Correlation between vitamin D levels and blood pressure in elderly hypertensive patients with osteoporosis.

Objectives: The association between vitamin D and blood pressure in elderly patients with hypertension complicated by osteoporosis remains unclear. The objective of this study is to explore whether vitamin D deficiency contributes to elevated blood pressure in elderly individuals with both hypertension and osteoporosis. Methods: This study represents a single-center retrospective observational investigation carried out at the Zhongshan Hospital Affiliated to Xiamen University. Ambulatory blood pressure, bone density, vitamin D levels, and additional laboratory parameters were collected upon admission. The association between vitamin D and ambulatory blood pressure outcomes was assessed using Spearman correlation tests and partial correlation analyses. The relationship between vitamin D and changes in blood pressure was analyzed through Generalized Additive Models, and threshold analysis was conducted to explore potential thresholds. Results: 139 patients with newly diagnosed osteoporosis were consecutively included (mean age 73 years, 84.9% female). There is a negative correlation between 25-(OH) D3 and 24 h mean systolic blood pressure (mSBP), diurnal mSBP, nocturnal mSBP, maximum SBP, respectively. The results of the generalized additive model analysis show that there is a nonlinear relationship between 25-(OH) D3 and 24 h mSBP, diurnal mSBP, nocturnal mSBP, respectively. After determining the critical point of 25-(OH) D3 as 42 nmol/L, a segmented linear regression model was used to calculate the effect size and 95% confidence interval on both sides of the critical point. When 25-(OH) D3 is ≤42 nmol/L, it significantly negatively correlates with 24 h, diurnal, and nocturnal mean SBP. Conversely, when 25-(OH) D3 exceeds 42 nmol/L, there is no statistically significant association with 24 h, diurnal, or nocturnal mSBP. Conclusion: There was a significant negative correlation between vitamin D levels and blood pressure levels in elderly patients with hypertension and osteoporosis.

Organoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization.

Intestinal organoid transplantation is a promising therapy for the treatment of mucosal injury. However, how the transplanted organoids regulate the immune microenvironment of recipient mice and their role in treating intestinal ischemia-reperfusion (I/R) injury remains unclear. Here, we establish a method for transplanting intestinal organoids into intestinal I/R mice. We find that transplantation improve mouse survival, promote self-renewal of intestinal stem cells and regulate the immune microenvironment after intestinal I/R, depending on the enhanced ability of macrophages polarized to an anti-inflammatory M2 phenotype. Specifically, we report that L-Malic acid (MA) is highly expressed and enriched in the organoids-derived conditioned medium and cecal contents of transplanted mice, demonstrating that organoids secrete MA during engraftment. Both in vivo and in vitro experiments demonstrate that MA induces M2 macrophage polarization and restores interleukin-10 levels in a SOCS2-dependent manner. This study provides a therapeutic strategy for intestinal I/R injury.

Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling.

Intestinal ischemia/reperfusion (I/R) injury is a severe clinical condition without optimal diagnostic markers nor clear molecular etiological insights. Plasma exosomal circular RNAs (circRNAs) are valuable biomarkers and therapeutic targets for various diseases, but their role in intestinal I/R injury remains unknown. Here we screen the expression profile of circRNAs in intestinal tissue exosomes collected from intestinal I/R mice and identify circEZH2_005 as a significantly downregulated exosomal circRNA. In parallel, circEZH2_005 is also reduced in the plasma of clinical cardiac surgery patients who developed postoperative intestinal I/R injury. Exosomal circEZH2_005 displays a significant diagnostic value for intestinal injury induced by I/R. Mechanistically, circEZH2_005 is highly expressed in intestinal crypt cells. CircEZH2_005 upregulation promotes the proliferation of Lgr5+ stem cells by direct interaction with hnRNPA1, and enhanced Gprc5a stability, thereby alleviating I/R-induced intestinal mucosal damage. Hence, exosomal circEZH2_005 may serve as a biomarker for intestinal I/R injury and targeting the circEZH2_005/hnRNPA1/Gprc5a axis may be a potential therapeutic strategy for intestinal I/R injury.

Gut microbe-derived milnacipran enhances tolerance to gut ischemia/reperfusion injury.

There are significant differences in the susceptibility of populations to intestinal ischemia/reperfusion (I/R), but the underlying mechanisms remain elusive. Here, we show that mice exhibit significant differences in susceptibility to I/R-induced enterogenic sepsis. Notably, the milnacipran (MC) content in the enterogenic-sepsis-tolerant mice is significantly higher. We also reveal that the pre-operative fecal MC content in cardiopulmonary bypass patients, including those with intestinal I/R injury, is associated with susceptibility to post-operative gastrointestinal injury. We reveal that MC attenuates mouse I/R injury in wild-type mice but not in intestinal epithelial aryl hydrocarbon receptor (AHR) gene conditional knockout mice (AHRflox/flox) or IL-22 gene deletion mice (IL-22-/-). Collectively, our results suggest that gut microbiota affects susceptibility to I/R-induced enterogenic sepsis and that gut microbiota-derived MC plays a pivotal role in tolerance to intestinal I/R in an AHR/ILC3/IL-22 signaling-dependent manner, revealing the pathological mechanism, potential prevention and treatment drugs, and treatment strategies for intestinal I/R.

Pedestrian Detection by Exemplar-Guided Contrastive Learning.

Typical methods for pedestrian detection focus on either tackling mutual occlusions between crowded pedestrians, or dealing with the various scales of pedestrians. Detecting pedestrians with substantial appearance diversities such as different pedestrian silhouettes, different viewpoints or different dressing, remains a crucial challenge. Instead of learning each of these diverse pedestrian appearance features individually as most existing methods do, we propose to perform contrastive learning to guide the feature learning in such a way that the semantic distance between pedestrians with different appearances in the learned feature space is minimized to eliminate the appearance diversities, whilst the distance between pedestrians and background is maximized. To facilitate the efficiency and effectiveness of contrastive learning, we construct an exemplar dictionary with representative pedestrian appearances as prior knowledge to construct effective contrastive training pairs and thus guide contrastive learning. Besides, the constructed exemplar dictionary is further leveraged to evaluate the quality of pedestrian proposals during inference by measuring the semantic distance between the proposal and the exemplar dictionary. Extensive experiments on both daytime and nighttime pedestrian detection validate the effectiveness of the proposed method.

Gut microbiota dysbiosis is associated with sepsis-induced cardiomyopathy in patients: A case-control study.

BACKGROUND: Myocardial injury is a major complication of sepsis and a key factor affecting prognosis. Therefore, early and accurate diagnosis and timely management of sepsis-induced cardiomyopathy (SICM) are of great significance for the prevention and treatment of sepsis. The gut microbiota has been shown to be closely associated with sepsis or myocardial injury, but the association between the gut microbiota and SICM is not fully understood. This study aimed to explore the link between gut microbiota composition and SICM. METHODS: A case-control and single-center study of clinical features and gut microbiota profiles by Metagenome and Virome was conducted in SICM patients (n = 15) and sepsis-uninduced cardiomyopathy patients (SNICM, n = 16). RESULTS: Compared with SNICM patients, SICM patients showed significant myocardial injury and higher 28-day mortality, SOFA scores, lactate levels, and infection levels on admission. Meanwhile, differences in the composition of gut bacteria, archaea, fungi, and viruses were analyzed between the two groups. Differential gut bacteria or viruses were found to have a good predictive effect on SICM. Furthermore, gut bacteria and viruses that differed between the two groups were strongly related. The abundance of Cronobacter and Cronobacter phage was higher in the SICM group than in the SNICM group, and the receiver operating characteristic curve showed that Cronobacter and Cronobacter phage both had a good predictive effect on SICM. CONCLUSIONS: SICM patients may have specific gut microbiota signatures, and Cronobacter and Cronobacter phages have a good ability to identify and diagnose SICM.

[Comparison on volatile components between Artemisiae Verlotori Folium and Artemisiae Argyi Folium based on GC-MS and chemometrics].

Artemisiae Argyi Folium is commonly used in clinical practice. Artemisiae Verlotori Folium, the dried leaves of Artemisia verlotorum, is often used as a folk substitute for Artemisiae Argyi Folium in Lingnan area. In this study, gas chromatography-triple quadrupole mass spectrometry(GC-MS) was used to detect the volatile oil components of 27 samples of Artemisiae Verlotori Folium and 13 samples of Artemisiae Argyi Folium, and the volatile components were compared between the two species. The internal standard method was combined with multi-reaction monitoring mode(MRM) to determine the content of six major volatile components. Hierarchical clustering analysis(HCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were carried out for the content data. The results showed that the Artemisiae Argyi Folium samples had higher content and more abundant volatile oils than the Artemisiae Verlotori Folium samples. Artemisiae Argyi Folium mainly had the components with lower boiling points, while Artemisiae Verlotori Folium mainly had the components with higher boiling points. Terpenoids were the main volatile components in Artemisiae Verlotori Folium(mainly sesquiterpenoids) and Artemisiae Argyi Folium(monoterpenoids). In addition, Artemisiae Argyi Folium had higher content of oxygen-containing derivatives than Artemisiae Verlotori Folium. Furthermore, the stoichiometric analysis showed that the two species could be distinguished by both HCA and OPLS-DA, indicating that the volatile components of the two were significantly different. This study can provide a scientific basis for the quality evaluation and data support for the local rational application of Artemisiae Verlotori Folium in Lingnan.

The incidence and mortality rate of catheter-related neonatal pericardial effusion: A meta-analysis.

BACKGROUD: Neonatal pericardial effusion (PCE) is one of the most severe complications of central catheters in neonates with its rapid progression and high mortality. We aim to estimate the overall incidence and mortality of catheter-related neonatal PCE, more importantly, to identify possible predictors for clinical reference. METHODS: We searched MEDLINE, Embase, Cochrane Library, Web of Science, china national knowledge infrastructure, Wanfang Data, and Sinomed databases for subject words "central catheter," "neonate," "pericardial effusion" and their random words till June 8, 2020. This meta-analysis is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Possible predictors of occurrences and deaths were extracted and assessed cooperatively. The pooled incidence rate of catheter-related neonatal PCE was calculated using a random effects model. RESULTS: Twenty-one cohort studies and 99 cases were eligible. Pooled incidence is 3·8‰[2.2‰, 6.7‰]. Polyurethane catheters generate significantly more neonatal PCE than silicone counterparts (P < .01). 27% of the patients die. The mortality of patients with bradycardia is higher than others (P < .05). Catheters with a guidewire result in more deaths than umbilical venous catheter (UVC) and peripherally inserted central catheters (PICC) (P < .05). Without pericardiocentesis, mortality increases (P < .01). The difference of deaths between reposition and removing the catheter is insignificant (P > .05). CONCLUSION: Central catheters in Seldinger Technique (with a guidewire) put neonates at greater risk of PCE and consequent death. Silicone catheters excel at avoiding deadly catheter-related PCE, which could be a better choice in neonatal intensive care units (NICU). When catheter-related PCE occurs, timely diagnosis and pericardiocentesis save lives.

The MELD-XI score predicts 3-year mortality in patients with chronic heart failure.

Objectives: The relationship between the MELD-XI score, a modified version of the MELD score, and the long-term prognosis of hospitalized patients with chronic heart failure is unclear. The aim of this study was to determine the long-term prognostic relationship of MELD-XI score in patients with chronic heart failure. Methods: This is a retrospective cohort study of patients with chronic heart failure who were initially hospitalized in the Second Affiliated Hospital of Chongqing Medical University from February 2017 to December 2017. The primary clinical outcome was all-cause mortality within 3 years. Cox regression and lasso regression were used to screen variables and build a prognostic model. Combined with the MELD-XI score, the final model was adjusted, and the predictive ability of the model was evaluated. Survival curves were estimated using the Kaplan-Meier method and compared by the log rank test. Results: A total of 400 patients with chronic heart failure were included (median age 76 years, 51.5% female). During the 3-year follow-up period, there were 97 all-cause deaths, including 63 cardiac deaths. Six characteristic variables (NT-proBNP, BUN, RDW CV, Na+ and prealbumin) were selected by univariate Cox regression and lasso regression. Survival analysis results showed that elevated MELD-XI score at baseline predicted the risk of all-cause mortality at 3 years in patients (HR 3.19, 95% CI 2.11-4.82, P < 0.001; HRadjusted 1.79, 95% CI 1.09-2.92, P = 0.020). Subgroup analysis showed that MELD-XI score still had prognostic value in the subgroup without chronic kidney disease (HR 3.30 95%CI 2.01-5.42 P < 0.001; HRadjusted 1.88 95%CI 1.06-3.35 P = 0.032, P for interaction = 0.038). Conclusions: This study proved that the MELD-XI score at admission was related to the poor prognosis of hospitalized patients with chronic heart failure within 3 years.

The role of intestinal microbiota and its metabolites in intestinal and extraintestinal organ injury induced by intestinal ischemia reperfusion injury.

Intestinal ischemia/reperfusion (I/R) is a common pathophysiological process in clinical severe patients, and the effect of intestinal I/R injury on the patient's systemic pathophysiological state is far greater than that of primary intestinal injury. In recent years, more and more evidence has shown that intestinal microbiota and its metabolites play an important role in the occurrence, development, diagnosis and treatment of intestinal I/R injury. Intestinal microbiota is regulated by host genes, immune response, diet, drugs and other factors. The metabolism and immune potential of intestinal microbiota determine its important significance in host health and diseases. Therefore, targeting the intestinal microbiota and its metabolites may be an effective therapy for the treatment of intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury. This review focuses on the role of intestinal microbiota and its metabolites in intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury, and summarizes the latest progress in regulating intestinal microbiota to treat intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury.

De novo assembly of the complete mitochondrial genome of sweet potato (Ipomoea batatas [L.] Lam) revealed the existence of homologous conformations generated by the repeat-mediated recombination.

Sweet potato (Ipomoea batatas [L.] Lam) is an important food crop, an excellent fodder crop, and a new type of industrial raw material crop. The lack of genomic resources could affect the process of industrialization of sweet potato. Few detailed reports have been completed on the mitochondrial genome of sweet potato. In this research, we sequenced and assembled the mitochondrial genome of sweet potato and investigated its substructure. The mitochondrial genome of sweet potato is 270,304 bp with 23 unique core genes and 12 variable genes. We detected 279 pairs of repeat sequences and found that three pairs of direct repeats could mediate the homologous recombination into four independent circular molecules. We identified 70 SSRs in the whole mitochondrial genome of sweet potato. The longest dispersed repeat in mitochondrial genome was a palindromic repeat with a length of 915 bp. The homologous fragments between the chloroplast and mitochondrial genome account for 7.35% of the mitochondrial genome. We also predicted 597 RNA editing sites and found that the rps3 gene was edited 54 times, which occurred most frequently. This study further demonstrates the existence of multiple conformations in sweet potato mitochondrial genomes and provides a theoretical basis for the evolution of higher plants and cytoplasmic male sterility breeding.

Lactobacillus murinus alleviate intestinal ischemia/reperfusion injury through promoting the release of interleukin-10 from M2 macrophages via Toll-like receptor 2 signaling.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury has high morbidity and mortality rates. Gut microbiota is a potential key factor affecting intestinal I/R injury. Populations exhibit different sensitivities to intestinal I/R injury; however, whether this interpopulation difference is related to variation in gut microbiota is unclear. Here, to elucidate the interaction between the gut microbiome and intestinal I/R injury, we performed 16S DNA sequencing on the preoperative feces of C57BL/6 mice and fecal microbiota transplantation (FMT) experiments in germ-free mice. The transwell co-culture system of small intestinal organoids extracted from control mice and macrophages extracted from control mice or Toll-like receptor 2 (TLR2)-deficient mice or interleukin-10 (IL-10)-deficient mice were established separately to explore the potential mechanism of reducing intestinal I/R injury. RESULTS: Intestinal I/R-sensitive (Sen) and intestinal I/R-resistant (Res) mice were first defined according to different survival outcomes of mice suffering from intestinal I/R. Fecal microbiota composition and diversity prior to intestinal ischemia differed between Sen and Res mice. The relative abundance of Lactobacillus murinus (L. murinus) at the species level was drastically higher in Res than that in Sen mice. Clinically, the abundance of L. murinus in preoperative feces of patients undergoing cardiopulmonary bypass surgery was closely related to the degree of intestinal I/R injury after surgery. Treatment with L. murinus significantly prevented intestinal I/R-induced intestinal injury and improved mouse survival, which depended on macrophages involvement. Further, in vitro experiments indicated that promoting the release of IL-10 from macrophages through TLR2 may be a potential mechanism for L. murinus to reduce intestinal I/R injury. CONCLUSION: The gut microbiome is involved in the postoperative outcome of intestinal I/R. Lactobacillus murinus alleviates mice intestinal I/R injury through macrophages, and promoting the release of IL-10 from macrophages through TLR2 may be a potential mechanism for L. murinus to reduce intestinal I/R injury. This study revealed a novel mechanism of intestinal I/R injury and a new therapeutic strategy for clinical practice. Video Abstract.

Blood urea nitrogen to serum albumin ratio as a new prognostic indicator in critical patients with chronic heart failure.

AIMS: Chronic heart failure (CHF) is often a common comorbidity in critically ill patients admitted to the intensive care unit (ICU) and carries an extremely poor prognosis. The study aimed to investigate the relationship between the blood urea nitrogen to serum albumin ratio (BAR) and the prognosis of patients with CHF admitted to the ICU. METHODS AND RESULTS: This retrospective cohort study included 1545 critically ill patients with CHF as a diagnosed comorbidity admitted to the ICU deposited in the MIMIC-III database, of whom 90 day all-cause mortality was 27.6% (n = 427) and in-hospital mortality was 17.3% (n = 267). The results of multiple logistic regression analysis indicated that BAR is an independent risk factor for in-hospital mortality in critically ill patients with CHF [compared with BAR ≤ 0.83; 0.83 < BAR ≤ 1.24: odds ratio (OR) 2.647, 95% confidence interval (CI) 1.797-3.900, P < 0.001; BAR ≥ 1.24: OR 3.628, 95% CI 2.604-5.057, P < 0.001]. Multiple COX regression analysis found a relationship between BAR and all-cause mortality at 90 day follow-up (0.83 < BAR ≤ 1.24: OR 1.948, 95% CI 1.259-3.014, P < 0.003; BAR ≥ 1.24: OR 1.807, 95% CI 1.154-2.830, P < 0.01; BAR ≤ 0.83 as a reference). Kaplan-Meier curves also showed similar results as well (P < 0.001). The areas under the receiver operating characteristic curves for predicting in-hospital mortality and 90 day all-cause mortality were 0.622 and 0.647, respectively. CONCLUSIONS: BAR is an independent risk factor for in-hospital mortality and 90 day mortality in critically ill patients with CHF admitted to the ICU.

Propionate alleviates myocardial ischemia-reperfusion injury aggravated by Angiotensin II dependent on caveolin-1/ACE2 axis through GPR41.

Myocardial ischemia/reperfusion (I/R) injury is still a lack of effective therapeutic drugs, and its molecular mechanism is urgently needed. Studies have shown that the intestinal flora plays an important regulatory role in cardiovascular injury, but the specific mechanism has not been fully elucidated. In this study, we found that an increase in Ang II in plasma was accompanied by an increase in the levels of myocardial injury during myocardial reperfusion in patients with cardiopulmonary bypass. Furthermore, Ang II treatment enhanced mice myocardial I/R injury, which was reversed by caveolin-1 (CAV-1)-shRNA or strengthened by angiotensin-converting enzyme 2 (ACE2)-shRNA. The results showed that CAV-1 and ACE2 have protein interactions and inhibit each other's expression. In addition, propionate, a bacterial metabolite, inhibited the elevation of Ang II and myocardial injury, while GPR41-shRNA abolished the protective effects of propionate on myocardial I/R injury. Clinically, the propionate content in the patient's preoperative stool was related to Ang II levels and myocardial I/R injury levels during myocardial reperfusion. Taken together, propionate alleviates myocardial I/R injury aggravated by Ang II dependent on CAV-1/ACE2 axis through GPR41, which provides a new direction that diet to regulate the intestinal flora for treatment of myocardial I/R injury.

Gut Microbial Metabolite Pravastatin Attenuates Intestinal Ischemia/Reperfusion Injury Through Promoting IL-13 Release From Type II Innate Lymphoid Cells via IL-33/ST2 Signaling.

Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.

Gamma-Glutamyl Transpeptidase to Platelet Ratio: A New Inflammatory Marker Associated with Outcomes after Cardiac Arrest.

INTRODUCTION: In recent years, gamma-glutamyl transpeptidase to platelet ratio (GPR) has been proposed as a new inflammatory marker. We aimed to evaluate the association between GPR and outcomes after cardiac arrest (CA). METHODS: A total of 354 consecutive patients with CA were included in this retrospective study. Patients were divided into three groups according to tertiles of GPR (low, n = 119; middle, n = 117; and high, n = 118). To determine the relationship between GPR and prognosis, a logistic regression analysis was performed. The ability of GPR to predict the outcomes was evaluated by receiver operating characteristic (ROC) curve analysis. Two prediction models were established, and the likelihood ratio test (LRT) and the Akaike Information Criterion (AIC) were utilized for model comparison. RESULTS: Among the 354 patients (age 62 [52, 74], 254/354 male) who were finally included in the analysis, those in the high GPR group had poor outcomes. Multivariate logistic regression analysis revealed that GPR was independently associated with the three outcomes, for ICU mortality (odds ratios (OR) = 1.738, 95% confidence interval (CI): 1.221-2.474, P = 0.002), hospital mortality (OR = 1.676[1.164 - 2.413], P = 0.005), and unfavorable neurologic outcomes (OR = 1.623[1.121 - 2.351], P = 0.010). The area under the ROC curve was 0.611 (95% Cl: 0.558-0.662) for ICU mortality, 0.600 (95% CI: 0.547-0.651) for hospital mortality, and 0.602 (95% CI: 0.549-0.653) for unfavorable neurologic outcomes. Further, the LRT analysis showed that compared with the model without GPR, the GPR-combined model had a higher likelihood ratio χ 2 score and smaller AIC. CONCLUSION: GPR, as an inflammatory indicator, was independently associated with outcomes after CA. GPR is helpful in estimating the clinical outcomes of patients with CA.

Sitagliptin on carotid intima-media thickness in type 2 diabetes and hyperuricemia patients: a subgroup analysis of the PROLOGUE study.

BACKGROUND AND AIMS: Studies have shown that dipeptidyl peptidase-4 (DDP-4) inhibitors have anti-atherosclerotic effects. However, in the PROLOGUE study, sitagliptin failed to slow the progression of carotid intima-media thickness (CIMT) relative to conventional therapy. We conducted a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in CIMT in subgroups with or without hyperuricemia. METHODS: The PROLOGUE study was a randomized controlled trial of 442 patients with type 2 diabetes mellitus (T2DM). Patients were randomized to receive sitagliptin added therapy or conventional therapy. Based on the serum uric acid levels of all study populations in the PROLOGUE study, we divided them into hyperuricemia subgroup (n = 104) and non-hyperuricemia subgroup (n = 331). The primary outcome was changed in carotid intima-media thickness (CIMT) parameters compared with baseline during the 24 months treatment period. RESULTS: In the hyperuricemia subgroup, compared with the conventional therapy group, the changes in the mean internal carotid artery (ICA)-IMT and max ICA-IMT at 24 months were significantly lower in the sitagliptin group [-0.233 mm, 95% confidence interval (CI) (-0.419 to 0.046), p = 0.015 and -0.325 mm, 95% CI (-0.583 to -0.068), p = 0.014], although there was no significant difference in the common carotid artery CIMT. CONCLUSION: The results of our analysis indicated that sitagliptin attenuated the progression of CIMT than conventional therapy in T2DM and hyperuricemia patients.

An efficient and label-free LC-MS/MS method for assessing drug's activity at dopamine and serotonin transporters using transporter-transfected HEK293T cells.

BACKGROUND: Dopamine transporter (DAT) and serotonin transporter (SERT) are targets for many psychoactive substances. Functional assays including uptake inhibition and release assays often involve radiolabeled compounds like [3H]-dopamine and [3H]-serotonin to assess drug activity at transporters, which have high requirements on handling radioactive samples. AIMS: The aim of this study was to establish a label-free method to assess drug activity at DAT and SERT. METHODS: A liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was established using transporter-transfected human embryonic kidney 293T (HEK293T) cells. This method was evaluated by testing the effects of amphetamine and cocaine in the assay procedure. RESULTS: The limits of detection of this method were 0.2 nM for both dopamine (DA) and serotonin (5-HT), with good linearities in the range of 0.5-160 nM. Amphetamine and cocaine's IC50 and EC50 on DAT and SERT determined by this method were consistent with previous reports. CONCLUSIONS: A rapid, reliable and label-free LC-MS/MS method for assessing drug activity was established, which affords an attractive alternative for those laboratories that do not have a radiation license or capabilities.

The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis.

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury. This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury. Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites. We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury. Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro. However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis. We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury.

Effects of oral administration of ß-hydroxy ß-methylbutyrate on lean body mass in older adults: a systematic review and meta-analysis.

OBJECTIVE: Beta-hydroxy beta-methylbutyrate (HMB), a metabolite of leucine, is currently widely used in athletes to increase muscle mass and strength and has also been used as a nutritional supplement in recent years to maintain muscle mass in muscular atrophic diseases of older people. However, the effects of HMB supplementation on muscle mass, muscle strength, and physical function in older people remain controversial. The purpose of this review was to explore the effects of HMB on body composition in older adults. METHODS: The PubMed, EMBASE and Cochrane Central Register of Controlled Trials databases were searched to obtain the randomized controlled trials needed as a basis for systematic review and meta-analysis. RESULT: A total of 9 studies (448 participants) were eventually found eligible. The pooled results showed that HMB supplementation significantly increased fat-free mass in older people compared with the control group (effect size: 0.37; 95% Cl 0.16, 0.58; Z value = 3.47, P = 0.001; Fixed-effect model). But it had no effect on fat mass (effect size: - 0.04 95% CI - 0.26, 0.18; Z value = 0.36, P = 0.716, fixed-effect model). Subgroup analysis of HMB supplementation alone showed a significant improvement in fat-free mass in older people (effect size: 0.59; 95% CI 0.32, 0.87; Z = 4.24, P < 0.001; fixed-effect model), whereas HMB supplementation combined with exercise intervention showed no additional fat-free mass change (effect size: 0.06; 95% CI - 0.26, 0.38; Z = 0.38, P = 0.705; Fixed-effect model). CONCLUSION: HMB supplementation is beneficial for improving body composition in older people. However, the effect of HMB supplementation combined with exercise therapy to improve muscle mass is not obvious. Exercise programs need to be designed according to the different physical health of older people.