Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT.

BACKGROUND: The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC. METHODS: MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drugresistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/Twist proteins, and EMT-related proteins. RESULTS: We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and Twist was down-regulated. CONCLUSION: Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

A-to-I RNA co-editing predicts clinical outcomes and is associated with immune cells infiltration in hepatocellular carcinoma.

Aberrant RNA editing has emerged as a pivotal factor in the pathogenesis of hepatocellular carcinoma (HCC), but the impact of RNA co-editing within HCC remains underexplored. We used a multi-step algorithm to construct an RNA co-editing network in HCC, and found that HCC-related RNA editings are predominantly centralized within the network. Furthermore, five pairs of risk RNA co-editing events were significantly correlated with the overall survival in HCC. Based on presence of risk RNA co-editings resulted in the categorization of HCC patients into high-risk and low-risk groups. Disparities in immune cell infiltrations were observed between the two groups, with the high-risk group exhibiting a greater abundance of exhausted T cells. Additionally, seven genes associated with risk RNA co-editing pairs were identified, whose expression effectively differentiates HCC tumor samples from normal ones. Our research offers an innovative perspective on the etiology and potential therapeutics for HCC.

Boosting the oxygen reduction activity of non-metallic catalysts via geometric and electronic engineering through nitrogen and chlorine dual-doping.

The development of heteroatom dual-doped porous carbon frameworks with uniform doping is highly desirable for achieving highly efficient oxygen reduction reaction (ORR) activity, due to their tunable chemical and electronic structures. Herein, porous covalent triazine-based frameworks (CTFs) incorporating nitrogen/chorine dual-doped porous carbon networks were fabricated by selecting 1,3-bis(4-cyanophenyl) imidazolium chloride as a building block, in a facile and controllable way via a bottom-up strategy. The resulting nitrogen/chorine dual-doped catalyst CCTF-700 exhibits excellent ORR performance with a more positive onset and half-wave potential (0.85 V vs. RHE), higher diffusion-limited current density and significantly improved stability in comparison with the benchmark commercial 20 wt% Pt/C catalyst. It is worth mentioning that CCTF-700 shows one of the best ORR performances among all the reported metal-free electrocatalysts under alkaline conditions. This work paves the way for a controllable and reliable strategy to craft highly efficient heteroatom dual-doped carbon catalysts for energy conversion.

Macrophage-derived exosomes promote telomere fragility and senescence in tubular epithelial cells by delivering miR-155.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent worldwide, and its global burden is substantial and growing. CKD displays a number of features of accelerated senescence. Tubular cell senescence is a common biological process that contributes to CKD progression. Tubulointerstitial inflammation is a driver of tubular cell senescence and a common characteristic of CKD. However, the mechanism by which the interstitial inflammation drives tubular cell senescence remains unclear. This paper aims to explore the role of exosomal miRNAs derived from macrophages in the development of tubular cell senescence. METHODS: Among the identified inflammation-related miRNAs, miR-155 is considered to be one of the most important miRNAs involved in the inflammatory response. Macrophages, the primary immune cells that mediate inflammatory processes, contain a high abundance of miR-155 in their released exosomes. We assessed the potential role of miR-155 in tubular cell senescence and renal fibrosis. We subjected miR-155-/- mice and wild-type controls, as well as tubular epithelial cells (TECs), to angiotensin II (AngII)-induced kidney injury. We assessed kidney function and injury using standard techniques. TECs were evaluated for cell senescence and telomere dysfunction in vivo and in vitro. Telomeres were measured by the fluorescence in situ hybridization. RESULTS: Compared with normal controls, miR-155 was up-regulated in proximal renal tubule cells in CKD patients and mouse models of CKD. Moreover, the expression of miR-155 was positively correlated with the extent of renal fibrosis, eGFR decline and p16INK4A expression. The overexpression of miR-155 exacerbated tubular senescence, evidenced by increased detection of p16INK4A/p21expression and senescence-associated ß-galactosidase activity. Notably, miR-155 knockout attenuates renal fibrosis and tubule cell senescence in vivo. Interestingly, once released, macrophages-derived exosomal miR-155 was internalized by TECs, leading to telomere shortening and dysfunction through targeting TRF1. A dual-luciferase reporter assay confirmed that TRF1 was the direct target of miR-155. Thus, our study clearly demonstrates that exosomal miR-155 may mediate communication between macrophages and TECs, subsequently inducing telomere dysfunction and senescence in TECs. CONCLUSIONS: Our work suggests a new mechanism by which macrophage exosomes are involved in the development of tubule senescence and renal fibrosis, in part by delivering miR-155 to target TRF1 to promote telomere dysfunction. Our study may provide novel strategies for the treatment of AngII-induced kidney injury.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, effectors of the SidE family interfere with host protein ubiquitination in a process that involves production of phosphoribosyl ubiquitin (PR-Ub). Here, we show that effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (SHxxxE) present in a large family of toxins from diverse bacterial pathogens. Thus, our study sheds light on the mechanisms by which a pathogen maintains ubiquitin homeostasis and identifies a family of enzymes capable of protein AMPylation.

Identification of stable reference genes for relative quantification of long RNA expression in urinary extracellular vesicles.

Urinary extracellular vesicles (uEVs) are rich in valuable biomolecule information which are increasingly recognized as potential biomarkers for various diseases. uEV long RNAs are among the critical cargos capable of providing unique transcriptome information of the source cells. However, consensus regarding ideal reference genes for relative long RNAs quantification in uEVs is not available as of date. Here we explored stable reference genes through profiling the long RNA expression by RNA-seq following unsupervised analysis and validation studies. Candidate reference genes were identified using four algorithms: NormFinder, GeNorm, BestKeeper and the Delta Ct method, followed by validation. RNA profile showed uEVs contained abundant long RNAs information and the core transcriptome was related to cellular structures, especially ribosome which functions mainly as translation, protein and RNA binding molecules. Analysis of RNA-seq data identified RPL18A, RPL11, RPL27, RACK1, RPSA, RPL41, H1-2, RPL4, GAPDH, RPS27A as candidate reference genes. RT-qPCR validation revealed that RPL41, RPSA and RPL18A were reliable reference genes for long RNA quantification in uEVs from patients with diabetes mellitus (DM), diabetic nephropathy (DN), IgA nephropathy (IgAN) and prostate cancer (PCA). Interestingly, RPL41 also outperformed traditional reference genes in renal tissues of DN and IgAN, as well as in plasma EVs of several types of cancers. The stable reference genes identified in this study may facilitate development of uEVs as novel biomarkers and increase the accuracy and comparability of biomarker studies.

Vernodalin Alleviates Cardiotoxicity and Inflammation in Isoproterenol-Mediated Myocardial Infarction through NF-κB/AMPK Signaling Pathways in Rats.

BACKGROUND: Myocardial infarction (MI) is the foremost cause of mortality in cardiovascular diseases. MI ultimately exacerbates cardiotoxicity due to the release of toxicity biomarkers and inflammatory infiltration. AIM: Vernodalin (VN) is a renowned cytotoxic sesquiterpene lactone that possesses antioxidant, anticancer, and anti-inflammatory properties. The cardioprotective mechanism of VN remains concealed. Hence, we explored the cardioprotective efficacy of VN on isoproterenol (ISO)- mediated MI and analyzed its underlying mechanism. METHODS: Wistar albino rats were injected ISO (85 mg/kg bw) subcutaneously to induce MI to evaluate the cardioprotective potential of VN (10 mg/kg bw) by assessing heart weight/ body weight index, hemodynamic, toxicity enzymes, histopathology, inflammatory mediators, and signaling pathway. ISO enhanced heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammation, and histopathological changes while reducing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. RESULTS: Treatment with VN could significantly (p<0.05) mitigate the heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammatory cytokines, and histopathological changes while enhancing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. Collectively, our findings revealed that the VN ameliorated defensive action against MI and averted myocardial injury by reducing the NF-κB-mediated inflammatory pathways in rats. CONCLUSION: These findings established that VN expressively preserves the myocardium and employs anti-inflammatory actions by regulating NF-κB, VEGF-B, AMPK, and eNOS signaling pathways.

Ubiquitin ligase TRIM22 inhibits ovarian cancer malignancy via TCF4 degradation.

Ovarian cancer (OC) is one of the most common malignancies in women. Tripartite motif-containing protein 22 (TRIM22) plays an important role in the initiation and progression of malignant tumors. Similarly, the transcription factor 4 (TCF4) is an essential factor involved in the initiation and progression of many tumors. However, it is still unclear whether TRIM22 can affect TCF4 in OC. Therefore, this study aims to investigate the mechanism related to TRIM22 and TCF4 in OC. TRIM22 protein and mRNA levels were analyzed in samples from both clinical and cell lines. The effects of TRIM22 knockdown and overexpression on cell proliferation, colony formation, migration, invasion, and related biomarkers were evaluated. In addition, the role of ubiquitination-mediated degradation of TCF4 was investigated by qRT-PCR and Western blotting. The association between TRIM22 and TCF4 was evaluated by Western blotting, co-immunoprecipitation, proliferation, colony formation, invasion, migration, and related biomarkers. The results showed that the expression of TRIM22 was minimal in OC tissues. Furthermore, upregulation of TRIM22 significantly inhibited OC cell proliferation, colony formation, migration, and invasion. In addition, TRIM22 was observed to regulate the degradation of TCF4 through the ubiquitination pathway. TCF4 can reverse the effects of TRIM22 on proliferation, colony formation, migration, and invasion in OC cells. TRIM22-mediated ubiquitination of TCF4 at K48 is facilitated by the RING domain. Implications: In conclusion, ubiquitination of TCF4 protein in OC is regulated by TRIM22, which has the potential to limit the proliferation, migration, and invasion of OC.

ERCC3-Related Genes May Aid in the Prognostic and Immunotherapeutic Analysis of Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has high morbidity and mortality worldwide. Excision repair cross-complement 3 (ERCC3), a key functional gene in the nucleotide excision repair (NER) pathway, is commonly mutated or overexpressed in cancers and is thought to be a key gene contributing to the development of HCC. The characteristics of immune cell infiltration in the global tumor microenvironment (TME) mediated by ERCC3 and its related key genes in HCC are still unclear. The aim of this study was to integrate the role of ERCC3-related key genes in assessing the TME cell infiltration characteristics, immunotherapy efficacy, and prognosis of HCC patients. This study provides a theoretical basis for the study of immunological mechanisms and prognosis prediction in HCC. METHODS: The HCC cohort from the TCGA database included 50 normal samples and 374 tumor samples to compare the differences in ERCC3-related gene expression and prognosis between liver tumor tissues and normal liver tissues and to analyze the extent to which different genes infiltrated TME cells by quantifying the relative abundance of 24 cells through single-sample genome enrichment analysis (ssGSEA). A risk score associated with the ERCC3 gene was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression model. RESULTS: The expression of 11 ERCC3-related genes was significantly upregulated in HCC tumor tissues compared to normal liver tissues, and high expression of these genes was significantly associated with poor prognosis in HCC patients. The key genes (11 ERCC3-related genes) were closely associated with the nucleic acid reduction signaling pathway in nucleic acid metabolism and the viral oncogenic pathway, suggesting that these key genes may play a role in tumor cell proliferation, migration, and invasion, as well as in the pathogenesis of virus-associated HCC. In addition, the infiltration characteristics of TME immune cells in normal and tumor tissues were different. Immune and mesenchymal activity was significantly lower in tumor tissues than in healthy liver tissues. This study revealed that key genes were significantly positively correlated with CTLA4 and enriched in central memory CD4 T cells, effector memory CD4 T cells, activated CD4 T cells, and type 2 T helper cells. The prognostic model constructed by regression analysis could better distinguish patients into high-risk and low-risk groups, and the survival analysis showed that the survival time of patients with high-risk score subtypes was significantly lower than that of patients with low-risk scores and that the high-risk group contained higher levels of immune-suppressive cells, which may be a mediator of immune escape. Moreover, multivariate analyses showed that the risk score profile is a reliable and unbiased biomarker for assessing the prognosis of HCC patients, and its value in predicting the outcome of immunotherapy was also confirmed. CONCLUSION: This study revealed a novel genetic signature that is significantly associated with TME cell infiltration and prognosis in HCC patients. It demonstrated that the combined action of multiple key genes associated with ERCC3 plays a crucial role in shaping the diversity and complexity of TME cell infiltrates. Evaluating the combined characteristics of multiple key genes associated with ERCC3 can help predict the outcome of immunotherapy in patients and provide new potential targets for immuno-individualized therapeutic studies on HCC.

Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms.

The reversal of ubiquitination induced by members of the SidE effector family of Legionella pneumophila produces phosphoribosyl ubiquitin (PR-Ub) that is potentially detrimental to host cells. Here we show that the effector LnaB functions to transfer the AMP moiety from ATP to the phosphoryl moiety of PR-Ub to convert it into ADP-ribosylated ubiquitin (ADPR-Ub), which is further processed to ADP-ribose and functional ubiquitin by the (ADP-ribosyl)hydrolase MavL, thus maintaining ubiquitin homeostasis in infected cells. Upon being activated by Actin, LnaB also undergoes self-AMPylation on tyrosine residues. The activity of LnaB requires a motif consisting of Ser, His and Glu (S-HxxxE) present in a large family of toxins from diverse bacterial pathogens. Our study not only reveals intricate mechanisms for a pathogen to maintain ubiquitin homeostasis but also identifies a new family of enzymes capable of protein AMPylation, suggesting that this posttranslational modification is widely used in signaling during host-pathogen interactions.

Rhodium-Catalyzed Highly Enantioselective Hydroboration of Acyclic Tetrasubstituted Alkenes Directed by an Amide.

Although progress has been made in enantioselective hydroboration of di- and trisubstituted alkenes over the past decades, enantioselective hydroboration of tetrasubstituted alkenes with high diastereo- and enantioselectivities continues as an unmet challenge since the 1950s due to its extremely low reactivity and the difficulties to simultaneously control the regio- and stereoselectivity of a tetrasubstituted alkene. Here, we report highly regio-, diastereo-, and enantioselective catalytic hydroboration of diverse acyclic tetrasubstituted alkenes. The delicate interplay of an electron-rich rhodium complex and coordination-assistance forms a highly adaptive catalyst that effectively overcomes the low reactivity and controls the stereoselectivity. The generality of the catalyst system is exemplified by its efficacy across various tetrasubstituted alkenes with diverse steric and electronic properties.

Erratum: Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury: Erratum.

[This corrects the article DOI: 10.7150/thno.54550.].

Urban flood modeling with a novel coupling method of surface and sewer hydrodynamic processes.

Drainage modeling that accurately captures urban storm inundation serves as the foundation for flood warning and drainage scheduling. In this paper, we proposed a novel coupling ideology that, by integrating 2D-1D and 1D-2D unidirectional processes, overcomes the drawback of the conventional unidirectional coupling approach that fails to properly represent the rainfall surface catchment dynamics, and provides more coherent hydrological implications compared to the bidirectional coupling concept. This paper first referred to a laboratory experimental case from the literature, applied and analyzed the coupling scheme proposed in this paper and the bidirectional coupling scheme that has been widely studied in recent years, compared the two coupling solutions in terms of the resulting accuracy and applicability, and discussed their respective strengths and weaknesses to validate the reliability of the proposed method. The verified proposed coupling scheme was then applied to the modeling of a real drainage system in a region of Nanjing, China, and the results proved that the coupling mechanism proposed in this study is of practical application value.

Discovery and Optimization of Novel SaFabI Inhibitors as Specific Therapeutic Agents for MRSA Infection.

As the rate-limiting enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI) emerges as a compelling target for combating methicillin-resistant S. aureus (MRSA) infections. Herein, compound 1, featuring a 4-(1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent SaFabI inhibitor (IC50 = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31, with improved inhibitory efficacy on enzymatic activity (IC50 = 174.2 nM) and selective potency against S. aureus (MIC = 1-2 µg/mL). Mechanistically, n31 directly inhibited SaFabI in cellular contexts. Moreover, n31 exhibited favorable safety and pharmacokinetic profiles, and dose-dependently treated MRSA-induced skin infections, outperforming the approved drug, linezolid. The chiral separation of n31 resulted in (S)-n31, with superior activities (IC50 = 94.0 nM, MIC = 0.25-1 µg/mL) and in vivo therapeutic efficacy. In brief, our research proposes (S)-n31 as a promising candidate for SaFabI-targeted therapy, offering specific anti-S. aureus efficacy and potential for further development.

Efficacy and mechanism of action of Yanxiao Di'naer formula for non-alcoholic steatohepatitis treatment based on metabolomics and RNA sequencing.

ETHNOPHARMACOLOGICAL RELEVANCE: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is a crucial component of this disease spectrum. The Yanxiao Di'naer formula (YXDNE) is an Uyghur medical extract that has been used in folk medicine to treat hepatitis for a long time. However, the role and mechanism of action of YXDNE in NASH treatment remains unclear. OBJECTIVE: The objective of this study was to assess the effectiveness of YXDNE in treating NASH induced by injections of carbon tetrachloride combined with a high-fat high-cholesterol diet (HFHCD), and to clarify the underlying mechanisms. METHODS: The compounds in the YXDNE extract were analysed for classification and proportions using ultra-performance liquid chromatography-mass spectrometry. The efficacy of YXDNE in treating abnormal lipid metabolism was evaluated in L02 cells in vitro. In addition, a C57BL/6 mouse model of NASH was established to evaluate the therapeutic efficacy of YXDNE in vivo. Metabolomics and RNA sequencing were used to analyse the therapeutic effects of YXDNE on the liver. The corresponding signalling pathways were found to target AMPKα1, PPARα, and NF-κB. The efficacy of YXDNE was validated using inhibitors or silencing RNA (siRNA) against AMPKα1 and PPARα. RESULTS: This study confirmed that YXDNE treatment ameliorated NASH in a murine model of this disease. Metabolomics analysis suggested that YXDNE efficacy was associated with fatty acid catabolism and AMPK signalling pathways. RNA sequencing results showed that YXDNE efficacy in treating NASH was highly correlated with the AMPK, PPARα and NF-κB pathways. Both in vitro and in vivo experimental data demonstrated that YXDNE affected the expression of p-AMPKα1, PPARα, p-NF-κB, IκB, and p-IκB. The efficacy of YXDNE in treating NASH in vitro was cancelled when AMPK was inhibited with Compound C or PPARα was modulated via siRNA. CONCLUSIONS: YXDNE may have a therapeutic effect on abnormal lipid metabolism in L02 cells and in a murine model of NASH by affecting the AMPKα1/PPARα/NF-κB signalling pathway. Therefore, YXDNE has the potential for clinical application in the prevention and treatment of NASH.

Comparative outcomes of video-assisted thoracoscopic surgery versus open surgery for bronchogenic cysts in adults: a retrospective cohort study.

Background: Open thoracotomy has been the traditional surgical approach for patients with bronchogenic cysts (BCs). This study aimed to evaluate the safety and efficacy of video-assisted thoracoscopic surgery (VATS) compared to open surgery for the treatment of BCs in adults. Methods: This single-institution, retrospective cohort study included 117 consecutive adult patients who underwent VATS (group A) or open surgery (group B) for BC resection between February 2019 and January 2023. Data regarding clinical history, operation duration, length of hospital stay, 30-day mortality, and recurrence during follow-up were collected and analyzed. Results: Of the total cohort, 103 (88.0%) patients underwent VATS, while 14 (12.0%) patients underwent open surgery. Patients' age in group B were much older than group A (P=0.014), and no significant differences in other demographic and baseline clinical characteristics were observed between the groups. The VATS group had shorter median operation duration (96 vs. 149.5 min, P<0.001) and shorter mean length of hospital stay (5.0±5.5 vs. 8.6±4.0 days, P<0.001). One death occurred in the open surgery group. During a median follow-up of 34 (interquartile range, 20.8-42.5) months, no instances of BC recurrence were observed in either group. Conclusions: Compared to open surgery, VATS is also a safe and efficacious approach for treating BCs in adults. What's more, VATS offered shorter operative times and hospital stays. Considering the minimally invasive, VATS may be a better choice in most patients with bronchial cysts.

CD8 T cells induce the peritubular capillary rarefaction during AKI to CKD transition.

Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.

HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension.

BACKGROUND AND PURPOSE: Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS: Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS: We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.

Endobronchial ultrasound-guided cautery-assisted transbronchial mediastinal cryobiopsy in the diagnosis of fibrosing mediastinitis secondary to atypical sarcoidosis: a case report.

Background: Fibrosing mediastinitis (FM) secondary to atypical sarcoidosis (atypical presentation of sarcoidosis) is rarely reported at home and abroad. Its clinical manifestations represent a lack of specificity, and the initial diagnosis is frequently difficult. In particular, this case has multiple pulmonary nodules with mediastinal lymph node enlargement and bilateral pleural effusion, and pulmonary fibrosis still exists after treatment, which is inconsistent with any clinical stage of pulmonary sarcoidosis, further increasing the diagnostic difficulty. We retrospectively analyzed the clinical data of a case of FM secondary to atypical sarcoidosis diagnosed by endobronchial ultrasound-guided cautery-assisted transbronchial mediastinal cryobiopsy (EBUS-CA-TBMCB) in Chongqing University Fuling Hospital, to improve clinicians' attention to FM and understand that EBUS-CA-TBMCB remains an effective way of etiological diagnosis. Case Description: A 70-year-old man was hospitalized with cough and dyspnea for two months. After admission, through chest computed tomography (CT), ultrasound guided bilateral lung biopsy, left parietal pleural biopsy, and EBUS-CA-TBMCB, the final diagnosis was atypical sarcoidosis secondary FM. After taking glucocorticoid orally, the patient's condition improved significantly, and was discharged from the hospital. We continued following up outside the hospital, and the patient's condition was further improved. Conclusions: The diagnosis of FM is mainly based on typical imaging manifestations. When the contrast-enhanced chest CT finds localized or diffuse soft tissue density shadows around the mediastinum and pulmonary hilum with an irregular shape, with or without calcification, particular attention should be paid to exclude FM. EBUS-CA-TBMCB, as an improved minimally invasive method, can obtain enough tissue samples for pathological diagnosis, which may be the effective biopsy method for the etiology of FM to avoid missed diagnosis and misdiagnosis in the future.