Search

Abstract In a retrospective analysis of clinical data from 587 DLBCL (diffuse large B-cell lymphoma) patients in China, 13.8% of cases were associated with HBV (hepatitis B virus) infection, leading to distinct clinical features and poorer prognosis. Moreover, HBV infection has a more pronounced impact on the survival of the GCB (germinal center B-cell-like) type DLBCL patients compared to the ABC (activated B-cell-like) type. In this study, we found that the expression of LncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was downregulated in the HBV-infected GCB-type DLBCL patients, and the HBV core protein (HBX) directly inhibited the MALAT1 expression in DLBCL cells. Notably, the overexpression of HBX could attenuate the Erastin-induced ferroptosis in the GCB-type DLBCLs, while MALAT1 re-expression restored sensitivity in the HBX-overexpressing DLBCLs in vitro and in vivo. Mechanistically, MALAT1 competitively hindered SFPQ (splicing factor proline and glutamine-rich) from effectively splicing the pre-mRNA of SLC7A11 (solute carrier family 7 member 11), due to a shared TTGGTCT motif, which impeded the SLC7A11 pre-mRNA maturation and hence diminished its negative regulation on ferroptosis. Together, our study identified HBX’s role in inhibiting MALAT1 expression, promoting SFPQ-mediated splicing of SLC7A11 pre-mRNA, and reducing the GCB-type DLBCL sensitivity to Erastin-induced ferroptosis. Combined with the recent studies that ferroptosis may be involved in the occurrence and development of DLBCL, these findings explain our clinical data analysis that DLBCL patients with low expression of MALAT1 have poorer prognosis and shorter overall survival, and provide a valuable therapeutic target for the HBV-infected GCB-type DLBCL patients.

Abstract Acute kidney injury (AKI) is a clinical condition characterized by a rapid decline in kidney function, which is associated with local inflammation and programmed cell death in the kidney. The G protein-coupled receptors (GPCRs) represent the largest family of signaling transduction proteins in the body, and approximately 40% of drugs on the market target GPCRs. The expressions of various GPCRs, prostaglandin receptors and purinergic receptors, to name a few, are significantly altered in AKI models. And the role of GPCRs in AKI is catching the eyes of researchers due to their distinctive biological functions, such as regulation of hemodynamics, metabolic reprogramming, and inflammation. Therefore, in this review, we aim to discuss the role of GPCRs in the pathogenesis of AKI and summarize the relevant clinical trials involving GPCRs to assess the potential of GPCRs and their ligands as therapeutic targets in AKI and the transition to AKI-CKD.

Background We aimed to compare the cardiovascular events and mortality in patients who underwent either physician-oriented or patient-oriented kidney replacement therapy (KRT) conversion due to discontinuation of peritoneal dialysis (PD).Methods Patients with end-stage kidney disease who were receiving PD and required a switch to an alternative KRT were included. They were divided into physician-oriented group or patient-oriented group based on the decision-making process. Logistic regression analysis was used to explore the influencing factors related to KRT conversion in PD patients. The association of physician-oriented or patient-oriented KRT conversion with outcomes after the conversion was assessed by using Cox proportional hazards models.Results A total of 257 PD patients were included in the study. The median age at catheterization was 35 years. 69.6% of the participants were male. The median duration of PD was 20 months. 162 participants had patient-oriented KRT conversion, while 95 had physician-oriented KRT conversion. Younger patients, those with higher education levels, higher income, and no diabetes were more likely to have patient-oriented KRT conversion. Over a median follow-up of 39 months, 40 patients experienced cardiovascular events and 16 patients died. Physician-oriented KRT conversion increased nearly 3.8-fold and 4.0-fold risk of cardiovascular events and death, respectively. After adjusting for confounders, physician-oriented KRT conversion remained about a 3-fold risk of cardiovascular events.Conclusion Compared to patient-oriented KRT conversion, PD patients who underwent physician-oriented conversion had higher risks of cardiovascular events and all-cause mortality. Factors included age at catheterization, education level, annual household income, and history of diabetes mellitus.

Because of early diagnosis and improved prognosis, patients with gastric cancer are now surviving longer and remnant gastric cancer after gastrectomy is becoming more common. Remnant gastric cancer is traditionally considered a malignancy with a dismal outcome. However, recent advances in diagnostic and therapeutic strategies have improved outcomes. In recent years, the development of endoscopic therapy has provided us with new therapeutic ideas. Although with some drawbacks, such as limited working space, gastric fibrosis and staples under the suture line, endoscopic management is still an effective treatment option with potential long-term survival advantage. For gastrectomy patients, endoscopic surveillance should also be recommended, for prompt surveillance and detection in the early remnant gastric cancer. This review aims to provide an overview of remnant gastric cancer, especially focusing on its pathogenesis as well as new advances in the diagnosis and endoscopic treatment of early-stage remnant gastric cancer.

The main goal of robot path planning is to design an optimal path for a robot to navigate from its starting point to its goal while avoiding obstacles and optimizing certain criteria. A novel method using marine predator algorithm which is used in the field of robot path planning is presented. The proposed method has two steps. First step is to build a mathematical model of path planning while second step is optimization process using marine predator algorithm. Simulation results show that the proposed method works well and has good performance in different situations. Therefore, this method is an effective method for robot path planning and related applications.

Virtual urban green environment images and audio stimuli had been proven to have restorative effects on subjects’ physical and mental health. In this area, researchers predominantly focused on visual, auditory and olfactory aspects, while tactile and gustatory senses have been minimally explored. However, the optimal combination of sensory stimuli for promoting physical and mental recovery remains unclear. Therefore, a simulated sensory stimulation approach involving 240 participants was employed, with 30 individuals included in each of the eight experimental groups: the visual–auditory (VA), visual–auditory-olfactory (VAO), visual–auditory-tactile (VAT), visual–auditory-gustatory(VAG), visual–auditory-olfactory-tactile (VAOT), visual–auditory-olfactory-gustatory (VAOG), visual–auditory-tactile-gustatory (VATG), and visual–auditory-olfactory-tactile-gustatory (VAOTG) groups. This study aimed to explore the differences in participants’ physiological and psychological health recovery after exposure to different combinations of simulated sensory stimuli in virtual UGSs. The results indicated that the following: (1) In terms of physiological recovery, the blood pressure of the 8 experimental groups decreased significantly after the experiment, indicating that the virtual urban green space environment has a certain recovery effect on physiological state. The combination of VAOTG stimuli in the multisensory group resulted in the best blood pressure recovery (p

Introduction: The triglyceride glucose (TyG) index is a reliable alternative biomarker of insulin resistance, but the association between the TyG index and acute kidney injury (AKI) in critically ill patients remains unclear. Methods: The data for the study were extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Cox regression and restricted cubic spline (RCS) analysis were performed to analyze the association between the TyG index and all-cause mortality. Besides, Cox regression was carried out in subgroups of age, gender, BMI, diabetes history, and dialysis status. Results: A total of 7,508 critically ill participants with AKI from the MIMIC-IV database were included in this study, with 3,688 (49.12%) participants failed to survive. In Cox regression, after confounder adjustment, patients with a higher TyG index had a higher risk of all-cause mortality (HR = 1.845, 95% CI = 1.49–2.285, p < 0.001). In RCS, after confounder adjustment, the risk of death was positively correlated with the increased value of the TyG index when TyG index surpassed 10.014. This relationship was validated in age, gender, BMI, diabetes subgroups but not in the dialysis subgroup. Interestingly, RCS analysis demonstrated that, in patients undertaking dialysis, there is a “U”-shaped curve for the value of TyG index and risk of all-cause mortality. When TyG index is less than 10.460, the risk of all-cause mortality would decrease with the increased value of TyG index, while when TyG index is higher than 11.180, the risk of all-cause mortality would increase firmly with the increased value of TyG index. Conclusion: Overall, a higher TyG index is associated with a higher risk of all-cause mortality in critically ill AKI. Interestingly, the relationship in the dialysis subgroup follows a “U”-shaped curve, indicating the importance of proper clinical blood glucose and lipid management in this particular population.

Abstract Organ regeneration necessitates precise coordination of accelerators and brakes to restore organ function. However, the mechanisms underlying this intricate molecular crosstalk remain elusive. In this study, the level of proenkephalin-A (PENK-A), expressed by renal proximal tubular epithelial cells, decreases significantly with the loss of renal proximal tubules and increased at the termination phase of zebrafish kidney regeneration. Notably, this change contrasts with the role of hydrogen peroxide (H2O2), which acts as an accelerator in kidney regeneration. Through experiments with penka mutants and pharmaceutical treatments, we demonstrate that PENK-A inhibits H2O2 production in a dose-dependent manner, suggesting its involvement in regulating the rate and termination of regeneration. Furthermore, H2O2 influences the expression of tcf21, a vital factor in the formation of renal progenitor cell aggregates, by remodeling H3K4me3 in renal cells. Overall, our findings highlight the regulatory role of PENK-A as a brake in kidney regeneration.

BackgroundSarcoma is a rare and aggressive malignancy with poor prognosis, in which oncogene activation and tumor suppressor inactivation are involved. Accumulated studies suggested basic leucine zipper transcription factor ATF-like 2 (BATF2) as a candidate tumor suppressor, but its specific role and mechanism in sarcoma remain unclear.MethodsThe expression levels of BATF2 and miR-939-3p were evaluated by using human sarcoma samples, cell lines and xenograft mouse models. Bioinformatics analysis, qPCR, Western blot, cell proliferation assay, overexpression plasmid construction, point mutation and dual luciferase reporter assay were utilized to investigate the role and mechanism of miR-939-3p in sarcoma.ResultsIn this study, we demonstrated that the expression of BATF2 was downregulated in human sarcoma tissues and cell lines. The downregulation of BATF2 was negatively associated with the prognosis of sarcoma patients. Subsequent bioinformatic prediction and experimental validations showed that BATF2 expression was reduced by microRNA (miR)-939-3p mimic and increased by miR-939-3p inhibitor. Additionally, miR-939-3p was upregulated in sarcoma tissues and cells, correlating with a poor prognosis of sarcoma patients. Moreover, miR-939-3p overexpression suppressed sarcoma cell proliferation, which was significantly attenuated by the restoration of BATF2, while siRNA-mediated knockdown of BATF2 aggravated the miR-939-3p-induced promotion of sarcoma cell proliferation. Further computational algorithms and dual-luciferase reporter assays demonstrated that miR-939-3p repressed BATF2 expression via directly binding to its 3’ untranslated region (3’ UTR).ConclusionCollectively, these findings identified miR-939-3p as a novel regulator of BATF2, as well as a prognostic biomarker in sarcoma, and revealed that suppressing miR-939-3p or inducing BATF2 expression may serve as a promising therapeutic strategy against sarcoma.

Background The relationship between arteriolar hyalinosis and renal progression in immunoglobulin A nephropathy (IgAN) is not fully understood. We aimed to investigate the clinicopathological features and outcomes of IgAN with or without arteriolar hyalinosis.Methods A total of 762 diagnosed with IgAN patients were retrospectively analyzed. We classified IgAN patients into two groups with or without arteriolar hyalinosis. Then, the clinicopathological characteristics of the two groups were compared. We used Kaplan–Meier survival analysis to compare the composite kidney outcome of the two groups and applied multivariate Cox regression analyses to test the association between arteriolar hyalinosis and composite kidney outcome.Results Overall, 412 (54.1%) patients had arteriolar hyalinosis, including 173 patients diagnosed with hypertension. IgAN patients with arteriolar hyalinosis were older and had higher proteinuria, urea, uric acid, and blood pressure, while lower eGFR than those without arteriolar hyalinosis. Subgroup analysis showed similar results in IgAN patients with hypertension. Kaplan–Meier survival analysis showed that IgAN patients with arteriolar hyalinosis had worse composite kidney outcome than those without arteriolar hyalinosis. In addition, subgroup analysis revealed that patients with hypertension have worse composite kidney outcome than those without hypertension. Multivariate Cox regression analyses confirm that arteriolar hyalinosis (HR 2.57; 95% CI 1.41–4.69; p = 0.002) is an independent risk factor for renal prognosis in IgAN patients.Conclusions Our study demonstrated that arteriolar hyalinosis is a common vascular lesion in IgAN patients. Arteriolar hyalinosis connects closely with hypertension, and arteriolar hyalinosis is an independent risk factor for renal prognosis in patients with IgAN.

Manganese toxicity is a major obstacle to agriculture in acid soils. Dark pericarp disease (DPD) is a newly spread physiological disorder induced by excess Mn in litchi, leading to undesirable fruit appearance and substantial economic loss. In this work, broadcast of alkaline soil conditioner in winter, followed by foliar sprays of ascorbic acid and sulfur solution at fruit development, was adopted to examine the effect of these combinations on DPD alleviation in a litchi orchard, with DPD morbidities of 70~85% in recent ten years. The combination of soil conditioner broadcast and foliar water spray was used as the control. At harvest, DPD incidence was significantly decreased by sulfur spray (3.3 ± 1.0%) and slightly reduced by ascorbic acid spray (10.7 ± 8.0%) compared to the control (12.9 ± 7.6%). Soil pH and available Mn were significantly increased and reduced by the soil conditioner broadcast. Sulfur spray significantly inhibited Mn uptake but enhanced the accumulation of Mg, Ca, sugars and cyanidin-3-rutinoside in the pericarp, leading to improved fruit pigmentation. Antioxidase activities were regulated to resist Mn stress by sulfur spray. The spray of ascorbic acid could not mitigate DPD as expected, probably due to the dose used. Conclusively, this study provides a practicable approach to mitigate Mn phytoavailability in acid soils.

Ischemic-reperfusion injury (IRI) is a major pathogenic factor in acute kidney injury (AKI), which directly leads to the hypoxic injury of renal tubular epithelial cells (RTECs). Although emerging studies suggest repressor element 1–silencing transcription factor (REST) as a master regulator of gene repression under hypoxia, its role in AKI remains elusive. Here, we found that REST was upregulated in AKI patients, mice, and RTECs, which was positively associated with the degree of kidney injury, while renal tubule–specific knockout of Rest significantly alleviated AKI and its progression to chronic kidney disease (CKD). Subsequent mechanistic studies indicated that suppression of ferroptosis was responsible for REST-knockdown-induced amelioration of hypoxia-reoxygenation injury, during which process Cre-expressing adenovirus–mediated REST downregulation attenuated ferroptosis through upregulating glutamate-cysteine ligase modifier subunit (GCLM) in primary RTECs. Further, REST transcriptionally repressed GCLM expression via directly binding to its promoter region. In conclusion, our findings revealed the involvement of REST, a hypoxia regulatory factor, in AKI-to-CKD transition and identified the ferroptosis-inducing effect of REST, which may serve as a promising therapeutic target for ameliorating AKI and its progression to CKD.

Abstract Background During the tumourigenesis and development of colorectal cancer (CRC), the inactivation of tumour suppressor genes is closely involved, although detailed molecular mechanisms remain elusive. Accumulating studies, including ours, have demonstrated that basic leucine zipper transcription factor ATF (activating transcription factor)‐like 2 (BATF2) is a capable tumour suppressor that localises in the nucleus. However, its different subcellular localisation, potential functions and underlying mechanisms are unclear. Methods The translocation of BATF2 and its clinical relevance were detected using CRC samples, cell lines and xenograft nude mice. Candidate BATF2‐binding proteins were screened using co‐immunoprecipitation, quantitative label‐free liquid chromatography–tandem mass spectrometry proteomic analysis, Western blotting and immunofluorescence. Recombinant plasmids, point mutations and siRNAs were applied to clarify the binding sites between BATF2 and chromosome region maintenance 1 (CRM1). Results The present study found that BATF2 was mainly localised in the cytoplasm, rather than nucleus, of CRC cells in vitro and in vivo, while cytoplasmic BATF2 expression was inversely correlated with the prognosis of CRC patients. Furthermore, we identified the nuclear export and subsequent ubiquitin‐mediated degradation of BATF2 in CRC cells. Mechanistically, a functional nuclear export sequence (any amino acid) was characterised in BATF2 protein, through which BATF2 bound to CRM1 and translocated out of nucleus, ultimately enhancing CRC growth via inducing activator protein 1 (AP‐1)/cyclin D1/phosphorylated retinoblastoma protein (pRb) signalling pathway. Additionally, nuclear export of BATF2 can be retarded by the mutation of NES in BATF2 or the knockdown of CRM1, whereas CRM1 expression was negatively associated with nuclear BATF2 expression and the prognosis of CRC patients. Conclusion These findings revealed the biological effects and underlying mechanisms of cytoplasmic localisation of BATF2. Furthermore, suppressing nuclear export of BATF2 via mutating its NES region or inhibiting CRM1 expression may serve as a promising therapeutic strategy against CRC.

Background: Dual-specificity phosphatases (DUSPs) belong to the family of protein tyrosine phosphatases, which can dephosphorylate both serine/threonine and tyrosine residues. During the past decades, DUSPs have been implicated in various physiological and pathological activities. Besides mitogen-activated protein kinases (MAPKs) as the main substrates, other protein and nonprotein substrates can also be dephosphorylated by DUSPs. Aberrant regulations of DUSPs have been found in various diseases such as cancer, neurological disorders, and kidney diseases, suggesting the involvement of DUSPs in the pathogenesis of diseases. Summary: In this review, we summarize the general characteristics of DUSPs and the research progress made in the field of kidney diseases, including diabetic nephropathy, hypertensive nephropathy, chronic kidney disease, acute kidney injury, and lupus nephritis. As the main biochemical function of DUSPs is to dephosphorylate MAPKs activity, decreased DUSPs are found in kidney disease models, whereas forced DUSPs expression reverses the disease presentation, which was proved by using transgenic or gene knockout model. Key Messages: Mounting evidence demonstrates that DUSPs have essential physiological and pathological functions in kidney disease. Fully understanding the functions and mechanisms of DUSPs in kidney disease contributes to their clinical application in translation medicine.

The social question answering based online counseling (SQA-OC) is easy access for people seeking professional mental health information and service, has become the crucial pre-consultation and application stage toward online counseling. However, there is a lack of efforts to evaluate and explain the counselors' service quality in such an asynchronous online questioning and answering (QA) format efficiently. This study applied the notion of perceived helpfulness as a public's perception of counselors' service quality in SQA-OC, used computational linguistic and explainable machine learning (XML) methods suited for large-scale QA discourse analysis to build an predictive model, explored how various sources and types of linguistic cues [i.e., Linguistic Inquiry and Word Count (LIWC), topic consistency, linguistic style similarity, emotional similarity] contributed to the perceived helpfulness. Results show that linguistic cues from counselees, counselors, and synchrony between them are important predictors, the linguistic cues and XML can effectively predict and explain the perceived usefulness of SQA-OC, and support operational decision-making for counselors. Five helpful counseling experiences including linguistic styles of “talkative”, “empathy”, “thoughtful”, “concise with distance”, and “friendliness and confident” were identified in the SQA-OC. The paper proposed a method to evaluate the perceived helpfulness of SQA-OC service automatically, effectively, and explainable, shedding light on the understanding of the SQA-OC service outcome and the design of a better mechanism for SQA-OC systems.

Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD.

Cardiorenal syndrome (CRS) is defined as a disorder of the heart and kidney, in which acute or chronic injury of one organ may lead to acute or chronic dysfunction of the other. It is characterized by high morbidity and mortality, resulting in high economic costs and social burdens. However, there is currently no effective drug-based treatment. Emerging evidence implicates the involvement of mitophagy in the progression of CRS, including cardiovascular disease (CVD) and chronic kidney disease (CKD). In this review, we summarized the crucial roles and molecular mechanisms of mitophagy in the pathophysiology of CRS. It has been reported that mitophagy impairment contributes to a vicious loop between CKD and CVD, which ultimately accelerates the progression of CRS. Further, recent studies revealed that targeting mitophagy may serve as a promising therapeutic approach for CRS, including clinical drugs, stem cells and small molecule agents. Therefore, studies focusing on mitophagy may benefit for expanding innovative basic research, clinical trials, and therapeutic strategies for CRS.

Extracting the profiles of images is critical because it can bring simplified description and draw special attention to particular areas in the images. In our work, we designed two filters via the exponential and hypotenuse functions for profile extraction. Their ability to extract the profiles from the images obtained from weak-light conditions, fluorescence microscopes, transmission electron microscopes, and near-infrared cameras is proven. Moreover, they can be used to extract the nesting structures in the images. Furthermore, their performance in extracting images degraded by Gaussian noise is evaluated. We used Gaussian white noise with a mean value of 0.9 to create very noisy images. These filters are effective for extracting the edge morphology in the noisy images. For the purpose of a comparative study, we used several well-known filters to process these noisy images, including the filter based on Gabor wavelet, the filter based on the watershed algorithm, and the matched filter, the performances of which in profile extraction are either comparable or not effective when dealing with extensively noisy images. Our filters have shown the potential for use in the field of pattern recognition and object tracking.

Selenium (Se) biofortification is an important strategy for reducing hidden hunger by increasing the nutritional quality of crops. However, there is limited metabolomic information on the nutritional quality of Se-enriched mung beans. In this study, physiological assays and LC–MS/MS based widely targeted metabolomics approach was employed to reveal the Se biofortification potential of mung bean by evaluating the effect of Se on mung bean nutraceutical compounds and their qualitative parameters. Physiological data showed that foliar application of 30 g ha−1 Se at key growth stages significantly increased the content of Se, protein, fat, total phenols, and total flavonoids content in two mung bean varieties. Widely targeted metabolomics identified 1,080 metabolites, among which L-Alanyl-L-leucine, 9,10-Dihydroxy-12,13-epoxyoctadecanoic acid, and 1-caffeoylquinic acid could serve as biomarkers for identifying highly nutritious mung bean varieties. Pathway enrichment analysis revealed that the metabolic pathways of different metabolites were different in the Se-enriched mung bean. Specifically, P1 was mainly enriched in the linoleic acid metabolic pathway, while P2 was mainly enriched in the phosphonate and phosphinate metabolic pathways. Overall, these results revealed the specific Se enrichment mechanism of different mung bean varieties. This study provides new insights into the comprehensive improvement of the nutritional quality of mung beans.

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.

Abstract Background Cardiovascular disease (CVD) is the most common complication and the leading cause of death in patients with chronic kidney disease (CKD). Accelerated atherosclerosis is a pathophysiological process that is vital to the occurrence of cardiovascular complications associated with CKD. Abnormal platelet activation is not only the leading cause of atherosclerosis but also plays a critical role in the occurrence of thrombotic events. Currently, antiplatelet drugs are commonly used as a secondary prevention strategy for high blood pressure, obesity, diabetes, and ischemic heart disease and can reduce the risk of CVD in the susceptible population. However, the benefits and evidence of using antiplatelet agents in patients with CKD remain controversial. This study aimed to determine whether antiplatelet therapy can safely prevent atherosclerosis in patients with CKD in the primary care setting. Methods/design The ALTAS-CKD study is a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 554 adult patients with stage 3–5 non-dialysis-dependent CKD recruited from 10 territory medical centers in China. A secured web-based computer randomization system will be used to administer aspirin 100 mg once daily or a matching inactive placebo for 36 months. The primary endpoint will be the occurrence of atherosclerosis, as measured by carotid ultrasonography. The secondary endpoints will be combined cardiovascular events, all-cause mortality, and 50% decrease in the estimated glomerular filtration rate. Trial registration {2a} Current controlled trials number: ChiCTR1900021393 . Registered on 18 February 2019.

The pathogenic mechanisms of cardiorenal syndrome type 4 (CRS4) remain unclear. Here, the authors identify IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling as a contributor to CRS4 pathogenesis, thus providing potential new targets for reducing cardiovascular events in CKD patients.

Abstract Background Klotho is a multifunctional protein, which exists both in a membrane bound and a soluble form. In renal tubules, Klotho is involved in cell senescence, anti-oxidant response, and renal fibrosis, thus regulation of its expression is critical to understand its roles in renal diseases. Indeed, reduced expression was observed in various renal disease. However, the mechanisms underlying transcriptional regulation of the human klotho gene (KL) largely remain unknown. Results Here we demonstrated that the Klotho expression in human renal tubular epithelial cells (RTECs) was enhanced by overexpression of the transcription factor Sp1. On the contrary, Klotho expression was decreased by Sp1 knockdown. Besides, increased expression of Sp1 alleviated TGF-β1-induced fibrosis in HK-2 cells by inducing Klotho expression. Luciferase reporter assays and chromatin immunoprecipitation assays further identified the binding site of Sp1 was located in − 394 to − 289 nt of the KL promoter, which was further confirmed by mutation analysis. Conclusions These data demonstrate that KL is a transcriptional target of Sp1 and TGF-β1-induced fibrosis was alleviated by Sp1 in human RTECs by directly modulating Klotho expression, which help to further understand the transcriptional regulation of Klotho in renal disease models.

Online mental health service (OMHS) has been named as the best psychological assistance measure during the COVID-19 pandemic. An interpretable, accurate, and early prediction for the demand of OMHS is crucial to local governments and organizations which need to allocate and make the decision in mental health resources. The present study aimed to investigate the influence of the COVID-19 pandemic on the online psychological help-seeking (OPHS) behavior in the OMHS, then propose a machine learning model to predict and interpret the OPHS number in advance. The data was crawled from two Chinese OMHS platforms. Linguistic inquiry and word count (LIWC), neural embedding-based topic modeling, and time series analysis were utilized to build time series feature sets with lagging one, three, seven, and 14 days. Correlation analysis was used to examine the impact of COVID-19 on OPHS behaviors across different OMHS platforms. Machine learning algorithms and Shapley additive explanation (SHAP) were used to build the prediction. The result showed that the massive growth of OPHS behavior during the COVID-19 pandemic was a common phenomenon. The predictive model based on random forest (RF) and feature sets containing temporal features of the OPHS number, mental health topics, LIWC, and COVID-19 cases achieved the best performance. Temporal features of the OPHS number showed the biggest positive and negative predictive power. The topic features had incremental effects on performance of the prediction across different lag days and were more suitable for OPHS prediction compared to the LIWC features. The interpretable model showed that the increase in the OPHS behaviors was impacted by the cumulative confirmed cases and cumulative deaths, while it was not sensitive in the new confirmed cases or new deaths. The present study was the first to predict the demand for OMHS using machine learning during the COVID-19 pandemic. This study suggests an interpretable machine learning method that can facilitate quick, early, and interpretable prediction of the OPHS behavior and to support the operational decision-making; it also demonstrated the power of utilizing the OMHS platforms as an always-on data source to obtain a high-resolution timeline and real-time prediction of the psychological response of the online public.

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.

AimsTo investigate the potential role of renal arterial resistance index (RI) in the differential diagnosis between diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) and establish a better-quantified differential diagnostic model.Materials and MethodsWe consecutively reviewed 469 type 2 diabetes patients who underwent renal biopsy in our center. According to the renal biopsy results, eligible patients were classified into the DKD group and the NDKD group. The diagnostic significance of RI was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis was used to search for independent risk factors associated with DKD. Then a novel diagnostic model was established using multivariate logistic regression analysis.ResultsA total of 332 DKD and 137 NDKD patients were enrolled for analysis. RI was significantly higher in the DKD group compared with those in the NDKD group (0.70 vs. 0.63, p< 0.001). The optimum cutoff value of RI for predicting DKD was 0.66 with sensitivity (69.2%) and specificity (80.9%). Diabetic retinopathy, diabetes duration ≥ 60 months, HbA1c ≥ 7.0(%), RI ≥ 0.66, and body mass index showed statistical significance in the multivariate logistic regression analysis. Then, we constructed a new diagnostic model based on these results. And the validation tests indicated that the new model had good sensitivity (81.5%) and specificity (78.6%).ConclusionsRI has a potential role in discriminating DKD from NDKD. The RI-based predicting model can be helpful for differential diagnosis of DKD and NDKD.

Cardiorenal syndrome type 3 (CRS3) is defined as acute kidney injury (AKI)-induced acute cardiac dysfunction, characterized by high morbidity and mortality. CRS3 often occurs in elderly patients with AKI who need intensive care. Approximately 70% of AKI patients develop into CRS3. CRS3 may also progress towards chronic kidney disease (CKD) and chronic cardiovascular disease (CVD). However, there is currently no effective treatment. Although the major intermediate factors that can mediate cardiac dysfunction remain elusive, recent studies have summarized the AKI biomarkers, identified direct mechanisms, including mitochondrial dysfunction, inflammation, oxidative stress, apoptosis and activation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS), inflammasome, as well as indirect mechanisms such as fluid overload, electrolyte imbalances, acidemia and uremic toxins, which are involved in the pathophysiological changes of CRS3. This study reviews the main pathological characteristics, underlying molecular mechanisms, and potential therapeutic strategies of CRS3. Mitochondrial dysfunction and inflammatory factors have been identified as the key initiators and abnormal links between the impaired heart and kidney, which contribute to the formation of a vicious circle, ultimately accelerating the progression of CRS3. Therefore, targeting mitochondrial dysfunction, antioxidants, Klotho, melatonin, gene therapy, stem cells, exosomes, nanodrugs, intestinal microbiota and Traditional Chinese Medicine may serve as promising therapeutic approaches against CRS3.

Background: T-lymphocyte subsets reflect patients' immune status and are associated with adverse outcomes in various diseases. However, the association between T-lymphocyte subsets and major infection and renal outcome in chronic kidney disease (CKD) patients has not been well-addressed.Methods: Patients diagnosed with stage 3–5 of non-dialysis CKD were recruited, and healthy subjects were selected as the controls. T-lymphocyte subsets (CD3+, CD4+, CD8+) were detected by flow cytometry, and the CD4+/CD8+ T cell ratio was then calculated. Patients were divided into the normal-level group and the low-level group according to the clinical reference value. The primary outcomes were the major infection and renal outcome.Results: A total of 410 CKD patients were enrolled; the average age was 47.25 years. Compared to the healthy controls, the level of CD3+, CD4+, CD8+ T cells, and the CD4+/CD8+ T cell ratio were significantly decreased in CKD patients (p < 0.05). During the median follow-up of 2.56 (quartile interval 1.24–3.46) years, major infections occurred in 15.10% of the CKD patients. The incidence of infection was significantly higher in the low-level group of CD3+, CD4+ T cells, and CD4+/CD8+ T cell ratio compared with the normal level groups. Kaplan-Meier analysis showed that the lower level of CD3+, CD4+ T cells, and CD4+/CD8+T cell ratio is associated with a greater risk of infection. Cox regression analysis further confirmed that low CD3+, CD4+ T cells, and CD4+/CD8+ T cell ratio were independent risk factors of infection in CKD patients. Moreover, during the follow-up, renal events occurred in 37.50% of patients. Kaplan-Meier analysis indicated that low levels of CD3+, CD4+, and CD8+ T cells are significantly associated with renal outcome in CKD patients. Cox regression analysis showed that low level of CD3+ T cells (HR = 2.407, 95% CI: 1.664–3.482, p < 0.001), CD4+ T cells (HR = 2.397, 95% CI: 1.633–3.518, p < 0.001) and CD8+ T cells (HR = 2.416, 95% CI: 1.476–3.955, p < 0.001) were independent risk factors for renal outcome after multivariable-adjusted.Conclusion: CKD patients had a defect in T-lymphocyte subpopulation. T-lymphocyte subsets were closely associated with infection and renal outcome in CKD patients. Suggesting T-lymphocyte subsets are independent predictors of infection and renal outcome in CKD patients.

Abstract Background There is an urgent need for targeted biological therapies for prostate cancer with greater efficacy and less toxicity, particularly for metastatic disease, where current therapies are not curative. Therapeutic adenoviral vectors or oncolytic adenoviruses offer the possibility of a competent, nontoxic therapeutic alternative for prostate cancer. However, free viral particles must be delivered locally, an approach that does not address metastatic disease, and they display poor tumor penetration. To fully exploit the potential of these vectors, we must develop methods that improve intratumoral dissemination and allow for systemic delivery. This study establishes a proof-of-principle rationale for a novel human mesenchymal stem (stromal) cell-based approach to improving vector delivery to tumors. Methods/results We have generated mesenchymal stem cell-derived packaging cells for adenoviruses (E1-modified mesenchymal stem cells) by modifying human mesenchymal stem cells with the adenovirus (type C) E1A/B genes needed for viral replication. Using cell-based assays, we have demonstrated that two adenoviral vectors, replication-defective adenovirus expressing p14 and p53 or conditionally replicating oncolytic adenovirus, packaged by E1A/B-modified mesenchymal stem cells, suppress the growth of prostate cancer cells in culture. Using subcutaneous xenograft models for human prostate cancer in mice, we have shown that E1A/B-modified mesenchymal stem cells display tumor tropism in tumor-bearing nude mice, that E1A/B-modified mesenchymal stem cells disseminate well within tumors, and that replication-defective adenovirus expressing p14 and p53 or conditionally replicating oncolytic adenovirus-loaded E1-modified mesenchymal stem cells suppresses tumor growth in mice. Conclusion The results show that this approach, if optimized, could circumvent the obstacles to efficient gene delivery encountered with current gene delivery approaches and provide an effective, nontoxic therapeutic alternative for metastatic disease.

Abstract Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E‐deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD‐associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE−/− mice are comprehensively investigated. Using multi‐omics analysis and targeted and VSMC‐specific gene knockout mice, VSMCs are identified as both type‐I‐interferon (IFN‐I)‐responsive and IFN‐I‐productive cells. Mechanistically, mitochondrial damage resulting from CKD‐induced oxidative stress primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway to trigger IFN‐I response in VSMCs. Enhanced IFN‐I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN‐I response remarkably attenuates CKD‐associated plaque vulnerability. These findings reveal that IFN‐I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD‐associated plaque vulnerability. Mitigating IFN‐I response may hold promise for the treatment of CKD‐associated cardiovascular diseases.

Globally, colon adenocarcinoma (COAD) is one of the most frequent types of malignant tumors. About 40~50% of patients with advanced colon adenocarcinoma die from recurrence and metastasis. Long non-coding RNAs (lncRNAs) and 5-methylcytosine (5mC) regulatory genes have been demonstrated to involve in the progression and prognosis of COAD. The goal of this study was to explore the biological characteristics and potential predictive value of 5mC-related lncRNA signature in COAD. In this research, The Cancer Genome Atlas (TCGA) was utilized to obtain the expression of genes and somatic mutations in COAD, and Pearson correlation analysis was used to select lncRNAs involved in 5mC-regulated genes. Furthermore, we applied univariate Cox regression and Lasso Cox regression to construct 5mC-related lncRNA signature. Then Kaplan–Meier survival analysis, principal components analysis (PCA), receiver operating characteristic (ROC) curve, and a nomogram were performed to estimate the prognostic effect of the risk signature. GSEA was utilized to predict downstream access of the risk signature. Finally, the immune characteristics and immunotherapeutic signatures targeting this risk signature were analyzed. In the results, we obtained 1652 5mC-related lncRNAs by Pearson correlation analysis in the TCGA database. Next, we selected a risk signature that comprised 4 5mC-related lncRNAs by univariate and Lasso Cox regression. The prognostic value of the risk signature was proven. Finally, the biological mechanism and potential immunotherapeutic response of the risk signature were identified. Collectively, we constructed the 5mC-related lncRNA risk signature, which could provide a novel prognostic prediction of COAD patients.

Background/Aims: Hyperphosphatemia is one of the most notable features of chronic kidney disease (CKD). Numerous epidemiological and clinical studies have found that high serum phosphate concentrations are associated with calcification in the coronary arteries. However, the mechanisms underlying the vascular calcification induced by high phosphate have not been understood fully. Methods: Vascular smooth muscle cells (VSMCs) were cultured in high-phosphate media to induce vascular calcification, which was detected by Alizarin red S staining. Gene expression and protein levels of differentiation markers were determined by real-time RT-PCR and western blotting, respectively. Protein levels of phosphorylated NF-κB and TLR4 were detected by western blotting, and the role of NF-κB/TLR4 was further confirmed by using an NF-κB inhibitor or TLR4 siRNA. Results: Our results showed that high-phosphate media induced obvious calcification of VSMCs. Simultaneously, VSMC differentiation was confirmed by the increased expression of bone morphogenetic protein-2 and Runt-related transcription factor 2 and decreased expression of the VSMC-specific marker SM22α, which was accompanied by the increased expression of inflammatory cytokines. Moreover, a significant upregulation of TLR4 and phosphorylated NF-κB was also detected in VSMCs with high-phosphate media. In contrast, VSMC calcification and the increased expression of inflammatory cytokines were markedly attenuated by pretreatment with TLR4 siRNA and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor. Conclusion: These data suggest that high-phosphate conditions directly induce vascular calcification via the activation of TLR4/NF-κB signaling in VSMCs. Moreover, inhibition of the TLR4/NF-κB signaling pathway might be a key intervention to prevent vascular calcification in patients with CKD.

We investigated the expression and function of miR-409-5p in human breast cancer. Quantitative real-time polymerase chain reaction was conducted to evaluate endogenous miR-409-5p expression in breast cancer tumors and breast cancer cell lines. Lentiviral transduction was performed to stably downregulate miR-409-5p in breast cancer cell lines MDA-MB-231 and MCF-7 and cells. The effects of miR-409-5p downregulation on breast cancer proliferation, migration, and xenograft development were then evaluated. Downstream target gene of miR-409-5p, Ras suppressor protein 1, was examined by dual-luciferase activity assay, quantitative real-time polymerase chain reaction, and western blot in lentiviral-transduced breast cancer cells. Ras suppressor protein 1 was also inhibited in miR-409-5p-downregulated breast cancer cells to examine its functional effect on breast cancer proliferation and migration. MiR-409-5p was aberrantly upregulated in both breast cancer tumors and cell lines. Lentiviral transduction successfully downregulated endogenous miR-409-5p expression as well as suppressed proliferation, migration, and xenograft development in MDA-MB-231 and MCF-7 cells. Ras suppressor protein 1 was confirmed to be directly targeted by miR-409-5p in breast cancer cells. Small interfering RNA–mediated Ras suppressor protein 1 inhibition reversely promoted cancer proliferation and migration in miR-409-5p-downregualted breast cancer cells. MiR-409-5p is downregulated in breast cancer and its inhibition has anti-cancer effect on breast cancer development both in vitro and in vivo. The regulatory effect of miR-409-5p inhibition is likely through the inverse upregulation of Ras suppressor protein 1 in breast cancer.

Big consumer data promises to be a game changer in applied and empirical marketing research. However, investigations of how big data helps inform consumers’ psychological aspects have, thus far, only received scant attention. Psychographics has been shown to be a valuable market segmentation path in understanding consumer preferences. Although in the context of e-commerce, as a component of psychographic segmentation, personality has been proven to be effective for prediction of e-commerce user preferences, it still remains unclear whether psychographic segmentation is practically influential in understanding user preferences across different product categories. To the best of our knowledge, we provide the first quantitative demonstration of the promising effect and relative importance of psychographic segmentation in predicting users’ online purchasing preferences across different product categories in e-commerce by using a data-driven approach. We first construct two online psychographic lexicons that include the Big Five Factor (BFF) personality traits and Schwartz Value Survey (SVS) using natural language processing (NLP) methods that are based on behavior measurements of users’ word use. We then incorporate the lexicons in a deep neural network (DNN)-based recommender system to predict users’ online purchasing preferences considering the new progress in segmentation-based user preference prediction methods. Overall, segmenting consumers into heterogeneous groups surprisingly does not demonstrate a significant improvement in understanding consumer preferences. Psychographic variables (both BFF and SVS) significantly improve the explanatory power of e-consumer preferences, whereas the improvement in prediction power is not significant. The SVS tends to outperform BFF segmentation, except for some product categories. Additionally, the DNN significantly outperforms previous methods. An e-commerce-oriented SVS measurement and segmentation approach that integrates both BFF and the SVS is recommended. The strong empirical evidence provides both practical guidance for e-commerce product development, marketing and recommendations, and a methodological reference for big data-driven marketing research.

Necrotic death of macrophages has long been known to be present in atherosclerotic lesions but has not been studied. We examined the role of receptor interacting protein (RIP) 3, a mediator of necrotic cell death, in atherosclerosis and found that RIP3−/−;Ldlr−/− mice were no different from RIP3+/+;Ldlr−/− mice in early atherosclerosis but had significant reduction in advanced atherosclerotic lesions. Similar results were observed in Apoe−/− background mice. Bone marrow transplantation revealed that loss of RIP3 expression from bone-marrow-derived cells is responsible for the reduced disease progression. While no difference was found in apoptosis between RIP3−/−;Ldlr−/− and RIP3+/+;Ldlr−/− mice, electron microscopy revealed a significant reduction of macrophage primary necrosis in the advanced lesions of RIP3−/− mice. In vitro cellular studies showed that RIP3 deletion had no effect on oxidized low-density lipoprotein (LDL)-induced macrophage apoptosis, but prevented macrophage primary necrosis occurring in response to oxidized LDL under caspase inhibition or RIP3 overexpression conditions. RIP3-dependent necrosis is not postapoptotic, and the increased primary necrosis in advanced atherosclerotic lesions most likely resulted from the increase of RIP3 expression. Our data demonstrate that primary necrosis of macrophages is proatherogenic during advanced atherosclerosis development.

BACKGROUND: Glucokinase (GCK) is the key glucose phosphorylation enzyme which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) based on its enzyme function as the first rate-limiting step in the glycolysis pathway and regulates glucose-stimulated insulin secretion. In the past decade, the relationship between GCK and T2D has been reported in various ethnic groups. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis. METHODS: Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. RESULTS: A total of 24 articles involving 88,229 cases and 210,239 controls were included. An overall random-effects per-allele OR of 1.06 (95% CI: 1.03-1.09; PA polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians; whereas no significant associations were found among Asians. In addition, we found that the -30G>A polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. Besides, -30G>A homozygous was found to be significantly associated with increased fasting plasma glucose level with weighted mean difference (WMD) of 0.15 (95%: 0.05-0.24, P = 0.001) compared with G/G genotype. CONCLUSIONS: This meta-analysis demonstrated that the -30G>A polymorphism of GCK is a risk factor associated with increased T2D susceptibility, but these associations vary in different ethnic populations.