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Erchen decoction (ECD) is a traditional Chinese prescription widely used in the treatment of various diseases such as obesity, fatty liver, diabetes, and hypertension. In this study, we investigated the effect of ECD on fatty acid metabolism in a colorectal cancer (CRC) mouse model fed a high-fat (HF) diet. The HF-CRC mouse model was established by azoxymethane (AOM)/dextran sulphate sodium (DSS) combined with a high-fat diet. Mice were then gavaged with ECD. Change in the body weight was recorded every two weeks for 26 weeks. Changes in blood glucose (GLU), total cholesterol (TC), total triglycerides (TG), and C-reactive protein (CRP) were measured. Colorectal tissues were collected to observe changes in colorectal length and tumorigenesis. Hematoxylin-eosin (HE) staining and immunohistochemical staining were performed to observe changes in intestinal structure and inflammatory markers. Fatty acids and the expression of related genes in colorectal tissues were also studied. ECD gavage inhibited HF-induced weight gain. CRC induction and HF diet intake resulted in increased GLU, TC, TG, and CRP, where ECD gavage reduced these elevated indicators. ECD gavage also increased colorectal length and inhibited tumorigenesis. HE staining revealed that ECD gavage suppressed inflammatory infiltration of colorectal tissues. ECD gavage suppressed the fatty acid metabolism abnormalities caused by HF-CRC in colorectal tissues. Consistently, ECD gavage lowered ACSL4, ACSL1, CPT1A, and FASN levels in colorectal tissues. Conclusions. ECD inhibited HF-CRC progression through the regulation of fatty acid metabolism.

ObjectivesThis study aims to evaluate the effect of coronavirus disease 2019 (COVID-19) on the long-term risk of digestive diseases in the general population.DesignLarge-scale population-based cohort study based on a prospective cohort.SettingUK Biobank cohort linked to multiple nationwide electronic health records databases.ParticipantsThe cohort consisted of 112,311 individuals who survived the initial 30 days following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as two control groups: a contemporary group (n = 359,671) without any history of COVID-19, and a historical control group (n = 370,979) that predated the COVID-19 outbreak.Main outcome measuresMain outcomes were predefined digestive diseases. Hazard ratios and corresponding 95% confidence intervals (CI) were computed utilizing the Cox regression models after inverse probability weighting.ResultsCompared with the contemporary control group, patients with previous COVID-19 infection had higher risks of digestive diseases, including functional gastrointestinal disorders (hazard ratios [HR] 1.95 (95% CI 1.62 to 2.35)); peptic ulcer disease (HR 1.27 (1.04 to 1.56)); gastroesophageal reflux disease (GERD) (HR 1.46 (1.34 to 1.58)); inflammatory bowel diseases (HR 1.40 (1.02 to 1.90)); gallbladder disease (HR 1.28 (1.13 to 1.46)); severe liver disease (HR 1.46 (1.12 to 1.90)); non-alcoholic liver disease (HR 1.33 (1.15 to 1.55)); and pancreatic disease (HR 1.43 (1.17 to 1.74)). The risks of GERD were stepwise increased with severity of the acute phase of COVID-19 infection. The results were consistent when using the historical cohort as the control group.ConclusionsOur study provides important insights into the association between COVID-19 and the long-term risk of digestive system disorders. COVID-19 patients are at a higher risk of developing gastrointestinal disorders, with stepwise increased risk with the severity and persisting even after one year follow-up.

Background For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers. Methods Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103. Results Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation. Conclusions A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded.

Radiation-induced intestinal injury (RIII) frequently occurs during radiotherapy; however, methods for treating RIII are limited. Ginsenoside Rk1 (RK1) is a substance that is derived from ginseng, and it has several biological activities, such as antiapoptotic, antioxidant and anticancer activities. The present study was designed to investigate the potential protective effect of Rk1 on RIII and the potential mechanisms. The results showed that RK1 treatment significantly improved the survival rate of the irradiated rats and markedly ameliorated the structural injury of the intestinal mucosa observed by histology. Treatment with RK1 significantly alleviated radiation-induced intestinal epithelial cell oxidative stress apoptosis. Moreover, RNA-Seq identified 388 differentially expressed genes (DEGs) and showed that the PI3K-AKT pathway might be a key signaling pathway by which RK1 exerts its therapeutic effects on RIII. The western blotting results showed that the p-PI3K, p-AKT and p-mTOR expression levels, which were increased by radiation, were markedly inhibited by Rk1, and these effects were reversed by IGF-1. The present study demonstrates that Rk1 can alleviate RIII and that the mechanism underlying the antiapoptotic effects of RK1 may involve the suppression of the PI3K/Akt/mTOR pathway. This study provides a promising therapeutic agent for RIII.

Anorexia nervosa (AN) is a severe and complex psychiatric disorder with the highest mortality rate of all psychiatric disorders. Previous observational studies indicated inconclusive association between inflammatory bowel disease (IBD) and AN, and the causal effect remains unclear. We aimed to test the hypothesis that a causal relationship exists between IBD and the risk of AN using the Mendelian randomization (MR) analysis. The inverse-variance weighted (IVW) method was employed as the primary analysis. Furthermore, various sensitivity analyses were conducted to assess the robustness of our results. Notably, IVW analysis of univariable MR revealed that genetically predicted IBD were significantly casually associated with AN risk (NSNP = 12, odds ratio [OR]: 1.143, 95% confidence interval [CI]: 1.032–1.266, P = 0.01). In subgroups, consistent positive causal associations with AN might show in ulcerative colitis (UC) (NSNP = 6, OR: 1.153, 95% CI: 1.022–1.301, P = 0.021), and Crohn's disease (CD) (NSNP = 4, OR: 1.153, 95% CI: 1.008–1.319, P = 0.037). Besides, there was no heterogeneity and horizontal pleiotropy observed in the sensitivity analysis. Our study identifies that patients diagnosed with IBD, including UC and CD, could be causally associated with an increased risk of AN. It may have clinical benefits for early detection of AN and clinical decisions on management of IBD patients.

ObjectivesTo prospectively investigate the associations of habitual fish oil use with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospital admission, or mortality with Corona Virus Disease-19 (COVID-19) in a large-scale cohort.DesignProspective population-based cohort study.SettingUK Biobank.ParticipantsA total of 110 440 participants aged 37 -73 years who completed a questionnaire on supplement use, which included fish oil at baseline were enrolled between 2006 and 2010 and followed up until 2022.Main exposureAll participants filled out questionnaires about the habitual use of supplements, including fish oil.Main outcome measuresSARS-CoV-2 infection, COVID-19 hospital admission and COVID-19 mortality.ResultsAt baseline, 29 424 (26.6%) of the 110 440 participants reported habitual use of fish oil supplements. The multivariable adjusted hazard ratios for habitual users of fish oil versus non-users were 0.95 (0.93 to 0.98) for SARS-CoV-2 infection among participants with follow-up time less than 12.1 years but no significant associations were observed for participants with follow-up time more than 12.1 years. For COVID-19-related outcomes, the hazard ratios were 0.79 (95% confidence interval 0.71 to 0.88) for COVID-19 hospital admission and 0.72 (0.60 to 0.87) for COVID-19 mortality. For COVID-19-related outcomes, the association seemed to be stronger among those with longstanding illness. The Cox proportional hazard analysis after propensity-score matching yielded consistent results.ConclusionsHabitual fish oil supplement is associated with a lower risk of hospital admission and mortality with COVID-19, but not associated with SARS-CoV-2 infection in the population with more than 12.1 years of follow-up.

ObjectivesTo assess the association of habitual glucosamine use with coronavirus 2 (SARS-CoV-2) infection, hospital admission, or mortality with Corona Virus Disease-19 (COVID-19) in a large population based cohort.DesignPopulation based, prospective cohort study.SettingUK Biobank.ParticipantsParticipants with complete information on habitual glucosamine use and SARS-CoV-2 infection or COVID-19-related outcomes were included. These participants were registered from 2006 to 2010, followed up until 2022 and participated in SARS-CoV-2 tests between 2020 and 2022.Main outcome measuresSARS-CoV-2 infection, COVID-19 hospital admission, and COVID-19 mortality.ResultsAt baseline, 20,118 (15.9%) of the 126,518 participants reported as habitual glucosamine users. During the median follow-up 12.16 years, there were 53,682 cases of SARS-CoV-2 infection, 2,120 cases of COVID-19 hospital admission and 548 cases of COVID-19 mortality. The multivariate adjusted hazard ratios of habitual glucosamine users to non-users were 1.02 (95% confidence interval [CI] 0.99 to 1.05) for SARS-CoV-2 infection, 0.73 (95% CI 0.63 to 0.85) for COVID-19 hospital admission, and 0.74 (95% CI 0.56 to 0.98) for COVID-19 mortality. The Cox proportional hazard analysis after propensity-score matching yielded consistent results.ConclusionsHabitual glucosamine use seems to be associated with a lower risk of hospital admission and mortality with COVID-19, but not the risk of SARS-CoV-2 infection.

Necrotizing enterocolitis (NEC) is a devastating disease predominately affecting neonates. Despite therapeutic advances, NEC remains the leading cause of mortality due to gastrointestinal conditions in neonates. Stem cells have been exploited in various diseases, and the application of different types of stem cells in the NEC therapy is explored in the past decade. However, stem cell transplantation possesses several deficiencies, and exosomes are considered potent alternatives. Exosomes, especially those derived from stem cells and breast milk, demonstrate beneficial effects for NEC both in vivo and in vitro and emerge as promising options for clinical practice. In this review, the function and therapeutic effects of stem cells and exosomes for NEC are investigated and summarized, which provide insights for the development and application of novel therapeutic strategies in pediatric diseases. Further elucidation of mechanisms, improvement in preparation, bioengineering, and administration, as well as rigorous clinical trials are warranted.

ObjectiveConcerns have been raised about the widespread use of proton pump inhibitors (PPIs), and current findings linking the regular use of PPIs to respiratory infections remain inconsistent. Our study aims to evaluate whether PPI use increases the risk of pneumonia, influenza, and COVID-19.MethodThe presented study included 160,923 eligible participants from the UK Biobank (mean age 56.5 years, 53% women). Cox proportional hazards regression and propensity score-matching analyses were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Effect modifications by stratifications, including indications andCYP2C19phenotypes were tested.ResultsThe regular use of PPIs was associated with increased risks of developing pneumonia (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.26-1.59) and influenza (HR 1.31, 95% CI 1.11-1.55). However, the risk of COVID-19 infection among regular PPI users was not significantly increased (HR 1.05, 95% CI 0.95-1.16). The burden was more notably observed in patients without indications of PPI use (HR 1.52, 95% CI 1.33-1.73 for pneumonia; HR 1.36, 95% CI 1.12-1.64 for influenza). The risk for pneumonia was higher among theCYP2C19rapid and ultrarapid metabolizers (HR 1.45, 95% CI 1.22-1.73,Pfor interaction < 0.001). The propensity score-matching analyses yielded similar trends.ConclusionsThe regular use of PPIs is associated with increased susceptibility to pneumonia and influenza, but not COVID-19 infection. The risks are even higher among recipients without main indications. Our study highlights the appropriate use and de-prescribing of PPIs according to indications andCYP2C19phenotypes for patients and clinical practitioners.What is already known on this topicProton pump inhibitors (PPIs) have been extensively used in clinical practice, while emerging studies suggest the adverse effects associated with their long-term use.The linkage between PPIs and respiratory infections has been indicated, whereas controversy remains.What this study addsIn the large cohort involving 160,923 individuals, regular use of PPIs was associated with 42% and 31% increased risks of pneumonia and influenza, respectively, but not COVID-19 infection.The burdens were more evident among PPI users without main indications, andCYP2C19rapid and ultrarapid metabolizers.How this study might affect research, practice or policyConsidering the potential risk of respiratory infections, appropriate use following indications and metabolic phenotypes, as well as de-prescribing of PPIs are highlighted.

Background and aimsInflammatory bowel disease (IBD) is usually comorbid with psychological disorders. Emerging observational studies have indicated the association between autism spectrum disorder (ASD) and IBD, including Crohn’s disease (CD) and ulcerative colitis (UC), whereas the causality remains unknown. Our study aimed to explore the causal association between IBD and ASD using bidirectional two-sample Mendelian randomization (MR) design.MethodsSummary-level data from large-scale genome-wide association (GWAS) studies of IBD (International Inflammatory Bowel Disease Genetics Consortium, Ncases=25,042, Ncontrols=34,915) and ASD (Integrative Psychiatric Research-Psychiatric Genomics Consortium, Ncases=18,382, Ncontrols=27,969) were retrieved. Gene variants for IBD and ASD were selected as instrumental variables. MR analyses were performed mainly including the inverse-variance-weighted method with a series of sensitivity tests.ResultsGenetic predisposition to IBD was associated with a high risk of ASD (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01-1.06, P = 0.01; OR [95% CI]: 1.03 [1.01-1.05], P = 0.02 for CD; OR [95% CI]: 1.03 [1.01-1.07], P = 0.04 for UC). In contrast, no causal association was found for the genetic liability to ASD on IBD.ConclusionsOur findings reveal that genetically predicted IBD is causally related to ASD, whereas the causal association of ASD on IBD is not supported. Our study highlights the early screening and surveillance of psychological symptoms, as well as sustaining support for patients with IBD. Further investigations on age-specific groups are warranted.

Background. Traditional Chinese medicine (TCM) typically attributes the etiopathogenesis of perimenopausal syndrome (PMS) to kidney deficiency in the TCM stratification system for diagnosis. However, the molecular basis of this classical attribution remains to be investigated. Aim of the Study. By unraveling the responses to TCM treatment for kidney deficiency, the metabolomic link between PMS and kidney deficiency can be evaluated for in-depth understanding of the mechanism of TCM treatment and development of better treatment protocols. Materials and Methods. With naturally aged rats as a model for PMS, the metabolomic response to TCM treatment for kidney deficiency was investigated by 1H NMR. Results. 1H NMR metabolomic evidence of plasma samples demonstrates that treatments with two classical TCM prescriptions for kidney deficiency, decoctions of Yougui and Zuogui, result in modulating the metabolic state of the disease model towards that of rats of younger age. Conclusion. The data support the notion that kidney deficiency is responsible, in part at least, for PMS, and the relevant prescriptions are helpful in dampening the changes in the body’s metabolic states to alleviate symptoms of the disorder.

ObjectivePublished observational studies have revealed the connection between inflammatory bowel disease (IBD) and neurodegenerative disorders, whereas the causality remains largely unclear. Our study aims to assess the causality and identify the shared genetic architecture between IBD and neurodegenerative disorders.DesignA series of two-sample Mendelian randomization analyses were performed to assess the causality between IBD and neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Alzheimer’s disease [AD], Parkinson’s disease [PD], and multiple sclerosis [MS]). Shared genetic loci and functional interpretation were further investigated for IBD and ALS. The transcriptomic expressions of shared genes were evaluated in patients with IBD and ALS.ResultsGenetic predisposition to IBD is associated with lower odds of ALS (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.94 to 0.99). In contrast, IBD is not genetically associated with an increased risk of AD, PD, or MS. Four shared genetic loci (rs6571361, rs10136727, rs7154847, and rs447853) were derived, and SCFD1, G2E3, HEATR5A were further identified as novel risk genes with enriched function related to membrane trafficking. G2E3 was differentially expressed and significantly correlated with SCFD1 in patients with IBD or ALS.ConclusionOur study reveals the casually protective role of IBD on ALS, and does not support the causality of IBD on AD, PD, or MS. Our findings indicate possible shared genetic architecture and pathways between IBD and ALS. The altered expressions of shared risk genes might contribute to the susceptibility to IBD and the protective effects for ALS. These results provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.What is already known on this topicEmerging evidence has supported the communication between the gastrointestinal tract and central nervous system (the “gut-brain axis”).Published epidemiological studies have revealed the association between inflammatory bowel disease (IBD) and neurodegenerative disorders.The causality remains largely unclear.What this study addsGenetic liability to IBD is associated with a decreased risk of amyotrophic lateral sclerosis (ALS), whereas the susceptibility to IBD does not lead to Alzheimer’s disease, Parkinson’s disease, or multiple sclerosis.Shared genetic loci (rs6571361, rs10136727, rs7154847, and rs447853) and risk genes (SCFD1, G2E3, HEATR5A) are identified in IBD and ALS.Transcriptomic profiles in patients with IBD or ALS indicate that G2E3 is differentially expressed and significantly correlated with SCFD1.How this study might affect research, practice or policyThe findings provide insights into the pathogenesis and therapeutics of IBD and neurodegenerative disorders.Lower expression of G2E3 in IBD might serve as a protective factor to ALS.Unsubstantiated concerns among patients with IBD could be alleviated.

Summary Rho guanosine triphosphatase (GTPases), as molecular switches, have been identified to be dysregulated and involved in the pathogenesis of various rheumatic diseases, mainly including rheumatoid arthritis, osteoarthritis, systemic sclerosis, and systemic lupus erythematosus. Downstream pathways involving multiple types of cells, such as fibroblasts, chondrocytes, synoviocytes, and immunocytes are mediated by activated Rho GTPases to promote pathogenesis. Targeted therapy via inhibitors of Rho GTPases has been implicated in the treatment of rheumatic diseases, demonstrating promising effects. In this review, the effects of Rho GTPases in the pathogenesis of rheumatic diseases are summarized, and the Rho GTPase-mediated pathways are elucidated. Therapeutic strategies using Rho GTPase inhibitors in rheumatic diseases are also discussed to provide insights for further exploration of targeted therapy in preclinical studies and clinical practice. Future directions on studies of Rho GTPases in rheumatic diseases based on current understandings are provided., Graphical abstract, Rheumatology; Molecular biology

Ethnopharmacological relevance: Two types of traditional Chinese formulas of botanical drugs are prescribed for treating perimenopausal syndrome (PMS), a disorder in middle-aged women during their transition to menopause. One is for treating PMS as kidney deficiency (KD) due to senescence and declining reproductive functions, and the other is for treating it as liver qi stagnation (LQS) in association with stress and anxiety. Despite the time-tested prescriptions, an objective attestation to the effectiveness of the traditional Chinese treatment of PMS is still to be established and the associated molecular mechanism is still to be investigated.Materials and methods: A model for PMS was generated from perimenopausal rats with chronic restraint stress (CRS). The effectiveness of traditional Chinese formulas of botanical drugs and a combination of two of the formulas was evaluated based on 1H NMR plasma metabolomic, as well as behavioral and physiological, indicators. To investigate whether the formulas contained ligands that could compensate for the declining level of estrogen, the primary cause of PMS, the ligand-based NMR technique of saturation transfer difference (STD) was employed to detect possible interacting molecules to estrogen receptors in the decoction.Results: Each prescription of the classical Chinese formula moderately attenuated the metabolomic state of the disease model. The best treatment strategy however was to combine two traditional Chinese formulas, each for a different etiology, to adjust the metabolomic state of the disease model to that of rats at a much younger age. In addition, this attenuation of the metabolomics of the disease model was by neither upregulating the estrogen level nor supplementing an estrogenic compound.Conclusion: Treatment of PMS with a traditional Chinese formula of botanical drugs targeting one of the two causes separately could ameliorate the disorder moderately. However, the best outcome was to treat the two causes simultaneously with a decoction that combined ingredients from two traditional prescriptions. The data also implicated a new paradigm for phytotherapy of PMS as the prescribed decoctions contained no interacting compound to modulate the activity of estrogen receptors, in contrast to the treatment strategy of hormone replacement therapy.

Esophageal adenocarcinoma (EAC) is a highly malignant type of digestive tract cancers with a poor prognosis despite therapeutic advances. Pyroptosis is an inflammatory form of programmed cell death, whereas the role of pyroptosis in EAC remains largely unknown. Herein, we identified a pyroptosis-related five-gene signature that was significantly correlated with the survival of EAC patients in The Cancer Genome Atlas (TCGA) cohort and an independent validation dataset. In addition, a nomogram based on the five-gene signature was constructed with novel prognostic values. Moreover, the genes in the pyroptosis-related signature, CASP1, GSDMB, IL1B, PYCARD, and ZBP1, might be involved in immune response and regulation of the tumor microenvironment. Our findings indicate that the five-gene signature provides insights into the involvement of pyroptosis in EAC progression, and is promising in the risk assessment as well as prognosis for EAC patients in clinical practice.

In the past decade, the study of extracellular vesicles (EVs), especially exosomes (50–150 nm) have attracted growing interest in numerous areas of cancer and tissue regeneration due to their unique biological features. A low isolation yield and insufficient targeting abilities limit their therapeutic applicability. Recently, superparamagnetic iron oxide nanoparticles (SPIONs) with magnetic navigation have been exploited to enhance the targeting ability of EVs. To construct targeted EV delivery systems engineered by SPIONs, several groups have pioneered the use of different techniques, such as electroporation, natural incubation, and cell extrusion, to directly internalize SPIONs into EVs. Furthermore, some endogenous ligands, such as transferrins, antibodies, aptamers, and streptavidin, were shown to enable modification of SPIONs, which increases binding with EVs. In this review, we summarized recent advances in targeted EV delivery systems engineered by SPIONs and focused on the key methodological approaches and the current applications of magnetic EVs. This report aims to address the existing challenges and provide comprehensive insights into targeted EV delivery systems. Statement of significance Targeted extracellular vesicle (EV) delivery systems engineered by superparamagnetic iron oxide nanoparticles (SPIONs) have attracted wide attention and research interest in recent years. Such strategies employ external magnet fields to manipulate SPION-functionalized EVs remotely, aiming to enhance their accumulation and penetration in vivo. Although iron oxide nanoparticle laden EVs are interesting, they are controversial at present, hampering the progress in their clinical application. A thorough integration of these studies is needed for an advanced insight and rational design of targeted EV delivery systems. In this review, we summarize the latest advances in the design strategies of targeted EV delivery systems engineered by SPIONs with a focus on their key methodological approaches, current applications, limitation and future perspectives, which may facilitate the development of natural theranostic nanoplatforms.

Emerging evidence suggested that mitophagy may play an important role in the progression of hepatocellular carcinoma (HCC), whereas the association between mitophagy-related genes and HCC patients’ prognosis remains unknown. In this study, we aimed to investigate the potential prognostic values of mitophagy-related genes (MRGs) on HCC patients at the genetic level. According to median immunoscore, we categorized HCC patients from TCGA cohort into two immune score groups, while 39 differential expression MRGs were identified. By using univariate analysis, we screened out 18 survival-associated MRGs, and then, the least absolute shrinkage and selection operator (LASSO) analysis was applied to construct a prognosis model that consisted of 9 MRGs (ATG7, ATG9A, BNIP3L, GABARAPL1, HTRA2, MAP1LC3B2, TFE3, TIGAR, and TOMM70). In our prognostic model, overall survival in the high and low-risk groups was significantly different P < 0.001 , and the respective areas under the curve (AUC) of our prognostic model were 0.686 for 3-year survival in the TCGA cohort and 0.776 for 3-year survival in the ICGC cohort. Moreover, we identified the risk score as the independent factor for predicting the HCC patients’ prognosis by using single and multifactor analyses, and a nomogram was also constructed for future clinical application. Further functional analyses showed that the immune status between two risk groups was significantly different. Our findings may provide a novel mitophagy-related gene signature, and these will be better used for prognostic prediction in HCC, thus improving patient outcome.

Bioactive constituents from Rhodiola rosea L. (RRL) exhibit multiple pharmacological effects on diverse diseases. However, whether they are suitable for the treatment of radiation-induced intestinal injury (RIII) remains unclear. This study aims to investigate their roles and mechanisms in the RIII rat model. The radioprotective effects of the four bioactive constituents of RRL (salidroside, herbacetin, rosavin and arbutin) were evaluated by the cell viability of irradiated IEC-6 cells. Intestinal tissues were collected for histological analysis, localized inflammation and oxidative stress assessments. Our work showed that salidroside, rosavin and arbutin improved the cell viability of the irradiated IEC-6 cells, with the highest improvement in 12.5 μM rosavin group. The rosavin treatment significantly improved survival rate and intestinal damage in irradiated rats by modulating the inflammatory response and oxidative stress. Our work indicated that rosavin may be the optimal constituent of RRL for RIII treatment, providing an attractive candidate for radioprotection.

Background and Aims. Treatment options for radiation-induced intestinal injury (RIII) are limited. Crocetin has been demonstrated to exert antioxidant, antiapoptotic, and anti-inflammatory effects on various diseases. Here, we investigate the effects of crocetin on RIII in vitro. Materials and Method. IEC-6 cells exposed to 10 Gy of radiation were treated with different doses of crocetin (0, 0.1, 1, 10, and 100 μM), and cell viability was assessed by CCK-8. The levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interferon-γ (IFN-γ) in culture supernatants were measured using colorimetric and ELISA kits, respectively. Cellular apoptosis was evaluated by Annexin V/PI double staining. Results. Crocetin dose-dependently improved the survival of irradiated IEC-6 cells with the optimal dose of 10 μM, as indicated by the reduction of cellular apoptosis, decreased levels of MDA, MPO, and proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ), and increased activities of antioxidative enzymes (SOD, CAT, and GPx). Conclusion. Our findings demonstrated that crocetin alleviated radiation-induced injury in intestinal epithelial cells, offering a promising agent for radioprotection.

Background: Emerging data have suggested colorectal cancer (CRC) often coexists with cardiovascular diseases, but whether cardiovascular risk factors play a role in CRC remains unclear. We performed a systematic review and meta-analysis of prospective cohort studies to better illustrate the associations between cardiovascular risk factors and CRC. Methods: We searched EMBASE, MEDLINE and Web of Science databases from inception up to June 14, 2020. Studies were included if they evaluated the association between at least one of cardiovascular risk factors and CRC incidence, contained sufficient data to obtain relative risk (RR) and 95% confidence interval (CI). We performed separate meta-analyses for each cardiovascular risk factor using random-effect model. Findings: Data from 84 prospective cohort studies, reporting 52, 348, 827 individuals and 384, 973 incident cases were included in the analysis. Overall, the risk of CRC was 1.31(95% CI, 1.21-1.42) for obesity, 1.14 (95% CI, 1.08-1.20) for per 5 kg/m 2 increase in BMI, 1.18 (95% CI, 1.14-1.23) for former smoker, 1.20 (95% CI, 1.11-1.30) for current smoker, 1.25 (95% CI, 1.16-1.35) for diabetes, 1.07 (95% CI, 1.02-1.12) for hypertension. The summary RRs of CRC for the highest versus lowest quartiles of total cholesterol, triglyceride, low-density lipoprotein were 1.12 (95% CI, 1.03-1.22), 1.18 (95% CI, 1.04-1.35), 0.85 (95% CI, 0.62-1.17) respectively and the pooled RR for the lowest versus highest quartile of high-density lipoprotein was 1.14 (95% CI, 1.02-1.28). Interpretation: Unfavorable cardiovascular risk factors are associated with increased risk of CRC. Although the potential mechanisms are still under investigation, these findings may provide novel insight into the primary and secondary prevention of CRC. Registration: PROSPERO CRD42020175537. Funding Statement: This work was supported by National Natural Science Foundation of China (Grant No. 81300279, 81741067 and 81600260), Guangdong Natural Science Foundation (Grant No. 2016A030313815, 2016A030313210, 2017A030313464 and 2018A030310655), Science and Technology Planning Project of Guangdong Province (Grant No. 2015A020212029 and 2017A020215174), Science and Technology Program of Guangzhou (Grant No. 201707010419 and 201804010050), Medical Scientific Research Foundation of Guangdong Province (Grant No. A2018343 and A2019063), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2020A1515011161), High-level Hospital Construction Project (Grant No. DFJH201803, KJ012019099 and DFJH201923), the Fundamental Research Funds for the Central Universities (Grant No. D2180600), the project of Kelin new star of the First Affiliated Hospital of Sun Yat-Sen University (Grant No. Y50186), and the Fundamental Research Funds for the Central Universities in Sun Yat-Sen University (Grant No.18ykpy08). Declaration of Interests: The authors declare that they have no potential conflicts of interest.

Background Emerging data have suggested colorectal cancer (CRC) often coexists with cardiovascular diseases, but whether cardiovascular risk factors play a role in CRC remains unclear. We performed a systematic review and meta-analysis to better illustrate the associations between cardiovascular risk factors and CRC. Methods We searched EMBASE, MEDLINE and Web of Science databases from inception up to June 14, 2020. Prospective cohort studies were included if they evaluated the association between at least one of cardiovascular risk factors and CRC incidence, containing sufficient data to obtain relative risk (RR) and 95% confidence interval (CI). We performed separate meta-analyses for each cardiovascular risk factor using random-effect model. PROSPERO registration number: CRD42020175537. Findings Data from 84 studies, reporting 52, 348, 827 individuals and 384, 973 incident cases were included in the analysis. Overall, the risk of CRC was 1.31(95% CI, 1.21–1.42) for obesity, 1.14 (95% CI, 1.09–1.20) for per 5 kg/m2 increase in body mass index, 1.18 (95% CI, 1.14–1.23) for former smoker, 1.20 (95% CI, 1.11–1.30) for current smoker, 1.25 (95% CI, 1.16–1.35) for diabetes, 1.07 (95% CI, 1.02–1.12) for hypertension. The summary RRs of CRC for the highest versus lowest quartiles of total cholesterol, triglyceride, low-density lipoprotein were 1.12 (95% CI, 1.03–1.22), 1.18 (95% CI, 1.04–1.35), 0.85 (95% CI, 0.62–1.17) respectively and the pooled RR for the lowest versus highest quartile of high-density lipoprotein was 1.14 (95% CI, 1.02–1.28). Interpretation Unfavorable cardiovascular risk factors are associated with increased risk of CRC, which may provide novel insight into the screening strategies of CRC in patient with these risk factors.