Exosome-related lncRNA score: A value-based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non-coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. AIMS: The purpose of this study is to construction a exosomes-related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. METHODS: Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes-related lncRNAs (ERLRs) from Top10 exosomes-related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs-based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high- and low-risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. RESULTS: A score consisting of 4ERLRs was identified, and patients with higher ERLRs-based score tended to have a worse prognosis than those with lower ERLRs-based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III-IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa-miR-31-5p/TLN2 axis. CONCLUSIONS: Based on machine learning, a novel ERLRs-based score was constructed for predicting the survival of ccRCC patients. The ERLRs-based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa-miR-31-5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

The mechanism of linear ubiquitination in regulating cell death and correlative diseases.

Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on substrates in order to regulate cellular processes. LUBAC comprised by HOIP, HOIL-1L, and SHARPIN as a sole E3 ligase catalyzes the generation of linear ubiquitin chains, and it is simultaneously adjusted by deubiquitinases such as OTULIN and CYLD. Several studies have shown that gene mutation of linear ubiquitination in mice accompanied by different modalities of cell death would develop relative diseases. Cell death is a fundamental physiological process and responsible for embryonic development, organ maintenance, and immunity response. Therefore, it is worth speculating that linear ubiquitin mediated signaling pathway would participate in different diseases. The relative literature search was done from core collection of electronic databases such as Web of Science, PubMed, and Google Scholar using keywords about main regulators of linear ubiquitination pathway. Here, we summarize the regulatory mechanism of linear ubiquitination on cellular signaling pathway in cells with apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Intervening generation of linear ubiquitin chains in relative signaling pathway to regulate cell death might provide novel therapeutic insights for various human diseases.

Sarmentosin Induces Autophagy-dependent Apoptosis via Activation of Nrf2 in Hepatocellular Carcinoma.

Background and Aims: Hepatocellular carcinoma (HCC) is a common and deadly cancer. Accumulating evidence supports modulation of autophagy as a novel approach for determining cancer cell fate. The aim of this study to evaluate the effectiveness of sarmentosin, a natural compound, on HCC in vitro and in vivo and elucidated the underlying mechanisms. Methods: Cell functions and signaling pathways were analyzed in HepG2 cells using western blotting, real-time PCR, siRNA, transmission electron microscopy and flow cytometry. BALB/c nude mice were injected with HepG2 cells to produce a xenograft tumour nude mouse model for in vivo assessments and their tumors, hearts, lungs and kidneys were isolated. Results: We found that autophagy was induced by sarmentosin in a concentration- and time-dependent manner in human HCC HepG2 cells by western blot assays and scanning electron microscopy. Sarmentosin-induced autophagy was abolished by the autophagy inhibitors 3-methyladenine, chloroquine, and bafilomycin A1. Sarmentosin activated Nrf2 in HepG2 cells, as shown by increased nuclear translocation and upregulated expression of Nrf2 target genes. Phosphorylation of mTOR was also inhibited by sarmentosin. Sarmentosin stimulated caspase-dependent apoptosis in HepG2 cells, which was impaired by silencing Nrf2 or chloroquine or knocking down ATG7. Finally, sarmentosin effectively repressed HCC growth in xenograft nude mice and activated autophagy and apoptosis in HCC tissues. Conclusions: This study showed sarmentosin stimulated autophagic and caspase-dependent apoptosis in HCC, which required activation of Nrf2 and inhibition of mTOR. Our research supports Nrf2 as a therapeutic target for HCC and sarmentosin as a promising candidate for HCC chemotherapy.

Analysis of fatty acid composition and sensitivity to dietary n-3 PUFA intervention of mouse n-3 PUFA-enriched tissues/organs.

PURPOSE: n-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA; C22:6 n3) and eicosapentaenoic acid (EPA; C20:5 n3), are of concern for their health-promoting effects such as anti-inflammatory, but the tissue selectivity for n-3 PUFA (i.e., which tissues and organs are rich in n-3 PUFA) is still not well known. In addition, it is unclear which tissues and organs are more sensitive to n-3 PUFA intervention. These unresolved issues have greatly hindered the exploring of the health benefits of n-3 PUFA. METHODS: Twenty-four 7-week-old male C57BL/6 J mice were assigned to the control, fish oil, DHA, and EPA groups. The last three groups were given a 4-week oral intervention of fatty acids in ethyl ester (400 mg/kg bw). The fatty acid profiles in 27 compartments were determined by gas chromatography. RESULTS: The proportion of long-chain n-3 PUFA (the total relative percentage of EPA, DPA n3, and DHA) was analyzed. Eight tissues and organs, including the brain (cerebral cortex, hippocampus, hypothalamus) and peripheral organs (tongue, quadriceps, gastrocnemius, kidney, and heart) were determined as being n-3 PUFA-enriched tissues and organs, owing to their high n-3 PUFA levels. The highest n-3 PUFA content was observed in the tongue for the first time. Notably, the content of linoleic acid (LA; C18:2 n6c) in peripheral organs was observed to be relatively high compared with that in the brain. Interestingly, the proportions of EPA in the kidney, heart, quadriceps, gastrocnemius, and tongue increased more markedly after the EPA intervention than after the DHA or fish oil intervention. As expected, the levels of proinflammatory arachidonic acid (AA; C20:4 n6) in the kidney, quadriceps, and tongue were markedly decreased after the three dietary interventions. CONCLUSION: Peripheral tissues and organs, including the tongue, quadriceps, gastrocnemius, kidney, and heart, besides the brain, showed obvious tissue selectivity for n-3 PUFA. In the whole body of mice, the tongue exhibits the strongest preference for n-3 PUFA, with the highest proportion of n-3 PUFA. Moreover, these peripheral tissues and organs, especially the kidney, are more sensitive to dietary EPA administration in comparison with the brain.

Efficacy of non-surgical periodontal treatment on patients with coronary artery disease: a meta-analysis of randomized controlled trials

Background: Coronary artery disease (CAD) is defined as one of the most common cardiovascular diseases (CVDs). Periodontitis is one of the risk factors for CAD. Material and methods: PubMed, Embase and Cochrane Library databases were carefully and thoroughly retrieved until October 2021. On the basis of the inclusion and exclusion criteria, eligible articles were selected strictly to identify randomized controlled trials (RCTs). Using Cochran's Q statistic, Review Manager 5.4 and Stata 16, data were extracted, and a comprehensive analysis was carried out. Results: Six RCTs of 619 patients were included in this study, including 360 in the intervention group (IG) and 259 in the control group (CG). Meta-analysis showed significant difference for C-reactive protein (CRP) (1.20mg/L, 95% CI: 1.13 to 1.27, p < 0.00001) after non-surgical periodontal therapy (NSPT), but showed no significant difference for interleukin-6 (IL-6) (1.19mg/L, 95% CI: -1.03 to 3.40, p=0.29), flow-mediated dilation (FMD) (-1.64%, 95% CI: -4.95 to 1.67, p=0.33), triacylglycerol (TG) (-0.02mg/dL, 95% CI: -0.31 to 0.27, p=0.90), total cholesterol (TC) (0.04mg/dL, 95% CI: -0.25 to 0.33, p=0.90), low-density lipoprotein cholesterol (LDL-C) (0.00mg/dL, 95% CI: -0.29 to 0.29, p=0.99) and high-density lipoprotein cholesterol (HDL-C) (0.11mg/dL, 95% CI: -0.18 to 0.40, p=0.46). Conclusions: The impact of NSPT on the reduction of CRP in patients of CAD with periodontitis is significant. NSPT can be considered as an important preventive strategy for major cardiovascular events in CAD. (AU)

Sarmentosin promotes USP17 and regulates Nrf2-mediated mitophagy and cellular oxidative stress to alleviate APAP-induced acute liver failure.

BACKGROUND: An overdose of acetaminophen (APAP), the main cause of acute liver failure (ALF), induces oxidative stress that ultimately causes mitochondrial impairment and hepatotoxicity. The nuclear factor erythroid 2-related factor 2 (Nrf2) was widely recognized as an anti-oxidative stress mechanism. The present study was aimed at investigating whether sarmentosin, extract from traditional Chinese medicine, protects the liver against APAP-induced injury via activating Nrf2 and subsequently decreasing oxidative stress. METHODS: Male ICR mice were treated with sarmentosin oral administration for 1 week and injected APAP (300 mg/kg. i.p.) for acute liver injury model. The liver and serum of mice for histological and biochemistry analysis. AML12 and LO2 cells were used in vitro assays. RESULTS: We found that sarmentosin moderately increased accumulation of Nrf2 via upregulating USP17-mediated ubiquitin inhibition at the early stage of hepatocytes damage. The Nrf2 separating from bonding protein Keap1 translocated into nucleus and activated downstream gene of antioxidants. Mitophagy, a unique autophagy can remove Reactive Oxygen Species (ROS) damaged mitochondria, was elevated in this progress to maintain mitochondria function and ROS homeostasis. CONCLUSION: In summary, our research revealed that sarmentosin could alleviate APAP-induced liver acute injury through USP17-mediated Nrf2 overexpression and PINK1-dependent mitophagy.

Potential mediators of the relationship between vision impairment and self-rated health in older adults: A comparison between long-term care insurance claimants in residential care institutions versus those living in the community.

OBJECTIVES: The objective of this study was to examine the mediating roles of functional and psychological factors on the relationship between vision impairment (VI) and self-rated health (SRH) in older adults in residential care institutions versus those living in the community. DESIGN: A cross-sectional survey study. SETTING AND PARTICIPANTS: We obtained data for this study from the public Long-term Care Insurance (LTCI) database of Yiwu, Zhejiang province, China. Our data included adults aged ≥ 60 years who had received the qualification assessment from September through December 2018. In total, 2,427 elderly individuals were included for analysis, including 747 older adults in residential care institutions and 1,680 older adults living in the community. MEASURES: VI and SRH were measured using participants' self-reported information. Potentially relevant functional and psychological factors were assessed using LTCI qualification assessment data, including self-care activities, mobility, incontinence, perceived usefulness, perceived fatigue, and perceived interest. The Karlson-Holm-Breen (KHB) method was used to examine whether functional and psychological factors mediated the relationship between VI and SRH and to calculate the mediated percentage among older adults. RESULTS: Controlling for sociodemographic characteristics, all functional and psychological factors except mobility mediated the effect of severe VI on SRH in older adults living in the community. For older adults living in residential care institutions, self-care activities, mobility, and perceived usefulness mediated the effects of both moderate and severe VI on SRH, while perceived fatigue and perceived interest mediated the effect of severe VI on SRH. CONCLUSIONS: The findings of this study support the idea that functional and psychological factors mediate the relationship between vision impairment and self-rated health in older adults, and that different mediating pathways exist between older adults in residential care institutions and those living in the community. Our research highlights the importance of developing tailored interventions for visually impaired older adults through an integrative model to improve their overall well-being.

Multimorbidity Patterns and the Disablement Process among Public Long-Term Care Insurance Claimants in the City of Yiwu (Zhejiang Province, China).

This study aimed to identify multimorbidity patterns and explore the disablement process by utilizing the model raised by Verbrugge and Jette as a theoretical framework. This cross-sectional study used public Long-term Care Insurance (LTCI) claimants' assessment data of Yiwu city in Zhejiang Province, China, for 2604 individuals aged 60 years and older, from September through December 2018. Latent Class Analysis (LCA) was conducted using 10 common chronic conditions. Structural Equation Modeling was used to examine the disablement process. The latent classes of multimorbidity patterns were the "coronary atherosclerotic heart disease" class (19.0%), the "lower limb fractures" class (26.4%), and the "other diseases" class (54.6%). The structural model results show that coronary atherosclerotic heart disease had a significant influence on incontinence, but it was not statistically significant in predicting vision impairment and mobility impairment. Lower limb fractures had significant effects on vision impairment, incontinence, and mobility impairment. Vision impairment, incontinence, and mobility impairment had significant effects on physical activities of daily living (ADLs). Our findings suggest that different impairments exist from specific patterns of multimorbidity to physical ADL disability, which may provide insights for researchers and policy makers to develop tailored care and provide support for physically disabled older people.

Sedum sarmentosum Bunge Attenuates Drug-Induced Liver Injury via Nrf2 Signaling Pathway: An Experimental Verification Based on Network Pharmacology Prediction.

Purpose: Using network pharmacology and in vivo experiments, we investigated the antidrug-induced liver injury components and functional processes of Sedum sarmentosum Bunge (SSBE). Methods: The effective components, primary active ingredients, and possible target in the therapy of DILI were predicted using network pharmacology and bioinformatics. APAP was inducing the DILI model. In vivo testing of the pharmacodynamic foundation of SSBE in the treatment of DILI was performed. Results: The TCMSP database evaluated five main active components and 299 related targets. In addition, 707 differential genes for DILI were obtained from the DisGeNET database, DigSee database, and OMIM database. 61 related targets were mapped to predict the targets of SSBE acting on DILI. The protein-protein interaction (PPI) core network contained 59 proteins, including IL-ß, MARK14, SSP1, and MMP9. These genes are closely related to the Nrf2/ARE signaling pathway, and they may play a key role in the hepatoprotective effect of SSBE. Verification experiment results showed that, in the DILI mouse model, SSBE promoted inflammation diminution and regulation of Nrf2-ARE cascade. SSBE protected normal hepatocyte growth and inhibited apoptosis of normal liver cells induced by APAP. SSBE inhibited the expression of Nrf2 and ARE proteins in the liver tissue of the DILI mouse model in vivo. Conclusion: By modulating the Nrf2 signaling pathway, the active components in SSBE may protect against drug-induced liver damage.

Differential effects of EPA and DHA on DSS-induced colitis in mice and possible mechanisms involved.

BACKGROUND: The anti-inflammatory effect of n-3 PUFAs has been widely documented. Emerging evidence suggests that the main component of n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects in ulcerative colitis (UC). It was aimed to clarify their differential effects in UC. METHODS: Eight-week-old male C57BL/6J mice were randomly divided into 7 groups, namely control, UC model, salicylazosulfapyridine (SASP), low-dose DHA, high-dose DHA, low-dose EPA, and high-dose EPA. DHA, EPA and SASP treatment groups were orally treated accordingly for 9 weeks. During the 5th to 9th week the control group was given distilled water, while other groups were given distilled water with 2% dextran sodium sulfate (DSS) to induce UC. Body weight loss, diarrhea, and stool bleeding were recorded to calculate the disease activity index (DAI). The level of tight junction proteins Claudin-1 and Occludin, and cytokines including TNF-α, IL-6, and IL-1ß as well as inflammatory cell markers such as MPO, F4/80, and MCP-1 in the intestinal epithelium were measured using western blotting. Activation of IL-6/STAT3 and NLRP3/IL-1ß inflammatory pathways was also assessed. Levels of proliferation-related proteins of the Wnt/ß-catenin pathway with c-myc, Cyclin-D1, and PCNA were detected. RESULTS: EPA, superior to DHA, significantly attenuated DSS-induced colitis evidenced by reduced DAI scores, cytokine production and inflammatory cell infiltration. Mechanically, EPA triggered a marked up-regulation of Claudin-1 and Occludin with down-regulation of their up-stream Akt and ERK. EPA also inhibited NLRP3/IL-1ß and IL-6/STAT3 inflammatory pathways and up-regulated the Wnt/ß-catenin pathway. CONCLUSIONS: EPA is more suitable to be used for the treatment of UC than DHA.

Simultaneous determination of eight flavonoids in Sedum sarmentosum Bunge from different areas by UHPLC with triple quadrupole MS/MS.

Sedum sarmentosum Bunge (SSB) is a traditional Chinese herbal medicine containing multiple components that has been extensively used clinically to treat chronic viral hepatitis and some inflammatory diseases. Total flavonoids are major pharmacologically active components of SSB. To gain a deeper understanding of SSB resources, we analyzed eight chemical constituents in 33 batches of SSB from 11 regions in China. An accurate, precise and sensitive ultra-high-performance liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry method was developed for the determination of eight flavonoids in SSB. Under the optimized chromatographic conditions, good separation for the eight target components was obtained on an Agilent Zobax SB C18 (50 × 2.1 mm, 5 µm) column within 4 min. The established methods were validated with good linearity (r ≥ 0.9988), precision (RSD ≤ 2.68%), stability (1.43-3.28%) and repeatability (1.14-2.89%). Moreover, the average recoveries were 95.91-100.68%, and the RSDs were 1.50-3.80%. In addition, the analytical conditions of UPLC-ESI-MS/MS provided better sensitivity with a shorter analysis time when compared with the HPLC-DAD method. Hierarchical clustering analysis and principal component analysis were performed to estimate and classify these samples based on the contents of the eight chemical constituents. This study provided the theoretical basis and scientific evidence for the development and utilization of SSB resources.

Celastrol inhibits colorectal cancer through TGF-ß1/Smad signaling.

BACKGROUND: There are few clinical challenges associated with the treatment of colorectal cancer (CRC). Studies have shown that TGF-ß plays a crucial role in CRC. Importantly, celastrol, a major components of the root extract of the traditional Chinese herb Tripterygium wilfordii Hook F, has been shown to inhibit the growth, adhesion, and metastasis of human CRC cells through the inhibition of TGF-ß1/Smad signaling. MATERIALS AND METHODS: Real-time PCR and Western blot tests were proceeded to present TGF-ß1, TGF-ß receptor type I (TGFßRI), TGF-ß receptor type II (TGFßRII), Smad2/3, p-Smad2/3, Smad4, and glyceraldehyde-3-phosphate dehydrogenase expression in human colon cancer cell samples. RESULTS: Our results indicated that celastrol can reduce the expression levels of TGF-ß1, TGFßRI, and TGFßRII in HCT116 and SW620 cells. Furthermore, celastrol could also prevent the increase in Smad4 and p-Smad2/3 in HCT116 and SW620 cells. CONCLUSION: Celastrol could inhibit tumor growth through TGF-ß1/Smad signaling and might be a promising therapeutic component against CRC.