Trends in cardiovascular health among US adults by glycemic status based on Life's Essential 8.

OBJECTIVE: We aimed to assess the secular trends in cardiovascular health (CVH) among U.S. adults with different glycemic statuses based on the Life's Essential 8 (LE8). METHODS: This cross-sectional study used nationally representative data from 6 cycles of the National Health and Nutrition Examination Surveys between 2007 and 2018. Survey-weighted linear models were used to assess time trends in LE8 scores. Stratified analyses and sensitivity analyses were conducted to validate the stability of the results. RESULTS: A total of 23,616 participants were included in this study. From 2007 to 2018, there was no significant improvement in overall CVH and the proportion of ideal CVH among participants with diabetes and prediabetes. We observed an opposite trend between health behavior and health factors in the diabetes group, mainly in increasing physical activity scores and sleep scores (P for trend<0.001), and declining BMI scores [difference, -6.81 (95% CI, -12.82 to -0.80)] and blood glucose scores [difference, -6.41 (95% CI, -9.86 to -2.96)]. Dietary health remained at a consistently low level among participants with different glycemic status. The blood lipid scores in the prediabetes group improved but were still at a lower level than other groups. Education/income differences persist in the CVH of participants with diabetes or prediabetes, especially in health behavior factors. Sensitivity analyses of the absolute difference and change in proportion showed a consistent trend. CONCLUSIONS: Trends in CVH among participants with diabetes or prediabetes were suboptimal from 2007 to 2018, with persistent education/income disparities.

Plantamajoside attenuates cardiac fibrosis via inhibiting AGEs activated-RAGE/autophagy/EndMT pathway.

Advanced glycation end products (AGEs) have been identified to transduce fibrogenic signals via inducing the activation of their receptor (RAGE)-mediated pathway. Recently, disrupting AGE-RAGE interaction has become a promising therapeutic strategy for chronic heart failure (CHF). Endothelial-to-mesenchymal transition (EndMT) is close to the cardiac fibrosis pathological process. Our previous studies have demonstrated that knockout RAGE suppressed the autophagy-mediated EndMT, and thus alleviated cardiac fibrosis. Plantamajoside (PMS) is the major bioactive compound of Plantago Asiatica, and its activity of anti-fibrosis has been documented in many reports. However, its effect on CHF and the underlying mechanism remains elusive. Thus, we tried to elucidate the protective role of PMS in CHF from the viewpoint of the AGEs/RAGE/autophagy/EndMT axis. Herein, PMS was found to attenuate cardiac fibrosis and dysfunction, suppress EndMT, reduce autophagy levels and serum levels of AGEs, yet did not affect the expression of RAGE in CHF mice. Mechanically, PMS possibly binds to the V-domain of RAGE, which is similar to the interaction between AGEs and RAGE. Importantly, this competitive binding disturbed AGEs-induced the RAGE-autophagy-EndMT pathway in vitro. Collectively, our results indicated that PMS might exert an anti-cardiac fibrosis effect by specifically binding RAGE to suppress the AGEs-activated RAGE/autophagy/EndMT pathway.

Association of dietary total antioxidant capacity with all-cause and cardiovascular mortality in patients with chronic kidney disease: based on two retrospective cohort studies of NHANES.

BACKGROUND: The relationship between dietary total antioxidant capacity (DTAC) and death risk among CKD populations remains unclear. METHODS: Based on vitamin C equivalent antioxidant capacity (VCEAC) and the component dietary antioxidant index (CDAI) indices, we analyzed two cohorts to investigate the association of DTAC with all-cause and CVD mortality in CKD patients using data from National Health and Nutrition Examination Survey (2007-2018). VCEAC (n = 6330) and CDAI (n = 6300) cohorts with mortality follow-up data available through 2018 were included. Cox models with restricted cubic splines was used to model the nonlinear association between VCEAC/CDAI and outcomes in CKD patients. RESULTS: Our results showed L-shaped associations of DTAC with all-cause mortality among individuals with CKD stages 1-2 in both cohorts. Compared to the lowest quartile, higher dietary total antioxidant intake was associated with lower all-cause mortality risks among CKD stages 1-2 after adjustment for covariates, with HRs (95%CI) of 1.00, 0.91 (0.71,1.17), 0.69 (0.53,0.90), and 0.70 (0.54,0.91) in VCEAC, and similar respective estimate trends in CDAI. After sensitivity and subgroup analyses, there were no benefits for patients with stage 3-5 CKD or albuminuria. Mediation analysis revealed that the proportions mediated in both cohorts were less consistent. CONCLUSIONS: Moderate dietary total antioxidants intake has potential benefits for early-stage CKD patients. However, further evidence is needed to confirm whether patients with worsening CKD can benefit in the long term.

Association of carbohydrate intake from different sources with all-cause and cardiovascular mortality among chronic kidney disease populations: assessment of 1999-2018 National Health and Nutrition Examination Survey participation.

This study analysed the data from the NHANES (1999-2018) to examine how different sources of carbohydrate intake affected the all-cause and cardiovascular mortality of 11,302 chronic kidney disease (CKD) patients. The data were adjusted for other factors using various methods. The results showed that CKD patients (stages 1-2 and 3-5) who consumed more carbohydrates from whole grains, fruits, vegetables and less carbohydrates from fruit juice or sauces had lower mortality rates. Replacing fat intake with carbohydrates from whole grains (HR = 0.86[0.78-0.95]), fruits (raw) (HR = 0.79[0.70-0.88]) and non-starchy vegetables (HR = 0.82[0.70-0.96]), but not protein intake, was linked to lower all-cause mortality. The fibre content in carbohydrates might partly account for the benefits of selected carbohydrate intake. This study provided practical recommendations for optimising the carbohydrate sources in CKD patients.

[Research advances in mechanism of lipid infiltration of coronary heart disease and simultaneous treatment of phlegm and blood stasis based on phlegm-blood stasis correlation theory].

Atherosclerosis(AS) is the key pathological basis of coronary heart disease(CHD), and lipid infiltration is a classical theory to explain the pathological mechanism of AS. The theory highlights that the occurrence and development of AS are closely related to abnormal lipid metabolism, with the essence of the pathological reaction caused by the invasion of lipids into arterial intima from plasma. Phlegm and blood stasis are physiologically homologous and subject to pathological co-existence. Phlegm-blood stasis correlation is the basic theory to explain the pathogenesis characteristics of CHD and has important guiding significance for revealing the mecha-nism of lipid infiltration of CHD. Phlegm is the pathological product of abnormal metabolism of Qi, blood, and body fluid, and a gene-ral summary of a series of abnormally expressed lipid substances. Among them, turbid phlegm invades the heart vessels, gradually accumulates, and condenses to achieve the qualitative change from "invisible pathogen" to "tangible pathogen", which corresponds to the mechanism of lipid migration and deposition in the intima of blood vessels, and is the starting factor of the disease. Blood stasis is the continuous development of phlegm, and it is a result of pathological states such as decreased blood fluidity, increased blood coagulation, and abnormal rheology. The fact that blood stasis caused by phlegm accords with the pathological process of "lipid abnormality-circulatory disturbance" and is the central link of the disease. Phlegm and blood stasis aggravate each other and lead to indissoluble cementation. The phlegm-blood stasis combination serves as common pathogen to trigger the disease, which is the inevitable outcome of the disease. Based on the phlegm-blood stasis correlation theory, the simultaneous treatment of phlegm and blood stasis is established. It is found that this therapy can simultaneously regulate blood lipid, reduce blood viscosity, and improve blood circulation, which can fundamentally cut off the biological material basis of the reciprocal transformation between phlegm and blood stasis, thus exerting a significant curative effect.

[Types of clinical data and statistical methodology of human use experience in traditional Chinese medicine].

Application experience in humans, a summary of the clinical practice of traditional Chinese medicine(TCM), serves as an important data source for evaluating the safety, effectiveness, and clinical value of drugs in the development of new Chinese medicine. The collected data serving as the evaluation evidence through statistical analysis are critical to the research on the application experience in humans. This article summarized and analyzed the data characteristics and statistical methodology of application experience of Chinese medicine in humans, and concluded the data types, outcome evaluation, bias evaluation, confounding factors, and missing values. Furthermore, the article emphasized the importance of data analysis of application experience of Chinese medicine in humans for TCM evidence and put forward the current difficulties, such as low data quality and large internal bias, lack of individualized data processing methods, and lack of methods for "disease-syndrome combination" data. We believe that with the development of methodology, the application experience of Chinese medicine in humans can strongly support the development of new drugs in TCM.

Knockdown of lncRNA PVT1 attenuated macrophage M1 polarization and relieved sepsis induced myocardial injury via miR-29a/HMGB1 axis.

BACKGROUND: LncRNA PVT1 was reported to be elevated in septic myocardial tissue. The underlying mechanism by which PVT1 aggravated sepsis induced myocardial injury needs further investigation. METHODS: Mice was subjected to LPS injection to mimic in vivo sepsis model. HE staining was applied to observe tissue injury. Cardiac function of mice was determined by echocardiography. Bone marrow derived macrophage (BMDM) was used to confirm the regulatory effect of PVT1 in macrophage polarization. Western blotting or qRT-PCR were performed to evaluate protein or mRNA levels, respectively. ELISA was conducted to determine cytokine levels. Interaction between PVT1 and miR-29a, miR-29a and HMGB1 were accessed by dual luciferase assay. RESULTS: Expression of PVT1 was elevated in myocardial tissue and heart infiltrating macrophages of sepsis mice. PVT1 knockdown alleviated LPS induced myocardial injury and attenuated M1 macrophage polarization. The mechanic study suggested that PVT1 targeted miR-29a, thus elevated expression of HMGB1, which was repressed by miR-29a targeting. The effect of PVT1 on M1 macrophage polarization was dependent on targeting miR-29a. CONCLUSION: PVT1 promoted M1 polarization and aggravated LPS induced myocardial injury via miR-29a/HMGB1 axis.

Arctigenin alleviates myocardial infarction injury through inhibition of the NFAT5-related inflammatory phenotype of cardiac macrophages/monocytes in mice.

In this study, we screened potential natural compounds for the treatment of myocardial infarction (MI) and explored the underlying mechanisms. We built three machine learning models to screen the potential compounds. qPCR, flow cytometry, immunohistochemistry, and immunofluorescence analyses were applied to analyze the pharmacological effects of the compounds on macrophages/monocytes in vivo and in vitro. Arctigenin (AG) was selected as a candidate, and echocardiography, Masson's trichrome staining, and TUNEL staining were utilized to detect the effect of AG on MI in vivo. Transcriptome analysis and subsequent bioinformatics analyses were performed to predict the target of the selected compound. Western blot and luciferase reporter assays were used to confirm the target and mechanism of AG. The reversibility of the effects of AG were verified through overexpression of NFAT5. The results showed that AG can improve cardiac injury after MI by reducing infarct size, improving heart function, and inhibiting cardiac death. In addition, AG suppresses inflammatory macrophages/monocytes and proinflammatory cytokines in vivo and in vitro. Transcriptomic and biological experiments revealed that AG modulates macrophage polarization via the NFAT5-induced signaling pathway. Therefore, our data suggest that AG can improve MI by inhibiting the inflammatory phenotype of macrophages/monocytes through targeting of NFAT5.

[Medication rules of traditional Chinese medicine for the treatment of premature ejaculation: An analysis based on data mining].

OBJECTIVE: To study the medication rules of traditional Chinese medicine (TCM) in the treatment of premature ejaculation. METHODS: We searched the databases of CNKI, Wan Fang, VIP, SinoMed (CBM) and PubMed for studies on the treatment of PE with TCM prescriptions and performed statistical analyses on the data obtained using the TCM inheritance auxiliary platform software. RESULTS: Totally 180 prescriptions were identified, involving 209 TCM drugs. The results of statistical analysis showed that the TCM drugs for the treatment of premature ejaculation were mostly warm, flat or cold in nature, sweet or spicy in taste, and with the kidney, liver and spleen meridian tropisms. The single TCM drugs most commonly used included Lycium barbarum L (Gouqizi), followed by Epimedium brevicornum Maxim (Yinyanghuo), Os draconis (Longgu), Fructus rosae laevigatae (Jinyingzi), and the drugs most frequently used in combination with others in a prescription were Os draconis (Longgu) and Concha ostreae (Muli). Seven newly derived prescriptions were identified in addition. CONCLUSIONS: The compatibility of TCM in the treatment of premature ejaculation is characterized by the combination of the drugs for tonifying the kidney and arresting seminal emission as the main medication strategy, with those for soothing the liver and invigorating the spleen as the adjuvant agents, which has a certain clinical application value.

The pleiotropic association between IL-10 levels and CVD prognosis: Evidence from a meta-analysis.

We examined the precise association between IL-10 levels and cardiovascular disease (CVD) prognosis and explored the pleiotropic role of IL-10 in different cardiac pathologies. We performed a meta-analysis of cross-sectional and longitudinal studies investigating IL-10 levels. Meta-regression analyses were used to determine the cause of the discrepancies. To assess publication bias, funnel plots were constructed, and Egger's tests were performed. Data from the GSE58015 dataset were used to investigate the levels of IL-10 under certain conditions. Because of substantial heterogeneity in the data used to compare the IL-10 levels between patients with CVD and healthy people, we could not determine the differences between the healthy controls and patients with ischemic or nonischemic pathologies (p > 0.05). The analysis of the association between IL-10 levels and CVD prognosis indicated that higher IL-10 levels were significantly associated with a poor prognosis in patients with nonischemic pathologies (HR = 1.10, 95% CI = 1.00-1.20, p = 0.043) but differentially associated with the prognosis of patients with ischemic pathologies based on the sampling time point (before percutaneous coronary intervention (PCI): HR = 4.90, 95% CI = 1.24-19.30, p < 0.001; after PCI: HR = 0.57, 95% CI = 0.43-0.75, p = 0.023). The meta-regression analysis showed that the pooled HR of the IL-10 levels was positively correlated with the IL-10/IL-6 ratio (ß = 0.644, p = 0.024). The funnel plots and Egger's tests revealed no statistically significant bias in our meta-analysis (p > 0.1). Furthermore, our data mining analysis supported our findings. Our analysis showed that IL-10 levels may be pleiotropically associated with the CVD prognosis possibly based on the type of pathology, disease stage and levels of other proinflammatory factors, such as IL-6.

CT-guided minimally-invasive penile fracture repair.

We present the case of a 28 year old patient with an incomplete tear of the tunica albuginea occurred after having sexual intercourse in the female superior position. The diagnostic assessment was performed first clinically, then with CT, owing to its high resolution, allowed to exactly detect the tear location leading to precise preoperative planning. After adequate diagnosis through imaging and proper planning, the patient was performed a selective minimally invasive surgical approach to repair the lesion. The patient had good erection with no angular deformity or plaque formation after a 3-month follow-up.

The C/EBPß-SESN2 Axis Promotes M2b Macrophage Polarization Induced by T.cp-MIF to Suppress Inflammation in Thelazia Callipaeda Infection.

Infection by the conjunctival sucking nematode Thelazia callipaeda results in ocular inflammation and immune impairment. T.cp-MIF, a macrophage migration inhibitor factor of T. callipaeda, can induce macrophage polarization and is involved in the host innate immune response, but little is known about the regulatory mechanisms and the actual immune effect. Understanding the immunoregulatory mechanisms carries significant clinical relevance for the development of novel preventative and therapeutic strategies. The macrophages were induced by T.cp-MIF in vitro, and the polarization direction at different times and the expression of inflammatory factors were detected by flow cytometry analysis, qPCR and western blotting. The key transcription factors and target genes were screened through transcriptome data, and the functions of transcription factors were verified by inhibition experiments in vitro. T.cp-MIF and T. callipaeda adult worms can cause inflammation of the ocular conjunctiva and macrophage infiltration. T.cp-MIF activated macrophages presenting M2b polarization after 48 h and played a role in inhibiting inflammation. Furthermore, based on the results of transcriptome data analysis and inhibition experiments, we demonstrate that this polarization is dependent on the involvement of the transcription factor C/EBPß and its target gene SESN2. Our results demonstrated that the C/EBPß-SESN2 axis plays an important regulatory role in T.cp-MIF-induced macrophage M2b polarization and it provides a new perspective for understanding the immune escape of ocular parasite infection.

Validation of intrinsic capacity and healthy sleep pattern in middle-aged and older adults: a longitudinal Chinese study assessing healthy ageing.

OBJECTIVES: Intrinsic capacity (IC), a multidimensional construct encompassing mental and physical capacities, has been established in the aging framework by the World Health Organization. However, the detailed relationship between IC and Chinese sleep patterns (nighttime sleep and post-lunch naps) remains inadequately elucidated. METHODS: Participants in this study were individuals aged ≥45 years residing in China, included in the China Health and Retirement Longitudinal Study (CHARLS). We analyzed 4 years of CHARLS data from the first wave (May 2011-March 2012) to the second wave (July 2015-January 2016). Data from these waves were utilized for longitudinal analysis. Self-reported data included nighttime sleep and nap duration, along with other baseline characteristics. The IC evaluation involved physical examinations and blood tests. Initially, linear regression was used to assess the relationship between total sleep duration, nighttime sleep duration, nap duration, and IC change between the two waves that were determined by marginal effects (ME) and their corresponding 95% confidence intervals (CIs). Regression splines were employed to explore potential nonlinear associations. Subgroup and sensitivity analyses were conducted to investigate the heterogeneity of IC change under specific conditions and the robustness of our results. Mediation analysis was performed to identify potential factors mediating the relationship between sleep patterns and IC change. RESULTS: Both excessive (>10 h) (total, ME: -1.12; 95% CI: -1.61, -0.64; nighttime, ME: -1.44; 95% CI: -2.29, -0.59) and insufficient (<6 h) sleep duration (total, ME: -0.43; 95% CI: -0.68, -0.18; nighttime, ME: -0.50; 95% CI: -0.73, -0.27) negatively impacted IC change. Moderate naps (≤60 min) mitigated the decline in IC change (ME: 0.28; 95% CI: 0.07, 0.49). IC values decreased at the slowest rate when nap time constituted one-seventh of total sleep time. The onset of dyslipidemia partially mediated the association between naps (≤60 min) and IC change (P = 0.02). CONCLUSIONS: These findings suggest that maintaining a healthy sleep pattern of 6-8 h of nighttime or total sleep, along with a post-lunch nap of ≤60 min, helps preserve optimal IC or delay its decline. This is particularly beneficial for cognitive, psychological, and locomotion performance among middle-aged and older adults.

Analysis of related factors for neuropsychiatric comorbidities in children with epilepsy.

OBJECTIVE: To analyze the risk factors affecting psychiatric behavior and study the psychobehavioral conditions of children with epilepsy. METHOD: We randomly selected and enrolled 294 children with epilepsy who visited and were hospitalized in the pediatric clinic of Hebei General Hospital between January 2017 and January 2022, as the study participants. We comprehensively assessed their cognitive functions using the Gesell development schedule or Wechsler Intelligence Scales. The participants were divided into the study group (n = 123) with cognitive impairment and the control group (n = 171) with normal cognitive functions, for analysis. RESULTS: There were statistically significant differences between the two groups in disease course, frequency of epilepsy, status epilepticus, and the number of antiseizure medications (ASMs) used (P < 0.05), while there were no statistically significant differences in age, gender, age of onset, form of onset, interictal epileptiform discharge, history of febrile convulsion, and the time from onset to initial visit (P > 0.05). Based on multivariate logistic regression analysis, the course of disease, frequency of onset, status epilepticus and number of ASMs used were identified as high-risk factors for cognitive impairment in children with epilepsy. Similarly, early onset, long course of disease, known etiology, and combination of multiple drugs have a negative impact on behavioral problems, school education, and social adaptability. CONCLUSION: The course of disease, the frequency of onset, status epilepticus, and the number of ASMs used are high-risk factors for cognitive impairment in children with epilepsy, which can be prevented and controlled early. When selecting ASMs, their advantages and disadvantages should be weighed. Moreover, the availability of alternative treatment options must be considered. With the help of genomic technology, the causes of epilepsy should be identified as early as possible, and precision medicine and gene therapy for children with epilepsy should be actively developed.

Association between dietary inflammatory index with all-cause and cardiovascular disease mortality among older US adults: A longitudinal cohort study among a nationally representative sample.

OBJECTIVE: To investigate the association between DII with all-cause and cardiovascular disease (CVD) mortality among older adults in the U. S METHODS: This prospective cohort study included older adults with complete DII data and mortality data from the National Health and Nutrition Examination Survey (NHANES) 2001-2018. Mortality outcomes were linked to National Death Index records through 31 December 2019. The multivariate Cox proportional hazards models were performed to evaluate the association between DII and mortality. Restricted cubic spline analyses were used to examine the nonlinear association of DII with all-cause and CVD mortality. RESULTS: During the median follow-up date of 6.7 years, 4446 all-cause deaths were documented among 10,827 representative older adults, including 1230 CVD deaths. After multivariate adjustment, linear relationships between DII with all-cause mortality (P non-linear = 0.17) and non-linear relationship between DII with CVD mortality (P non-linear = 0.04) were observed. Compared to participants with the lowest quartile of DII scores (-5.28 to≤0.43), the multivariate-adjusted HRs and 95 %CI for participants with higher DII scores were 1.19 (Q2, 95 %CI: 1.08-1.31), 1.28 (Q3, 95 %CI: 1.14-1.44), 1.30 (Q4, 95 %CI: 1.17-1.44) for all-cause mortality (P trend <0.001) and 1.19 (Q2, 95 %CI: 0.99-1.43), 1.34 (Q3, 95 %CI: 1.10-1.62), 1.30 (Q4, 95 %CI: 1.06-1.58) for CVD mortality (P trend < 0.01), respectively. CONCLUSIONS: In the representative sample of older adults in the U.S, higher DII scores were associated with increased risks of all-cause and CVD mortality.

A simplified herbal decoction attenuates myocardial infarction by regulating macrophage metabolic reprogramming and phenotypic differentiation via modulation of the HIF-1α/PDK1 axis.

BACKGROUND: Myocardial infarction (MI) poses a global public health challenge, often associated with elevated mortality rates and a grim prognosis. A crucial aspect of the inflammatory injury and healing process post-MI involves the dynamic differentiation of macrophages. A promising strategy to alleviate myocardial damage after MI is by modulating the inflammatory response and orchestrating the shift from pro-inflammatory (M1) to anti-inflammatory (M2) macrophages, aiming to achieve a reduced M1/M2 ratio. Nuanxinkang (NXK), a simplified herbal decoction, has demonstrated noteworthy cardioprotective, inflammation-regulating, and myocardial energy metabolism-regulating properties. METHODS: In this study, we constructed an MI model by ligating coronary arteries to investigate the efficacy of NXK in improving ventricular remodeling and cardiac function. Mice were administered NXK (1.65 g/kg/d) or an equivalent volume of regular saline via gavage for 28 consecutive days, commencing the day after surgery. Then, we conducted echocardiography to assess the cardiac function, Masson staining to illustrate the extent of myocardial fibrosis, TUNEL staining to reveal myocardial apoptosis, and flow cytometry to analyze the polarization of M1 and M2 macrophages in the hearts. Besides, a lipopolysaccharide (LPS)-induced pro-inflammatory macrophage (M1) polarization model was implemented in RAW264.7 cells to elucidate the underlying mechanism of NXK in regulating macrophage polarization. RAW264.7 cells were pre-treated with or without NXK-containing serum. Oxidative stress was detected by MitoSox staining, followed by Seahorse energy metabolism assay to evaluate alterations in mitochondrial metabolic patterns and ATP production. Both In vivo and in vitro, HIF-1α and PDK1 were detected by fluorescent quantitative PCR and Western blotting. RESULTS: In vivo, MI mice exhibited a decline in cardiac function, adverse ventricular remodeling, and an increase in glycolysis, coupled with M1-dominant polarization mediated by the HIF-1α/PDK1 axis. Notably, robust responses were evident with high-dose NXK treatment (1.65 g/kg/day), leading to a significant enhancement in cardiac function, inhibition of cardiac remodeling, and partial suppression of macrophage glycolysis and the inflammatory phenotype in MI mice. This effect was achieved through the modulation of the HIF-1α/PDK1 axis. In vitro, elevated levels of mitochondrial ROS production and glycolysis were observed in LPS-induced macrophages. Conversely, treatment with NXK notably reduced the oxidative stress damage induced by LPS and enhanced oxidative phosphorylation (OXPHOS). Furthermore, NXK demonstrated the ability to modify the energy metabolism and inflammatory characteristics of macrophages by modulating the HIF-1α/PDK1 axis. The influence of NXK on this axis was partially counteracted by the HIF-1α agonist DMOG. And NXK downregulated PDK1 expression, curtailed glycolysis, and reversed LPS-induced M1 polarization in macrophages, similar to the PDK1 inhibitor DCA. CONCLUSION: In conclusion, NXK protects against MI-induced cardiac remodeling by inducing metabolic reprogramming and phenotypic differentiation of macrophages, achieved through the modulation of the HIF-1α/PDK1 axis. This provides a novel and promising strategy for the treatment of MI.

Xinyang tablet alleviated cardiac dysfunction in a cardiac pressure overload model by regulating the receptor-interacting serum/three-protein kinase 3/FUN14 domain containing 1-mediated mitochondrial unfolded protein response and mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Xinyang tablet (XYT) has been used for heart failure (HF) for over twenty years in clinical practice, but the underlying molecular mechanism remains poorly understood. AIMS OF THE STUDY: In the present study, we aimed to explore the protective effects of XYT in HF in vivo and in vitro. MATERIALS AND METHODS: Transverse aortic constriction was performed in vivo to establish a mouse model of cardiac pressure overload. Echocardiography, tissue staining, and real-time quantitative PCR (qPCR) were examined to evaluate the protective effects of XYT on cardiac function and structure. Adenosine 5'-triphosphate production, reactive oxygen species staining, and measurement of malondialdehyde and superoxide dismutase was used to detect mitochondrial damage. Mitochondrial ultrastructure was observed by transmission electron microscope. Immunofluorescence staining, qPCR, and Western blotting were performed to evaluate the effect of XYT on the mitochondrial unfolded protein response and mitophagy, and to identify its potential pharmacological mechanism. In vitro, HL-1 cells and neonatal mouse cardiomyocytes were stimulated with Angiotensin II to establish the cell model. Western blotting, qPCR, immunofluorescence staining, and flow cytometry were utilized to determine the effects of XYT on cardiomyocytes. HL-1 cells overexpressing receptor-interacting serum/three-protein kinase 3 (RIPK3) were generated by transfection of RIPK3-overexpressing lentiviral vectors. Cells were then co-treated with XYT to determine the molecular mechanisms. RESULTS: In the present study, XYT was found to exerta protective effect on cardiac function and structure in the pressure overload mice. And it was also found XYT reduced mitochondrial damage by enhancing mitochondrial unfolded protein response and restoring mitophagy. Further studies showed that XYT achieved its cardioprotective role through regulating the RIPK3/FUN14 domain containing 1 (FUNDC1) signaling. Moreover, the overexpression of RIPK3 successfully reversed the XYT-induced protective effects and significantly attenuated the positive effects on the mitochondrial unfolded protein response and mitophagy. CONCLUSIONS: Our findings indicated that XYT prevented pressure overload-induced HF through regulating the RIPK3/FUNDC1-mediated mitochondrial unfolded protein response and mitophagy. The information gained from this study provides a potential strategy for attenuating mitochondrial damage in the context of pressure overload-induced heart failure using XYT.

Crosstalk between endothelial cells with a non-canonical EndoMT phenotype and cardiomyocytes/fibroblasts via IGFBP5 aggravates TAC-induced cardiac dysfunction.

Heart failure (HF) is a complex chronic condition characterized by structural and functional impairments. The differentiation of endothelial cells into myofibroblasts (EndoMT) in response to cardiac fibrosis is controversial, and the relative contribution of endothelial plasticity remains to be explored. Single-cell RNA sequencing was used to identify endothelial cells undergoing fibrotic differentiation within 2 weeks of transverse aortic constriction (TAC). This subset of endothelial cells transiently expressed fibrotic genes but had low expression of alpha-smooth muscle actin, indicating a non-canonical EndoMT, which we named a transient fibrotic-like phenotype (EndoFP). The role of EndoFP in pathological cardiac remodeling may be correlated with increased levels of osteopontin. Cardiomyocytes and fibroblasts co-cultured with EndoFP exhibited heightened pro-hypertrophic and pro-fibrotic effects. Mechanistically, we found that the upregulated expression of insulin-like growth factor-binding protein 5 may be a key mediator of EndoFP-induced cardiac dysfunction. Furthermore, our findings suggested that Rab5a is a novel regulatory gene involved in the EndoFP process. Our study suggests that the specific endothelial subset identified in TAC-induced pressure overload plays a critical role in the cellular interactions that lead to cardiac fibrosis and hypertrophy. Additionally, our findings provide insight into the mechanisms underlying EndoFP, making it a potential therapeutic target for early heart failure.

Drug vector representation and potential efficacy prediction based on graph representation learning and transcriptome data: Acacetin from traditional Chinese Medicine model.

ETHNOPHARMACOLOGICAL RELEVANCE: Acacetin is widely distributed in traditional Chinese medicine and traditional herbs, with strong biological activity. Perhaps there are many potential effects that have not been explored. In the field of drug discovery, Mainstream methods focus on chemical structure. Traditional medicine cannot adapt to the mainstream prediction methods due to its complex composition. AIM OF THE STUDY: Our aim is that provide a prediction method more suitable for traditional medicine by graph representation learning and transcriptome data. And use this method to predict acacetin. MATERIALS AND METHODS: Our method mainly consists of two parts. The first part is to use the method of graph representation learning to vectorize drugs as a database. The original data of this part comes from transcriptome data on Gene Expression Omnibus. The method of graph representation learning is an unsupervised learning. If there is no prior knowledge as the label data, the training effect cannot be analyzed. Therefore, we define a standard score to evaluate our results through the idea of Jaccard index. The second part is to put the target drug into our database. The potential similarity between drugs was evaluated by the Euclidean distance between vectors, and the potential efficacy of the target drug is predicted by combining the chemical-disease relationship data in the Comparative Toxicogenomics Database. The target drug in this paper uses acacetin. We compared the predicted results with existing reports, and we also experimentally verified the efficacy of improving insulin resistance in the predicted results. RESULTS: The prediction results are relatively consistent with the existing reports, which demonstrated that our method has a certain degree of predictive performance. And for the efficacy of improving insulin resistance in the predicted result, we verified it through experiments. CONCLUSIONS: We propose a method to predict the potential efficacy of drugs based on transcriptome data, using Graph representation learning, which is very suitable for traditional medicine. Through this method, we predicted the efficacy of acacetin, and the results are relatively consistent with the current reports. This provides a new idea for unsupervised learning to apply medical information.

MLK3 silence suppressed osteogenic differentiation and delayed bone formation via influencing the bone metabolism and disturbing MAPK signaling.

Background: Mixed lineage kinase 3 (MLK3) is a member of a serine/threonine MAP3K family, and it has been demonstrated to play critical roles in various biological activities and disease progression. Previous studies showed that impaired skeletal mineralization and spontaneous tooth fracture in the MLK3-deficient mice, suggesting MLK3 actively participated in the bone formation. However, the detailed function and underlying mechanisms remain obscure. Methods: The MLK3 knockout (KO) mouse was applied in the present study, and multi-omics were performed to compare the metabolites and gene expression between wild type (WT) and KO mice. The bone fracture model was successfully established, and the healing process was evaluated by X-ray, micro-CT examination, histomorphometry and immunohistochemistry (IHC) staining. On the other hand, the effects of MLK3 on osteogenic differentiation were assessed by alkaline phosphatase (ALP) activity, Alizarin red S (ARS) staining and qRT-PCR examination. Finally, the downstream signaling pathways were screened out by RNA-sequencing (RNA-seq) and then validated by Western blotting. Results: In the present study, imbalanced bone metabolism was observed in these MLK3 KO mice, suggesting MLK3 may participate in bone development. Moreover, MLK3 -/- mice displayed abnormal bone tissues, impaired bone quality, and delayed fracture healing. Further investigation showed that the inhibition of MLK3 attenuated osteoblast differentiation in vitro. According to the RNA-seq data, MAPK signaling was screened out to be a downstream pathway, and its subfamily members extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal protein kinase (JNK) were subjected to Western blotting examination. The results revealed that although no differences in their expression were observed between MSCs derived from WT and KO mice, their phosphorylated protein levels were all suppressed in MLK3 -/- MSCs. Conclusion: In conclusion, our results demonstrated that loss of MLK3 suppressed osteoblast differentiation and delayed bone formation via influencing metabolism and disturbing MAPK signaling. The translational potential of this article: The findings based on the current study demonstrated that MLK3 promoted osteogenesis, stimulated new bone formation and facilitated fracture healing, suggesting that MLK3 may serve as a potential therapeutic target for bone regeneration. MLK3 activator therefore may be developed as a therapeutic strategy for bone fracture.