the kidney tissues from CKD patients, UUO-induced fibrotic mouse models and TGF-β1-incubated RTECs. Notably, kidney-specific knockout of Rest prominently alleviated renal fibrosis by improving mitochondrial energy metabolism and restoring fatty acid oxidation. Mechanically, REST disturbed mitochondrial energy metabolism through repressing the transcription of oxoglutarate dehydrogenase-like (OGDHL) via directly binding to its promotor region. Further, pharmacological inhibition of REST using the specific REST inhibitor, X5050, significantly ameliorated the progression of renal fibrosis both in vitro and in vivo. Conclusions Our explorations revealed the upregulation of REST in renal fibrosis disrupts mitochondrial energy metabolism through transcriptionally suppressing OGDHL, which may act as a promising therapeutic target for renal fibrosis.

Proteasome inhibition emerges as a promising strategy for cancer prevention. PNO1, pivotal for colorectal cancer (CRC) progression, is involved in proteasome assembly in Saccharomyces cerevisiae . Hence, we aimed to explore the role of PNO1 in proteasome assembly and its up- and down-streams in CRC. Here, we demonstrated that PNO1 knockdown suppressed CRC cells growth, proteasome activities and assembly, as well as CDKN1B / p27Kip1 (p27) degradation. Moreover, p27 knockdown partially attenuated the inhibition of HCT116 cells growth by PNO1 knockdown. The up-stream studies of PNO1 identified miR-326 as a candidate miRNA directly targeting to CDS-region of PNO1 and its overexpression significantly down-regulated PNO1 protein expression, resulting in suppression of cell growth, decrease of proteasome activities and assembly, as well as increasing the stability of p27 in CRC cells. These findings indicated that miR-326 overexpression can suppress CRC cell growth, acting as an endogenous proteasome inhibitor by targeting PNO1.

Background: Acute kidney injury (AKI) occurs in approximately 7–18% of all hospitalizations, but there are currently no effective drug therapy for preventing AKI or delaying its progression to chronic kidney disease (CKD). Recent studies have shown that Scutellaria baicalensis , a traditional Chinese herb, could attenuate cisplatin-induced AKI, although the mechanism remains elusive. Further, it is unknown whether its major active component, Oroxylin A (OA), can alleviate kidney injury. Methods: The therapeutic effect of OA was evaluated by using ischemia-reperfusion (IR) and cisplatin mediated-AKI mice and HK-2 cells under hypoxia-reoxygenation (HR) conditions. HE staining, transmission electron microscopy, flow cytometry, immunofluorescence, qPCR, Western blot, PPARα inhibitor, BNIP3 siRNA and ChIP assay were used to explore the role and mechanism of OA in AKI. Results: OA ameliorated tubular damage and dramatically decreased serum creatinine (Scr) and urea nitrogen (BUN), and the expressions of renal injury markers (Kim-1, Ngal) in AKI mice induced by both IR injury and cisplatin, as well as attenuating AKI-to-CKD transition. In vitro experiments showed that OA alleviated HR-induced mitochondrial homeostasis imbalance in renal tubular epithelial cells. Mechanistically, OA dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 expression reversed the protection of OA against HR-mediated mitochondrial injury. Network pharmacological analysis and experimental validation suggested that OA enhanced BNIP3 expression via upregulating the expression of peroxisome proliferator activated receptor alpha (PPARα), which induced the transcription of BNIP3 via directly binding to its promoter region. Both in vitro and in vivo experiments confirmed that the renoprotective effect of OA was dramatically reduced by GW6471, a PPARα antagonist. Conclusion: Our findings revealed that OA ameliorates AKI-to-CKD transition by maintaining mitochondrial homeostasis through inducing PPARα-BNIP3 signaling pathway, indicating that OA may serve as a candidate therapeutic strategy for alleviating AKI and CKD.

The incidence of non-HIV-infected Pneumocystis Jirovecii Pneumonia (PJP) is increasing. The prognosis for non-HIV PJP is poor and diagnostic tests are of lower sensitivity in non-HIV patients. Metagenomic next-generation sequencing (mNGS) was compared with routine detection assays, including Gomori methenamine silver (GMS) stain and polymerase chain reaction (PCR) technique. Specimens of 4 bronchoalveolar lavages (BAL) and 1 lung tissue samples were obtained from 4 non-HIV patients from our hospitals. Although both GMS and mNGS were positive for P. jirovecii with PCR as positive control, the testing time of mNGS was obviously shorter than GMS. Compared with the traditional GMS method, mNGS has absolute advantages. However, the issue with PJP presentations having atypical symptoms and ambiguous imaging features persists. Hence, the disease can easily be ignored. Secondly, PJP progresses rapidly in non-HIV-infected patients and can cause severe respiratory failure with unfavorable prognosis. This study affirms that mNGS can be used to quickly and accurately diagnose PJP, but a combination of clinical judgement of symptoms, laboratory testing, and imaging examination is required to make a comprehensive judgment along with mNGS test results.