Pyroptosis contributes to activation of the innate immunity system and defense against infection by pathogens. Endotoxemia is the host inflammatory storm occurring in response to severe and life-threatening infections caused by endotoxin from gram-negative bacilli. However, whether pyroptosis is involved in intestinal epithelial cell (IEC) or intestinal stem cell (ISC) injury induced by endotoxemia remains unclear. Mice with NF-κB p65 deletion in IECs (p65IEC − KO) were used to investigate the role of NF-κB-mediated pyroptosis in endotoxemia-induced intestinal injury. Morphology, pyroptosis, permeability, inflammation, endoplasmic reticulum stress in the intestine and survival were evaluated in WT and p65IEC − KO mice. Pyroptosis was found in intestinal epithelial cells of mice treated with lipopolysaccharide (LPS), but was significantly reduced in p65IEC − KO mice. Mice with endotoxemia exhibited morphological alterations in intestinal tissue, with a shortened villus length and crypt depth, increased intestinal permeability, increased inflammatory factors, and reduced survival rate, all of which were markedly improved in p65IEC − KO mice. Importantly, ER stress was found to be downregulated in IECs of p65IEC − KO mice with endotoxemia. Furthermore, the ER stress activator tunicamycin markedly enhanced IEC pyroptosis and aggravated intestinal injury in p65IEC − KO mice with endotoxemia. NF-κB p65–mediated pyroptosis participates in IEC injury in response to endotoxemia via regulation of ER stress. It may provide a potential therapeutic target for protecting against endotoxemia-induced intestinal injury.

Coenzyme Q10 (CoQ10) is a fat-soluble nutrient, which has antioxidant and anti-inflammatory properties. However, there is insufficient evidence on its daily use and the association with mortality. We aimed to evaluate the trends of CoQ10 supplement use among US noninstitutionalized adults and explore its associations with all-cause and CVD mortality. A prospective cohort study used data from the National Health and Nutrition Examination Survey (1999-2018). The association of CoQ10 supplementation with mortality was assessed with Cox proportional hazard models. The overall reported prevalence of CoQ10 supplement use increased from 1.2% (95% CI 0.7%-1.8%) in 1999-2000 to 4.6% (95% CI 3.4%-6.1%) in 2017-2018 (linear p = 0.002). During an average of 9.8 years of follow-up, 5237 deaths were identified, including 1428 deaths due to CVD. In the multivariable model, CoQ10 supplement use was not associated with all-cause mortality (HR 1.00, 95% CI 0.77-1.30, p = 0.996) and CVD mortality (HR 1.30, 95% CI 0.89-1.90, p = 0.170). Subgroup analyses suggested that the use of CoQ10 supplements was associated with a higher all-cause mortality in obese participants (HR 1.45, 95% CI 1.01-2.08, p for interaction = 0.013). Although the prevalence of CoQ10 supplement use experienced continuous growth from 1999 to 2018 in the general adults of NHANES, CoQ10 supplementation was not associated with all-cause and CVD mortality.

The association of food-sourced Coenzyme Q10(CoQ10) intake with hyperuricemia (HUA) remains unclear. We aimed to investigate the association between dietary CoQ10 intake and HUA among Chinese adults. A total of 7953 Chinese adults from the 2009 China Health and Nutrition Survey (CHNS) were included in the present cross-sectional. Dietary CoQ10 was assessed by 3 consecutive 24-h dietary recall interviews combined with a household food inventory. Multivariable logistic regression models and restricted cubic spline models were used to explore the associations between dietary CoQ10 and HUA. In an adjusted logistic regression model, the multivariable odds ratio (OR) and 95

INTRODUCTION/AIMS:Postoperative myasthenic crisis (POMC), which occurs specifically after thymectomy in myasthenia gravis (MG) patients, is a serious complication with known risk factors such as prior myasthenic crisis. However, the predictive value of perioperative blood lactic acid levels (BLAL) for POMC remains unclear. This study aims to determine whether changes in perioperative BLAL can predict POMC in MG patients undergoing thymectomy. METHODS:A total of 340 patients diagnosed with MG and undergoing thymectomy at the First Affiliated Hospital of Sun Yat-sen University were enrolled (January 2008-September 2018). Multivariate logistic regression analyses were employed to discern independent factors linked with POMC. RESULTS:Among the patients with POMC, notable differences including higher Myasthenia Gravis Foundation of America (MGFA) stage, and history of preoperative myasthenic crisis were observed. Higher postoperative lactic acid levels and the extent of changes were more prevalent in the POMC group. The multivariate analysis unveiled history of myasthenic crisis (odds ratio, OR: 67.18), postoperative BLAL change ratio greater than 50% (OR: 2.86), the video-assisted thoracoscopic surgery (VATS) approach (OR: 4.33), and higher preoperative BLAL (OR per unit: 2.68) were associated with POMC. Both continuous and grouped lactic acid models demonstrated a good predictive capability, yielding area under the curve (AUC) values of 0.84 and 0.83, respectively. The optimal threshold for 24-h postoperative BLAL was 1.98 mmol/L. DISCUSSION:These findings offer valuable insights for clinical decision-making and monitoring of prognosis in managing patients with MG. Future research should explore further the underlying mechanisms linking elevated lactate levels to POMC.

Emerging studies have demonstrated that phagocytosis checkpoints, which promote tumor-mediated immune evasion, are potential targets for cancer immunotherapy. In this study, the TCGA colorectal cancer (CRC) dataset and our RNA sequencing dataset suggested that SLAMF8 expression is significantly positively correlated with the expression levels of multiple phagocytosis checkpoint molecules. In vitro, we confirmed that SLAMF8 significantly regulated the phagocytosis of mouse CRC cells. RNA sequencing revealed that the expression of genes that promote Fc receptor (FcR)-mediated phagocytosis, such as FCGR1, FCGR3, FCGR2b, FCGR4, and ITGAM, was significantly upregulated after SLAMF8 knockdown. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results suggested that the significantly enriched signaling pathways after SLAMF8 knockdown or overexpression included the PI3K-Akt signaling pathway. The protein expression levels of p-PI3K and p-Akt were significantly increased after SLAMF8 knockdown. When PI3K inhibitors and Fc blockers were added after SLAMF8 knockdown, mouse macrophage phagocytosis, and FcR expression decreased. Our results suggest that SLAMF8 may impair FcR-mediated phagocytosis through the PI3K-Akt signaling pathway and negatively regulate the antitumor immune response.

INTRODUCTION:The study aimed to evaluate the stability and compatibility of diverse antibiotics in 7.5% icodextrin peritoneal dialysis (PD) solution, subjected to various temperatures over a span of 14-day period. METHODS:Antibiotics, namely, amikacin, imipenem, ciprofloxacin, vancomycin, and cefazolin, were incorporated into 7.5% icodextrin solution and subsequently stored at various temperature and period. The concentrations of these antibiotics were measured using high-performance liquid chromatography. Stability of antibiotics is defined as the remaining drug concentration >90% of the initial one throughout the test period. RESULTS:Ciprofloxacin and amikacin were demonstrated stable for a period of 14 days in icodextrin solution across all tested temperatures. Amikacin retained over 90% of its initial concentration when combined with either vancomycin, cefazolin, or ciprofloxacin at various temperatures for 14 days. In combination with amikacin, ciprofloxacin maintained stability for 14 days at all tested temperatures, while vancomycin maintained stability for 14 days at both 4°C and 25°C, and 7 days at 37°C. Cefazolin, however, only exhibited stability for 8 h at 37°C and 7 days at both 4°C and 25°C. The stability of imipenem in icodextrin solution was notably low, remaining stable for a maximum 6 h at 4°C. CONCLUSION:Ciprofloxacin, amikacin, as well as combinations of amikacin and vancomycin, amikacin and cefazolin, amikacin and ciprofloxacin, can be added to icodextrin solution for treatment of PD-associated peritonitis because they maintain stability for a minimum of 7 days at the temperatures of 4°C and 25°C, and 8 h at 37°C.

ObjectiveThis study aimed to determine the average intake of CoQ10 from dietary sources and explore the dose–response relationships between the dietary-derived CoQ10 intake and lipid profiles.MethodsWe performed a cross-sectional study based on the China Health and Nutrition Survey, which included 7,938 adults. The dietary intake assessment used three consecutive 24-h recalls combined with a household inventory. Serum was used for lipid profiling.ResultsThe average dietary-derived CoQ10 intake was 5.4 mg/day in Chinese adults. The dietary CoQ10 intake of the highest quartile (Q4 ≥ 6.96 mg/day) was negatively associated with total cholesterol (TC) [−0.12 (−0.19, −0.06) mmol/L], low-density lipoprotein cholesterol (LDL-C) [−0.17 (−0.23, −0.10) mmol/L], and non-high-density lipoprotein cholesterol (non-HDL-C) [−0.12 (−0.18, −0.05) mmol/L], while positively associated with apolipoprotein A-1 (ApoA1) [0.10 (0.08, 0.13) g/L] and triglycerides (TG) [0.14 (0.05, 0.23) mmol/L], compared to the lowest quartile (Q1 < 1.88 mg/day). Besides, dietary CoQ10 intake showed nonlinear dose–response associations with the above lipid variables (all Pnonlinear < 0.05).ConclusionDietary-derived CoQ10 intake may be associated with some lipid profiles, such as TG, ApoA1, TC, LDL-C, and non-HDL-C. However, CoQ10 from dietary sources may not be a good choice for individuals who need to CoQ10 supplement.

Background: The Global Diet Quality Score (GDQS) is a simple and practical dietary metric associated with a number of chronic diseases. The GDQS included various foods related to blood pressure, especially diverse plant -based foods that have shown to lower blood pressure. However, studies on the role of the GDQS in reducing the risk of new -onset hypertension and whether its performance differs from that of other dietary metrics are lacking. Objective: We aimed to examine the association between the GDQS and new -onset hypertension and to compare its performance with that of other dietary patterns, including the Plant -based Diet Index (PDI), alternate Mediterranean diet (aMED) score, Alternative Healthy Eating Index -2010, and Dietary Approaches to Stop Hypertension (DASH) score in Chinese adults. Methods: We included a total of 12,002 participants (5644 males and 6358 females) aged > 18 y from the China Health and Nutrition Survey (1997 - 2015). Dietary intake was estimated using average food intakes from 3 consecutive 24-h dietary recalls. Multivariable relative risks (RRs) were computed for hypertension using modi fi ed Poisson regression models. Results: With < 18 y of follow-up (mean 8.7 +/- 5.4 y), we ascertained 4232 incident cases of hypertension. Compared with participants with a low GDQS score ( < 15), the multivariable-adjusted RR of hypertension was 0.72 [95% con fi dence interval (CI): 0.62, 0.83] among participants with a high score ( >= 23). A 25% increment in the GDQS was associated with a 30% (RR, 0.70; 95% CI: 0.64, 0.76) lower risk of new -onset hypertension, which was comparable with the RRs of new -onset hypertension associated with every 25% increment in the PDI (RR, 0.84; 95% CI: 0.76, 0.93), DASH score (RR, 0.84; 95% CI: 0.78, 0.91), and aMED score (RR, 0.89; 95% CI: 0.84, 0.93). Conclusion: A higher GDQS was associated with a lower risk of new -onset hypertension, with comparable associations of new -onset hypertension with PDI, DASH, and aMED scores in Chinese adults.

Despite the approval of immune checkpoint blockade (ICB) therapy for various tumor types, its effectiveness is limited to only approximately 15% of patients with microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) colorectal cancer (CRC). Approximately 80%-85% of CRC patients have a microsatellite stability (MSS) phenotype, which features a rare T-cell infiltration. Thus, elucidating the mechanisms underlying resistance to ICB in patients with MSS CRC is imperative. In this study, we demonstrate that ubiquitin-specific peptidase 4 (USP4) is upregulated in MSS CRC tumors and negatively regulates the immune response against tumors in CRC. Additionally, USP4 represses the cellular interferon (IFN) response and antigen presentation and impairs PRR signaling-mediated cell death. Mechanistically, USP4 impedes the nuclear localization of interferon regulator Factor 3 (IRF3) by deubiquitinating the K63-polyubiquitin chain of TRAF6 and IRF3. Knockdown of USP4 enhances the infiltration of T cells in CRC tumors and overcomes ICB resistance in an MC38 syngeneic mouse model. Moreover, published datasets revealed that patients showing higher USP4 expression exhibited decreased responsiveness to anti-PD-L1 therapy. These findings highlight an essential role of USP4 in the suppression of antitumor immunity in CRC.

Preoperative neoadjuvant therapy is widely used in cancer treatment; however, its efficacy in different subtypes of non-small cell lung cancer (NSCLC) is unknown. The present study compared the clinical efficacy of preoperative neoadjuvant therapy for two major NSCLC subtypes. Patients with NSCLC who underwent preoperative neoadjuvant therapy between January 2016 and August 2022 were reviewed. Patients were stratified according to histology and treatment strategy. Retrospective analysis was performed by comparing the basic clinical characteristics of the patients, clinicopathological characteristics of the tumors, imaging data and pathological responses to treatment. A total of 36 cases of lung squamous cell carcinoma (LUSC) and 31 cases of lung adenocarcinoma (LUAD) were included. After neoadjuvant chemotherapy combined with immunotherapy, the pathological response rates were higher for patients with LUSC than LUAD, but there was no statistically significant difference between the two subgroups (P=0.06). However, the pathological complete response rates after neoadjuvant chemotherapy combined with immunotherapy were significantly higher for LUSC than those after chemotherapy alone (P=0.01). These preliminary findings suggested that preoperative chemotherapy combined with immunotherapy could improve the pathological response of patients, particularly in those with LUSC. The present study provided new insights into the treatment of NSCLC.

BACKGROUND:Long non-coding RNAs (lncRNAs) play important roles in the biology of colorectal cancer (CRC). There are several lncRNAs associated with invasion and metastasis have been characterized in CRC. However, studies focusing on the precise molecular mechanisms by which lncRNAs function in lymph node (LN) metastasis in CRC are still limited. METHODS:In this study, by analyzing TCGA dataset, we identified that AC244100.2 (termed CCL14-AS), a novel lncRNA enriched in the cytoplasm, was negatively correlated with LN metastasis and unfavorable prognosis of CRC. In situ hybridization was used to examine CCL14-AS expression in clinical CRC tissues. Various functional experiments including migration assay and wound-healing assay were used to investigate the effects of CCL14-AS on CRC cells migration. The nude mice popliteal lymph node metastasis model assay further confirmed the effects of CCL14-AS in vivo. RESULTS:CCL14-AS expression was significantly downregulated in CRC tissues compared to adjacent normal tissues. In addition, low CCL14-AS expression was correlated with advanced T classification, LN metastasis, distant metastasis, and shorter disease-free survival of CRC patients. Functionally, CCL14-AS overexpression inhibited the invasiveness of CRC cells in vitro and LN metastasis in nude mice. On the contrary, knockdown of CCL14-AS promoted the invasiveness and LN metastasis abilities of CRC cells. Mechanistically, CCL14-AS downregulated the expression of MEP1A via interacting with MEP1A mRNA and reduced its stability. Overexpression of MEP1A rescued the invasiveness and LN metastasis abilities in CCL14-AS-overexpressing CRC cells. Moreover, the expression levels of CCL14-AS was negatively correlated with that of MEP1A in CRC tissues. CONCLUSIONS:We identified a novel lncRNA, CCL14-AS, as a potential tumor suppressor in CRC. Our findings supported a model in which the CCL14-AS/MEP1A axis serves as critical regulator in CRC progression, suggesting a novel biomarker and therapeutic target in advanced CRC.

To the Editor, We thank Dr. Modarressi and Dr. Derakhshan (1) for their interest in our recent publication (2). We appreciate their suggestion and respond to their letter here. In our article, we primarily found the beneficial effects of coenzyme Q10 (CoQ10) supplementation on lipid profiles. The main concern of Dr. Modarressi and Dr. Derakhshan was the potential effect of CoQ10 supplementation on cardiovascular diseases (CVDs) by reducing low-density lipoprotein cholesterol (LDL-C). In the Discussion section, we combined the relative risk reduction value obtained by the 2005 Cholesterol Treatment Trialists’ Collaboration data (3) with our results to explore the potential effect of CoQ10 supplementation on coronary mortality by reducing LDL-C. As Dr. Modarressi and Dr. Derakhshan mentioned, the relative risk reduction may be relatively low, but we believe that any significant effect of the nutritional supplements, such as CoQ10, should not be ignored at a population level because it could be used as daily supplement with minor side effects (4) compared with some drugs.

Background Immune checkpoint inhibitor-related myocarditis is the deadliest complication of immunotherapy. However, the underlying pathophysiological mechanisms of its occurrence and development remain unclear. Due to the long-term lack of effective early diagnosis and treatment options, it is of great significance to understand the pathophysiological mechanism of immune checkpoint inhibitor-related myocarditis. Methods Tissue samples from three patients with immune checkpoint inhibitor-related myocarditis and three control tissue samples were collected for protein analysis. Differentially expressed proteins were screened out using quantitative proteomics technology based on TMT markers. Protein–protein interaction (PPI) and Gene Ontology (GO) functional enrichment analyses of cross-factors were subsequently performed. Combined with the PD-L1 subcellular organelle- level protein interaction network, we searched for hub proteins involved in immune checkpoint inhibitor-related myocarditis and explored potential drug sensitivity and disease correlation. Results A total of 306 differentially expressed proteins were identified in immune checkpoint inhibitor-related myocarditis. Enrichment analysis showed that the differentially expressed proteins were closely related to mitochondrial metabolism. By analyzing mitochondria-related proteins and PD-L1-related proteins, we found four hub proteins, mammalian target of rapamycin (mTOR), Glycogen synthase kinase 3β (GSK3β), Protein tyrosine phosphatase non-receptor type 11 (PTPN11), and Mitofusin 2 (MFN2), indicating that they are closely related to immune checkpoint inhibitor-related myocarditis. Finally, we explored potential drugs for the treatment of immune checkpoint inhibitor-related myocarditis. Conclusion Mitochondrial metabolism is involved in the process of immune checkpoint inhibitor-related myocarditis, and we identified four hub proteins, which may become new biomarkers for the early diagnosis and treatment of immune checkpoint inhibitor-related myocarditis.

Aims: A growing body of evidence demonstrates that Stress granules (SGs), a non-membrane cytoplasmic compartments, are important to colorectal development and chemoresistance. However, the clinical and pathological significance of SGs in colorectal cancer (CRC) patients is unclear. The aim of this study is to propose a new prognostic model related to SGs for CRC on the basis of transcriptional expression. Main methods: Differentially expressed SGs-related genes (DESGGs) were identified in CRC patients from TCGA dataset by limma R package. The univariate and Multivariate Cox regression model was used to construct a SGs-related prognostic prediction gene signature (SGPPGS). The CIBERSORT algorithm was used to assess cellular immune components between the two different risk groups. The mRNA expression levels of the predictive signature from 3 partial response (PR) and 6 stable disease (SD) or progress disease (PD) after neoadjuvant therapy CRC patients’ specimen were examined. Key findings: By screening and identification, SGPPGS comprised of four genes (CPT2, NRG1, GAP43, and CDKN2A) from DESGGs is established. Furthermore, we find that the risk score of SGPPGS is an independent prognostic factor to overall survival. Notably, the abundance of immune response inhibitory components in tumor tissues is upregulated in the group with a high-risk score of SGPPGS. Importantly, the risk score of SGPPGS is associated with the chemotherapy response in metastatic colorectal cancer. Significance: This study reveals the association between SGs related genes and CRC prognosis and provides a novel SGs related gene signature for CRC prognosis prediction.

Sepsis or endotoxemia can induce intestinal dysfunction in the epithelial and immune barrier. Th17 cells, a distinct subset of CD4+ T-helper cells, act as “border patrol” in the intestine under pathological condition and in the previous studies, Th17 cells exhibited an ambiguous function in intestinal inflammation. Our study will explore a specific role of Th17 cells and its relevant mechanism in endotoxemia-induced intestinal injury. Lipopolysaccharide was used to establish mouse model of endotoxemia. miR-681 was analyzed by RT-PCR and northern blot analysis and its regulation by HIF-1α was determined by chromatin immunoprecipitation and luciferase reporter assay. Intestinal Th17 cells isolated from endotoxemic mice were quantitatively evaluated by flow cytometry and its recruitment to the intestine controlled by miR-681/CCR6 pathway was assessed by using anti-miRNA treatment and CCR6 knockout mice. Intestinal histopathology, villus length, intestinal inflammation, intestinal permeability, bacterial translocation and survival were investigated, by histology and TUNEL analysis, ELISA, measurement of diamine oxidase, bacterial culture, with or without anti-miR-681 treatment in endotoxemic wild-type and (or) CCR6 knockout mice. In this study, we found that miR-681 was significantly promoted in intestinal Th17 cells during endotoxemia, which was dependent on hypoxia-inducible factor-1α (HIF-1α). Interestingly, miR-681 could directly suppress CCR6, which was a critical modulator for Th17 cell recruitment to the intestines. In vivo, anti-miR-681 enhanced survival, increased number of intestinal Th17 cells, reduced crypt and villi apoptosis, decreased intestinal inflammation and bacterial translocation, resulting in protection against endotoxemia-induced intestinal injury in mice. However, CCR6 deficiency could neutralize the beneficial effect of anti-miR-681 on the intestine during endotoxemia, suggesting that the increment of intestinal Th17 cells caused by anti-miR-681 relies on CCR6 expression. The results of the study indicate that control of intestinal Th17 cells by regulating novel miR-681/CCR6 signaling attenuates endotoxemia-induced intestinal injury.

ScopeCoenzyme Q10 (CoQ10) has become a popular nutritional supplement due to its wide range of beneficial biological effects. Previous meta‐analyses show that the attenuation of CoQ10 on inflammatory biomarkers remains controversial. This meta‐analysis aims to assess the efficacy and optimal dose of CoQ10 supplementation on inflammatory indicators in the general population.Methods and resultsDatabases are searched up to December 2022 resulting in 6713 articles, of which 31 are retrieved for full‐text assessment and included 1517 subjects. Double‐blind randomized controlled trials (RCTs) of CoQ10 supplementation are eligible if they contain C reactive protein (CRP), interleukin‐6 (IL‐6), and tumor necrosis factor‐α (TNF‐α). CoQ10 supplementation can significantly reduce the levels of circulating CRP (SMD: −0.40, 95% CI: [−0.67 to −0.13], p = 0.003), IL‐6 (SMD: −0.67, 95% CI: [−1.01 to −0.33], p < 0.001), and TNF‐α (SMD: −1.06, 95% CI: [−1.59 to −0.52], p < 0.001) and increase the concentration of circulating CoQ10.ConclusionThis meta‐analysis provides evidence for CoQ10 supplementation to reduce the level of inflammatory mediators in the general population and proposes that daily supplementation of 300–400 mg CoQ10 show superior inhibition of inflammatory factors.

As the most common malignancy from mediastinum, the metabolic reprogramming of thymoma is important in its development. Nevertheless, the connection between the metabolic map and thymoma development is yet to be discovered. Thymoma was categorized into three subcategories by unsupervised clustering of molecular markers for metabolic pathway presentation in the TCGA dataset. Different genes and functions enriched were demonstrated through the utilization of metabolic Gene Ontology (GO) analysis. To identify the main contributors in the development of thymic malignancy, we utilized Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The prognosis of thymoma was evaluated by screening the essential pathways and genes using GSVA scores and machine learning classifiers. Furthermore, we integrated the transcriptomics findings with spectrum metabolomics investigation, detected through LC-MS/MS, in order to establish the essential controller network of metabolic reprogramming during thymoma progression. The thymoma prognosis is related to glycosphingolipid biosynthesis-lacto and neolacto series pathway, of what high B3GNT5 indicate poor survival. The investigation revealed that glycosphingolipid charts have a significant impact on metabolic dysfunction and could potentially serve as crucial targets in the clinical advancement of metabolic therapy.

The number of circulating endothelial progenitor cells (EPCs) was found to increase in patients with breast cancer, but the alteration in EPC function remains to be elusive. We conducted this study to evaluate the number and function of peripheral EPCs of breast cancer patients and its possible underlying mechanism. Besides, the vascular endothelial growth factor (VEGF), VCAM-1, IL-6, and IL-34 levels were measured in blood samples and also in vitro in a medium of EPCs. We found that the number of circulating EPCs in breast cancer patients was significantly higher than that in normal control and remarkably augmented in a stage-dependent manner. Meanwhile, a similar enhancement was observed in the migratory, proliferative, and adhesive activity of circulating EPCs originating from breast cancer patients. More importantly, the VEGF level in blood samples was dramatically elevated in comparison to the control, which was correlated positively with the number and activity of circulating EPCs from breast cancer patients. Moreover, in vitro medium of EPCs from breast cancer patients highly expressed VEGF compared with that from the control, which also had a positive correlation with the number and activity of circulating EPCs from breast cancer patients. This is the first time to demonstrate that the number and function of circulating EPCs are promoted in breast cancer patients, which are positively related to an enhanced VEGF production. These may provide a novel target for improving the outcome of breast cancer.

Previous studies have shown beneficial effects of coenzyme Q10 (CoQ10) supplementation on blood pressure (BP). However, the optimal intake of CoQ10 for BP regulation in patients with cardiometabolic disorders is unknown, and its effect on circulating CoQ10 is also unclear. We aimed to assess the dose-response relation between CoQ10 and BP, and quantify the effect of CoQ10 supplementation on the concentration of circulating CoQ10 by synthesizing available evidence from randomized controlled trials (RCTs). A comprehensive literature search was performed in 3 databases (PubMed/MEDLINE, Embase, and Cochrane Library) to 21 March, 2022. A novel 1-stage restricted cubic spline regression model was used to evaluate the nonlinear dose-response relation between CoQ10 and BP. Twenty-six studies comprising 1831 subjects were included in our meta-analysis. CoQ10 supplementation significantly reduced systolic blood pressure (SBP) (-4.77 mmHg, 95% CI: -6.57, -2.97) in patients with cardiometabolic diseases; this reduction was accompanied by a 1.62 (95% CI: 1.26, 1.97) mu g/mL elevation of circulating CoQ10 compared with the control group. Subgroup analyses revealed that the effects of reducing SBP were more pronounced in patients with diabetes and dyslipidemia and in studies with longer durations (>12 wk). Importantly, a U-shaped dose-response relation was observed between CoQ10 supplementation and SBP level, with an approximate dose of 100-200 mg/d largely reducing SBP (chi(2) = 10.84, P-nonlinearity = 0.004). The quality of evidence was rated as moderate, low, and very low for SBP, diastolic blood pressure (DBP), and circulating CoQ10 according to the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE), respectively. The current finding demonstrated that the clinically beneficial effects of CoQ10 supplementation may be attributed to the reduction in SBP, and 100-200 mg/d of CoQ10 supplementation may achieve the greatest benefit on SBP in patients with cardiometabolic diseases. This study was registered on PROSPERO as CRD42021252933. Statement of Significance: This systematic review and meta-analysis provided a recommended dose of 100-200 mg/d to achieve the greatest benefit in the regulation of blood pressure in patients with cardiometabolic diseases.