TRIM34 suppresses non-small-cell lung carcinoma via inducing mTORC1-dependent glucose utilization and promoting cellular death.

Non-small-cell lung carcinoma (NSCLC) is a type of pernicious tumor, which owns high morbidity and mortality. TRIM34 has a stimulative role in cell apoptosis and a suppressive role in inflammation. However, no studies were focused on the regulatory impacts of TRIM34 in NSCLC. This study aimed to examine the underlying regulatory effects of TRIM34 in NSCLC. TRIM34 exhibited lower expression in NSCLC. TRIM34 facilitated mitochondrial damage and apoptosis in NSCLC. TRIM34 induced the increased activity of mTORC1 and accelerated glycolysis in NSCLC. Enhanced mitochondrial damage induced by TRIM34 overexpression was reversed after rapamycin (mTORC1 inhibitor) treatment in NSCLC. The strengthened cell apoptosis stimulated by TRIM34 overexpression was rescued after rapamycin treatment. TRIM34 activated mTORC1 to suppress NSCLC progression in vivo. TRIM34 suppressed NSCLC via inducing mTORC1-dependent glucose utilization and promoting cellular death. The results suggest that TRIM34 can be a useful therapeutic biomarker for NSCLC patients.

Online-to-offline combined with problem-based learning is an effective teaching modality in the standardized residency training of nephrology.

BACKGROUND: The online-to-offline (O2O) teaching method is recognized as a new educational model that integrates network learning into offline classroom education, while problem-based learning (PBL) is a teaching modality that guides students to apply acquired theoretical knowledge to solve practical problems. However, implementing O2O combined with PBL has not been extensively explored in nephrology residency training. This study aims to explore the efficacy of O2O combined with PBL in the standardized residency training of nephrology by comparing it with the traditional lecture-based teaching (LBT). METHODS: Sixty residency trainees who participated in the standardized training of internal medicine in the nephrology department of the Second Affiliated Hospital of Zhejiang University School of Medicine were equally allocated into O2O combined with PBL (O2O/PBL) or the LBT group demographically matched. Examinations of theory, practice skills, clinical thinking and teaching satisfaction surveys were utilized to assess the teaching effects of the two groups. RESULTS: Participants from the O2O/PBL group outperformed those from the LBT group in the examination of theory (81.233 ± 9.156 vs. 75.800 ± 7.009, mean ± SEM), practice skills (104.433 ± 3.569 vs.100.316 ± 4.628, mean ± SEM) and clinical thinking (88.933 ± 4.473 vs. 86.667 ± 3.844, mean ± SEM). There was no significant difference in the teaching satisfaction between the two groups. CONCLUSION: The current study shows the positive impact of O2O combined with PBL approach on standardized residency training in nephrology without reducing teaching satisfaction.

Military training-related abdominal injuries and diseases: Common types, prevention and treatment.

Military training is intense, difficult and often dangerous, so all kinds of injuries or diseases frequently occur during training. Most of the previous studies and reviews on military training-related injuries focused on musculoskeletal system, whereas there are no reviews of abdominal injuries and diseases. Although the incidence of military training-related abdominal injuries and diseases is relatively low, the patients' condition is often critical especially in the presence of abdominal organ injury, leading to multi-organ dysfunction syndrome and even death. This paper elaborates on common types of military training-related abdominal injuries and diseases as well as the prevention and treatment measures, which provides some basis for scientific and reasonable training and improvement of medical security.

C1-C2 Pedicle Screw Fixation for Pediatric Atlantoaxial Dislocation: Initial Results and Long-term Follow-up.

BACKGROUND: There are few studies reporting the use of atlantoaxial pedicle screws and the long-term effects of C1-C2 posterior fusion in children. Our study is to investigate the initial results of C1-C2 pedicle screw fixation for pediatric atlantoaxial dislocation (AAD) and assessed spontaneous change of postoperative radiography after a long-term follow-up period. METHODS: Posterior pedicle screw fixations were performed in 21 pediatric patients with AAD. All the patients underwent implant removal 1 year after their initial surgery and had regular follow-up with an average duration of 76.4 months (range, 52 to 117 mo). Clinical and radiographic data were then collected and compared. RESULTS: Frankel Grade was significantly improved at 3 months follow-up compared with pretreatment values. All patients had good bony fusion at a mean of 4.2±0.9 months (range, 3 to 6 mo) after treatment. None of the patients experienced worsening neurological symptoms or injury to the vertebral artery. However, 2 cases experienced minor complications. Following removal of the implants, no spinal deformities or subaxial instabilities were found. The mean angle of sagittal curvature increased from 12.1±2.4 degrees (range, 0 to 22 degrees) immediately postoperatively to 19.1±2.7 degrees (range, 6 to 31 degrees) at the final follow-up (P>0.05). CONCLUSIONS: The results demonstrated that C1-C2 pedicle screw fixation could achieve satisfactory initial results for the management of the pediatric AAD. Moreover, removal of the metal implant after bony fusion did not increase the risk of spinal deformity or subaxial instability at long-term follow-up.

Anti-Proliferation Effect of Theasaponin E1 on the ALDH-Positive Ovarian Cancer Stem-Like Cells.

Ovarian cancer has the highest mortality rate of all gynecological malignancies and the five-year death rate of patients has remained high in the past five decades. Recently, with the rise of cancer stem cells (CSCs) theory, an increasing amount of research has suggested that CSCs give rise to tumor recurrence and metastasis. Theasaponin E1 (TSE1), which was isolated from green tea (Camellia sinensis) seeds, has been proposed to be an effective compound for tumor treatment. However, studies on whether TSE1 takes effect through CSCs have rarely been reported. In this paper, ALDH-positive (ALDH+) ovarian cancer stem-like cells from two platinum-resistant ovarian cancer cell lines A2780/CP70 and OVCAR-3 were used to study the anti-proliferation effect of TSE1 on CSCs. The ALDH+ cells showed significantly stronger sphere forming vitality and stronger cell migration capability. In addition, the stemness marker proteins CD44, Oct-4, Nanog, as well as Bcl-2 and MMP-9 expression levels of ALDH+ cells were upregulated compared with the original tumor cells, indicating that they have certain stem cell characteristics. At the same time, the results showed that TSE1 could inhibit cell proliferation and suspension sphere formation in ALDH+ cells. Our data suggests that TSE1 as a natural compound has the potential to reduce human ovarian cancer mortality. However, more research is still needed to find out the molecular mechanism of TSE1-mediated inhibition of ALDH+ cells and possible drug applications on the disease.

NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury.

The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been implicated in podocyte injury and glomerular sclerosis during hyperhomocysteinemia (hHcys). However, it remains unclear whether the NLRP3 inflammasome can be a therapeutic target for treatment of hHcys-induced kidney injury. Given that DHA metabolites-resolvins have potent anti-inflammatory effects, the present study tested whether the prototype, resolvin D1 (RvD1), and 17S-hydroxy DHA (17S-HDHA), an intermediate product, abrogate hHcys-induced podocyte injury by targeting the NLRP3 inflammasome. In vitro, confocal microscopy demonstrated that 17S-HDHA (100 nM) and RvD1 (60 nM) prevented Hcys-induced formation of NLRP3 inflammasomes, as shown by reduced colocalization of NLRP3 with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1. Both DHA metabolites inhibited Hcys-induced caspase-1 activation and interleukin-1ß production. However, DHA had no significant effect on these Hcys-induced changes in podocytes. In vivo, DHA lipoxygenase metabolites substantially inhibited podocyte NLRP3 inflammasome formation and activation and consequent glomerular sclerosis in mice with hHcys. Mechanistically, RvD1 and 17S-HDHA were shown to suppress Hcys-induced formation of lipid raft redox signaling platforms and subsequent O2·- production in podocytes. It is concluded that inhibition of NLRP3 inflammasome activation is one of the important mechanisms mediating the beneficial action of RvD1 and 17S-HDHA on Hcys-induced podocyte injury and glomerular sclerosis.

Necrostatin-1 Mitigates Endoplasmic Reticulum Stress After Spinal Cord Injury.

Necrostatin-1 (Nec-1) has been shown to inhibit necroptosis and convey a significant protective effect after spinal cord injury (SCI). This small molecule inhibitor may reduce tissue damage and restore neurological function by lessening mitochondrial injury after SCI and preserving energy homeostasis. However, the effects of Nec-1 on endoplasmic reticulum stress (ERS)-an important pathological consequence of SCI-are still not clear. The present study investigates the relationship between necroptosis and ERS in a rat model of SCI. Electron microscopy was employed to observe ultra-structural changes in the endoplasmic reticulum and mitochondria after lesioning. Real-time quantitative PCR was used to measure the mRNA levels of ERS-related pro-apoptotic molecules such as C/EBP homologous protein (CHOP), immunoglobulin-binding protein (BiP/GRP78) and X box-binding protein-1 (XBP-1). Western blot and immunofluorescence were conducted to analyze CHOP, GRP78 and XBP-1 protein expression after lesioning. Results demonstrated that applying Nec-1 in SCI reduces ultra-structural damage to the endoplasmic reticulum and mitochondria and inhibits expression of ERS-related genes and proteins after lesioning. Immunofluorescence also shows ERS-related proteins mainly expressed in the cytoplasm of nerve cells. Taken together, these results demonstrate that Nec-1 has protective effect on the endoplasmic reticulum and mitochondria and alleviates ERS after SCI.

A comparative study of three approaches for the treatment of lumbosacral tuberculosis.

The posterior (P), antero-posterior (AP), and anterior approaches (A) with a new complex locking rod system (D-rod system) were performed on 64 patients with lumbosacral tuberculosis respectively and the efficacies of the three approaches were compared in our study. Related data were then collected and compared with an average of 27.0 months follow up. The lumbosacral angles, VAS, ODI, ESR, and Frankel Grade were significantly improved at the post-operation or final follow-up when compared to preoperative scores. The average surgical time, blood loss, and hospital stay following anterior and posterior approaches were markedly less than those following antero-posterior approach. Moreover, there was no tuberculosis recurrence in AP and A group. However, P group had a recurrence rate of 11.1% (2/18). None of the patients in P and A group developed intraoperative or postoperative complications, while two cases were found in AP group. Taken together, anterior approach with the D-rod system is an appropriate method for lumbosacral tuberculosis treatment.

Comparison of the PEEK cage and an autologous cage made from the lumbar spinous process and laminae in posterior lumbar interbody fusion.

BACKGROUND: A prospective cohort study was performed to evaluate the clinical and radiological outcomes following posterior lumbar interbody fusion (PLIF) in patients treated with a PEEK cage compared to those treated with an autologous cage using the lumbar spinous process and laminae (ACSP). METHODS: Sixty-nine consecutive patients with lumbar degenerative disc disease were randomly assigned to either a PEEK cage (group A, n = 34) or an ACSP (group B, n = 35). Monosegmental PLIF was performed in all patients. Mean lumbar lordosis, mean disc height, visual analog scale (VAS) scores, functional outcomes, fusion rates and complication rates were recorded and compared. The patients were followed postoperatively for a minimum of 2 years. RESULTS: Successful radiographic fusion was documented in all patients. No flexion-extension hypermobility or pedicle screw loosening or breakage occurred during the follow-up period. No significant difference existed between the 2 groups when comparing the mean lumbar lordosis, mean disc height, visual analog scale (VAS) scores, functional outcomes, fusion rates or complication rates. Overall satisfactory results were achieved in both groups. CONCLUSIONS: The results suggest that the ACSP appears to be equally as safe and effective as the PEEK cage. TRIAL REGISTRATION: ISRCTN25558534 . Retrospectively registered 16/02/2016.

Management of combined atlas-axis fractures: a review of forty one cases.

PURPOSE: To outline a management principle for the combined atlas (C1)-axis (C2) fractures and assess its therapeutic effects. METHODS: Forty-one patients with combined C1-C2 fractures were treated according to their C2 fracture types. Non-operative external immobilization in the form of a cervical collar or halo vest was used in 22 patients. Early posterior pedicle screw fixations were performed in 19 patients whose fractures had a combination of any of the three conditions: an atlantodens interval (ADI) ≥ 5 mm, lateral mass displacement (LMD) > 7 mm, and/or C2-C3 angulation > 11°. Thirty-nine patients were followed up regularly with an average of 19.3 months (range, 12 to 45 months). Clinical and radiographic data were then collected and compared. RESULTS: At three months following treatment, patients' visual analog scale (VAS), Neck Disability Index (NDI), American Spinal Injury Association (ASIA) scale, and Frankel grades were all significantly improved when compared to pretreatment. These results indicated that the cervical collar, halo vest, and posterior pedicle screw fixation approaches were all able to effectively treat cases of combined C1-C2 fractures. One patient in the non-surgical group developed nonunion which required late surgical treatment and one patient had pin site infection in the non-surgical group (2/22), while there were three minor complications in the surgical group. CONCLUSION: We propose a management principle that bases the treatment of a combined C1-C2 fracture on the nature of the C2 fracture. This treatment strategy has yielded promising results as a satisfactory means for the management of combined C1-C2 fractures.

Treating Eyres type IV and V coracoid fracture using the acromion osteotomy approach.

PURPOSE: To introduce a surgical method of treating Eyres type IV and V coracoid fracture using the acromion osteotomy approach and to further analyse the clinical effectiveness of this surgical procedure. METHODS: Nine patients were included in this study with a mean follow-up time of 23.3 months (range, 14.0-34.0 months). Patients were evaluated with use of the Constant score, the Simple Shoulder Test (SST) score and a visual analogue scale (VAS) pain score. Moreover, the shoulder range of motion was also observed. RESULTS: The mean operation time was 91.6 min with a blood loss volume ranging from 310 to 530 ml. The fractures of eight patients had recovered between 10 and 12 weeks post operation with no signs of infection, screw loosening, plate breaking or other internal fixation failures, while one case had non-union at 34 months' follow-up. The mean Constant score increased from 75.6 points preoperatively to 91.0 points at follow-up. The mean VAS score decreased from 5.3 preoperatively to 1.0 at follow-up, while the average SST score increased from 7.1 points preoperatively to 10.0 points at follow-up. The mean abduction, forward flexion, external rotation, internal rotation and backward extension angles were 162°, 159° 50°, 55° and 47°. Five cases were classified as excellent, three cases were marked as good and one case was classified as fair. CONCLUSIONS: Treating coracoid fracture through the approach of acromion osteotomy could be an effective treatment option with minimise damages.

Silencing of Kv1.5 Gene Inhibits Proliferation and Induces Apoptosis of Osteosarcoma Cells.

Kv1.5 (also known as KCNA5) is a protein encoded by the KCNA5 gene, which belongs to the voltage-gated potassium channel, shaker-related subfamily. Recently, a number of studies have suggested that Kv1.5 is overexpressed in numerous cancers and plays crucial roles in cancer development. However, until now, the expression and functions of Kv1.5 in osteosarcoma are still unclear. To characterize the potential biological functions of Kv1.5 in osteosarcoma, herein, we examined the expression levels of Kv1.5 in osteosarcoma cells and tissues using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry assays. Four short hairpin RNAs (shRNAs) targeting Kv1.5 were designed and homologous recombination technology was used to construct pGeneSil-Kv1.5 vectors. In addition, the vectors were transfected into osteosarcoma MG63 cells and Kv1.5 mRNA level was measured by qRT-PCR and the Kv1.5 protein level was examined by western blot. We also examined the effects of Kv1.5 silencing on proliferation, cell cycle and apoptosis of the osteosarcoma cells using CCK-8, colony formation, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Our results showed that Kv1.5 was aberrantly expressed in osteosarcoma and that the synthesized shRNA targeting Kv1.5 reduced Kv1.5 mRNA and protein expression effectively. Silencing Kv1.5 expression in the osteosarcoma cells significantly inhibited the proliferation of osteosarcoma cells, induced cell cycle arrest at G0/G1 phase, and induced cell apoptosis through up-regulation of p21, p27, Bax, Bcl-XL and caspase-3 and down-regulation of cyclins A, cyclins D1, cyclins E, Bcl-2 and Bik. In summary, our results indicate that Kv1.5 silencing could suppress osteosarcoma progression through multiple signaling pathways and suggest that Kv1.5 may be a novel target for osteosarcoma therapeutics.

Mesenchymal Stem Cell-Derived Exosomes Attenuate Murine Cytomegalovirus-Infected Pneumonia via NF-κB/NLRP3 Signaling Pathway.

Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.

Comparison of Clinical Characteristics, Therapy, and Short-Term Prognosis between Blunt and Penetrating Abdominal Trauma: A Multicentric Retrospective Cohort Study.

Objective: Large-scale studies on the characteristics and management of abdominal trauma in megacities in China are lacking. The aim of this study was to analyze and present the clinical patterns and treatment status of abdominal trauma in regional medical centers. Methods: Cases of abdominal trauma treated at seven medical centers in Beijing from 2010 to 2021 were collected. Clinical information about age, sex, injury cause, geographic distribution, abbreviated injury scale/injury severity score (AIS/ISS) value, injury-hospital time, preoperative time, surgically identified organ injuries, type of surgery, causes of reoperation and 90-day mortality was included in this study. Clinical characteristics, treatment methods, and short-term prognoses (90-days survival) were compared between blunt abdominal trauma (BAT) and penetrating abdominal trauma (PAT) cases. Non-normally distributed data are described as medians (IQR), and the Mann‒Whitney U test was performed; qualitative data were analyzed using the X2 test. Univariate and multivariate survival analyses were performed by the Cox proportional hazards model. Results: A total of 553 patients (86.98% male) with a median age of 36.50 (27.00-48.00) years were included. The BAT group had a significantly higher proportion of serious injury (P=0.001), lower initial hemoglobin level (P=0.001), and a lower laparoscopy surgery rate (P=0.044) compared to the PAT group. Additionally, more BAT cases were from the area around Beijing (P=0.008) and a longer injury-regional hospital time (10.47 (5.18-22.51) hours vs. 7.00 (3.80-15.38) hours, P=0.001). In the hollow viscus injury subgroup, the BAT group had a significantly longer injury-regional hospital time and preoperative time compared to the PAT group (injury-regional hospital time: 10.23 (6.00-21.59) hours vs. 7.07 (3.99-13.85) hours, P=0.002; preoperative time: 3.02 (2.01-5.58) hours vs. 2.81 (1.85-3.63) hours, P=0.047). The overall 90-day mortality was 11.9%, and longer injury-regional hospital time (HR: 1.01, 95% CI: 1.00-1.02, P=0.008), receipt of ICU treatment (HR: 4.69, 95% CI: 2.54-8.65, P=0.001), and severe ISSs (ISS > 25 vs. ISS < 16, HR: 2.78, 95% CI: 1.38-5.601, P=0.004) had a worse impact on survival. Conclusion: More patients with BAT were transferred to higher-level hospital, leading to significantly longer prehospital and preoperation time. In the subgroup of hemodynamically stable individuals, more patients with BAT experienced hollow viscus injuries. For those patients, aggressive diagnostic laparoscopic exploration may be beneficial. Patients with longer injury-regional hospital intervals, the need for ICU care, and higher injury severity scores (ISSs) suffered from worse prognoses.

Retraction: Radical Covalent Organic Frameworks Associated with Liquid Na-K toward Dendrite-Free Alkali Metal Anodes.

10.1002/advs.202203058 Adv. Sci. 2022, 9, 2203058 The above article from Advanced Science, published online on 21 July 2022 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202203058), has been retracted by agreement between the authors, the Editor-in-Chief, Kirsten Severing, and Wiley-VCH GmbH. The retraction has been agreed as the article is based on research results and data that the authors were not authorized to use. Moreover, the majority of co-authors have been listed despite insufficient qualification for contributorship.

Retraction: Dual-Ion Stabilized Layered Structure of O-V-OforZero-Strain Potassium Insertion and Extraction.

10.1002/advs.202202550 Adv. Sci.2022, 9, 2202550 The above article from Advanced Science, published online on 5 June 2022 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/advs.202202550), has been retracted by agreement between the authors, the Editor-in-Chief, Kirsten Severing, and Wiley-VCH GmbH. The retraction has been agreed as the article is based on research results and data that the authors were not authorized to use. Moreover, the majority of co-authors have been listed despite insufficient qualification for contributorship.

Posterior pedicle screw fixation combined with local steroid injections for treating axial eosinophilic granulomas and atlantoaxial dislocation: A case report.

BACKGROUND: Eosinophilic granuloma (EG) is a proliferative condition that affects the cells of bone tissue. There are no specific clinical signs or imaging manifestations in the early stages of the disease, making it simple to overlook and misdiagnose. Because of the disease's rarity, there is presently no standardized treatment principle. There are few accounts of such occurrences affecting the axis among children. We discovered a case of a child whose EG resulted in atlantoaxial joint dislocation and destruction of the axial bone. CASE SUMMARY: After having pharyngeal discomfort for more than six months without a clear explanation, a 6-year-old boy was brought to our hospital. Following a careful evaluation, the pathology indicated a strong likelihood of an axial EG. Ultimately, we decided to treat the boy with posterior pedicle screw fixation and local steroid injections. CONCLUSION: EGs of the upper cervical spine are quite uncommon in children, and they are exceedingly easy to overlook or misdiagnose. Posterior pedicle screw fixation and local steroid injections are effective treatments for patients with axial EGs affecting the atlantoaxial junction.

Comprehensive metabolic analyses provide new insights into primary and secondary metabolites in different tissues of Jianghua Kucha tea (Camellia sinensis var. assamica cv. Jianghua).

Background: Jianghua Kucha (JHKC) is a special tea germplasm with enriched specialized secondary metabolites, including theacrine, non-epimeric flavanols and methylated flavanols. Moreover, primary metabolites provide precursors and energy for the production of secondary metabolites. However, the accumulation patterns of primary and secondary metabolites in different tissues of JHKC are unclear. Methods: The changes of primary and secondary metabolites and related metabolic pathways (primary and secondary metabolism) in different JHKC tissues (the bud, 1st-4th leaves, and new stem) were investigated via metabolomics analysis with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Results: Significant differences were observed in 68 primary and 51 secondary metabolites mainly related with the pathways of starch and sucrose, amino acids, caffeine, and flavanols metabolism and TCA cycle. The bud exhibited higher levels of glucose-6-phosphate, citric acid, most amino acids, theobromine, catechin-gallate, epicatechin-gallate, procyanidins, and theasinensins; the 1st leaf showed higher levels of caffeine and epigallocatechin-3-gallate; and the 4th leaf contained higher levels of most monosaccharides, theacrine, and epigallocatechin-3-O-(3"-O-methyl)-gallate. In addition, primary metabolites and important secondary metabolites had certain correlations. Conclusion: This study provides comprehensive insight into primary and secondary metabolites in JHKC and offers guidelines for efficiently utilizing specialized metabolites of JHKC in the future.

ELABELA/APJ Axis Prevents Diabetic Glomerular Endothelial Injury by Regulating AMPK/NLRP3 Pathway.

ELABELA (ELA), a recently discovered peptide, is highly expressed in adult kidneys and the endothelium system. It has been identified as a novel endogenous ligand for the apelin receptor (APJ). This study aims to investigate the role of ELA in diabetic glomerular endothelial pyroptosis and its underlying mechanism. Initially, a significant decrease in ELA mRNA levels was observed in the renal cortex of db/db mice and high glucose-treated glomerular endothelial cells (GECs). It was also found that ELA deficiency in ELA+/- mice significantly accelerated diabetic glomerular injury, as shown by exacerbated glomerular morphological damage, increased serum creatine and blood urea nitrogen, and elevated 24-h urinary albumin excretion. In addition, in vivo overexpression of ELA prevented diabetic glomerular injury, reduced von Willebrand factor expression, restored endothelial marker CD31 expression, and attenuated the production of adhesive molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Furthermore, in vitro studies confirmed that treatment with ELA inhibited GEC injury by regulating the NOD-like receptor protein 3 (NLRP3) inflammasome, as indicated by blocking NLRP3 inflammasome formation, decreasing cleaved Caspase-1 production, and inhibiting interleukin-1ß and interleukin-18 production. Moreover, in vitro experiments demonstrated that the protective effects of ELA in GECs during hyperglycemia were diminished by inhibiting adenosine monophosphate-activated protein kinase (AMPK) using Compound C or by APJ deficiency. Taken together, this study provides the first evidence that ELA treatment could prevent diabetic glomerular endothelial injury, which is partly mediated by the regulation of the AMPK/NLRP3 signaling pathway. Therefore, pharmacologically targeting ELA may serve as a novel therapeutic strategy for diabetic kidney disease.

hMSCs treatment attenuates murine herpesvirus-68 (MHV-68) pneumonia through altering innate immune response via ROS/NLRP3 signaling pathway.

Immunocompromised individuals are particularly vulnerable to viral infections and reactivation, especially endogenous herpes viruses such as Epstein-Barr virus (EBV), a member of oncogenic gamma-herpesviruses, which are commonly linked to pneumonia and consequently significant morbidity and mortality. In the study of human and animal oncogenic gammaherpesviruses, the murine gamma-herpesviruses-68 (MHV-68) model has been applied, as it can induce pneumonia in immunocompromised mice. Mesenchymal stem cell (MSC) treatment has demonstrated therapeutic potential for pneumonia, as well as other forms of acute lung injury, in preclinical models. In this study, we aim to investigate the therapeutic efficacy and underlying mechanisms of human bone marrow-derived MSC (hMSC) on MHV-68-induced pneumonia. We found that intravenous administration of hMSCs significantly reduced lung damages, diminished inflammatory mediators and somehow inhibited MHV-68 replication. Furthermore, hMSCs treatment can regulate innate immune response and induce macrophage polarization from M1 to M2 phenotype, could significantly alter leukocyte infiltration and reduce pulmonary fibrosis. Our findings with co-culture system indicated that hMSCs effectively reduced the secretion of of inflammation-related factors and induced a shift in macrophage polarization, consistent with in vivo results. Further investigations revealed that hMSCs treatment suppressed the activation of macrophage ROS/NLRP3 signaling pathway in vivo and in vitro. Moreover, administration of MCC950, a selective NLRP3 inhibitor has been shown to effectively reduce ROS production and subsequently alleviate inflammation induced by MHV-68. Taken together, our work has shown that hMSCs can effectively protect mice from lethal MHV-68 pneumonia, which may throw new light on strategy for combating human EBV-associated pneumonia.