Association of Delirium with Long-Term Mortality in Critically Ill Patients with COPD Who Survived to Discharge: A Retrospective Cohort Study.

BACKGROUND: Critically ill patients with chronic obstructive pulmonary disease (COPD) face significant mortality after hospital discharge. Delirium is common in patients with COPD, but its impact on long-term mortality in critically ill COPD patients who survive to discharge remains uncertain. METHODS: Critically ill patients with COPD who survived to discharge were selected from the Medical Information Mart for Intensive Care IV database. Delirium was assessed using the Confusion Assessment Method for Intensive Care Unit. The primary outcome was 365- and 180-day mortality after discharge. The secondary outcomes included 90- and 30-day mortality following discharge, length of intensive care unit (ICU) and hospital stays, and nursing care needs after hospital discharge. RESULTS: Of the 2621 survivors of critically ill COPD patients, 982 had suffered delirium during their ICU stay and 709 died within 365 days after hospital discharge. Delirium was significantly associated with 365-day mortality after hospital discharge (adjusted hazard ratio [HR] 1.22; 95% confidence interval [CI] 1.02-1.47). The results were consistent for 180-, 90-, and 30-day post-discharge mortality (adjusted HR [95% CI]: 1.35 [1.09-1.66], 1.48 [1.16-1.89], and 1.68 [1.21-2.32], respectively). Additionally, patients with delirium had longer ICU and hospital stay (adjusted ß 2.75; 95% CI 2.35-3.16 and 4.25; 95% CI 3.51-4.98, respectively) and increased nursing care needs after hospital discharge (adjusted odds ratio, 1.56; 95% CI 1.13-2.14). CONCLUSION: ICU delirium was an independent risk factor for both long-term and short-term mortality in critically ill patients with COPD who survived to discharge.

Age affects vascular morphology and predictiveness of anatomical landmarks for aortic zones in trauma patients: implications for resuscitative endovascular balloon occlusion of the aorta.

PURPOSE: Understanding the vascular morphology is fundamental for resuscitative endovascular balloon occlusion of the aorta. This study aimed to evaluate the effect of aging on length and diameter of aorta and iliac arteries in trauma patients, and to investigate the predictiveness of anatomical landmarks for aortic zones. METHODS: A total of 235 patients in a regional trauma center registry from September 1, 2018, to January 3, 2024, participated in the study. Reconstruction of computed tomography was applied to the torso area. The marginal diameter and length of aorta and iliac arteries were measured. Anatomical landmark distances and aortic marginal lengths were compared. RESULTS: The length and diameter of aorta and iliac arteries increased with age, and a tortuous and enlarged morphology was observed in older patients. There was a good regression between age and diameter of the aorta. Neither the jugular notch, the xiphisternal joint, nor the umbilicus could reliably represent specific margins of aortic zones. The distance between the mid-sternum and femoral artery (427 ± 25 to 442 ± 25 mm for right, and 425 ± 28 to 440 ± 26 mm for left) was predictive for zone 1 in all groups. The distance between the lower one-third junction of the xiphisternum to the umbilicus and femoral artery (232 ± 19 to 240 ± 17 mm for right, and 229 ± 20 to 237 ± 19 mm for left) was predictive for zone 3 aorta. CONCLUSION: Aging increases the length and diameter of aorta and iliac arteries, with a tortuous and enlarged morphology in geriatric populations. The mid-sternum and the lower one-third junction of the xiphisternum to the umbilicus were predictive landmarks for zone 1 and zone 3, respectively.

The Chinese Herbal Formula Huoxiang Zhengqi Dropping Pills Prevents Acute Intestinal Injury Induced by Heatstroke by Increasing the Expression of Claudin-3 in Rats.

Intestinal injury has been regarded as an important causative factor for systemic inflammation during heatstroke, and maintaining intestinal integrity has been a potential target for the prevention of HS. Huoxiang Zhengqi Dropping Pills (HZPD) is a modern preparation of Huoxiang Zhengqi and widely used to prevent HS. The present study aims to explore the protective effect of HZDP on intestinal injury during heatstroke and analyze its potential pharmacodynamic basis. Male rats in the control and HS groups were given normal saline, and those in the HZDP groups were given HZDP (0.23, 0.46, and 0.92 g/kg) before induction of HS. Serum contents of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), intestinal fatty acid-binding protein (iFABP), and diamine oxidase (DAO) were determined using ELISA. Histopathology of intestinal injury was observed following H&E staining. The expression of claudin-3 was determined using western blot, immunohistochemistry, and immunofluorescence techniques. Moreover, network pharmacological tools were used to analyze the potential pharmacodynamic basis and the mechanism of HZDP. Treatment with HZDP significantly prolonged the time to reach Tc. Compared with the control group, the contents of TNF-α, IL-6, iFABP, and DAO in HS rats increased markedly. HZDP treatments reduced these levels significantly, and the effects in the middle dose group (0.46 g/kg) were most obvious. HZDP also attenuated intestinal injury and significantly reversed the decrease in claudin-3 expression. Bioinformatics analysis suggested that 35 active ingredients and 128 target genes of HZDP were screened from TCMSP and 93 target genes intersected with heatstroke target genes, which were considered potential therapeutic targets. TNF-α and IL-6 were the main inflammatory target genes of HZDP correlated with HS. These results indicated that HZDP effectively protected intestinal barrier function and prevented acute intestinal injury by increasing the expression of claudin-3 in rats, eventually improving heat resistance.

Self-limiting bidirectional positive feedback between P53 and P21 is involved in cardiac hypertrophy.

Pathological cardiac hypertrophy is an independent risk factor of cardiovascular diseases. Although the function of p53 and p21 in pathological cardiac hypertrophy have been studied, the relationship between them in cardiomyocytes is still unclear. By using specific adenoviruses and siRNAs to modulate p53 or p21 expression in neonatal rat ventricular myocytes (NRVMs), we found that both upregulated p53 and p21 expression induced hypertrophic responses, and they promote each other's expression. Overexpression of p53 aggravated the hypertrophic response of cardiomyocytes in vitro and in vivo, while knockdown of p21 diminished the hypertrophic responses induced by angiotensin Ⅱ and the increase of p53 expression. Additionally, Angiotensin Ⅱ treatment promoted the nuclear translocation of p21 in NRVMs. Notably, increased p53 expression alone did not promote p21 translocation to the nucleus. Together, these data suggest a self-limiting bidirectional positive feedback interaction between p53 and p21 during cardiac hypertrophy.

Cardiomyocytic FoxP3 is involved in Parkin-mediated mitophagy during cardiac remodeling and the regulatory role of triptolide.

Rationale: Forkhead/winged helix transcriptional factor P3 (FoxP3) is a well-studied transcription factor that maintains the activity of T cells, but whether cardiomyocytic FoxP3 participates in cardiac remodeling (CR) remains unclear. The present study was to investigate the role of cardiomyocytic FoxP3 in CR from the perspective of mitophagy. Methods: CR was induced by angiotensin II (AngII) in vitro, or by isoproterenol (Iso) in vivo using male C57 mice or FoxP3DTR mice. Histological changes were observed by hematoxylin-eosin and Masson staining. Molecular changes were detected by immunohistochemistry, immunofluorescence, immunoblotting, and real-time PCR. Mitophagy was shaped by transmission electron microscopy and co-localization. The mRNA expression was operated by siRNA or adeno associated virus (AAV). Molecular interactions were detected by co-localization, immunoprecipitation (IP), and chromatin IP. Results: The expression and nuclear translocation of cardiomyocytic FoxP3 were downregulated in CR, while they were upregulated after triptolide (TP) treatment. In left ventricle (LV) remodeling in mice, autophagy was activated continuously in the myocardium, and TP significantly attenuated it. AngII induced massive mitophagy characterized by the activation of autophagy regulatory protein 5 (Atg5)-dependent autophagic flux. Critically, Parkin was identified as the main adaptor mediated myocardial mitophagy and was responsible for the effect of TP. Moreover, FoxP3 was responsible for the downregulation of Parkin and inhibited AngII-induced cardiac mitophagy. We found that mitophagy increased significantly and the inhibition of TP treatment reversed completely in FoxP3-deficient LVs. Mechanistically, FoxP3 interacted with a motif located downstream of the activating transcription 4 (ATF4)-binding motif involved in the promoter of Parkin and hijacked free nuclear ATF4 to decrease Parkin mRNA expression in CR. Conclusion: Cardiomyocytic FoxP3 could negatively regulate Parkin-mediated mitophagy in CR, and restoring cardiomyocytic FoxP3 activity provided a cardioprotective strategy by inhibiting excessive cardiac mitophagy.

Transcription Factors Involved in the Development and Prognosis of Cardiac Remodeling.

To compensate increasing workload, heart must work harder with structural changes, indicated by increasing size and changing shape, causing cardiac remodeling. However, pathological and unlimited compensated cardiac remodeling will ultimately lead to decompensation and heart failure. In the past decade, numerous studies have explored many signaling pathways involved in cardiac remodeling, but the complete mechanism of cardiac remodeling is still unrecognized, which hinders effective treatment and drug development. As gene transcriptional regulators, transcription factors control multiple cellular activities and play a critical role in cardiac remodeling. This review summarizes the regulation of fetal gene reprogramming, energy metabolism, apoptosis, autophagy in cardiomyocytes and myofibroblast activation of cardiac fibroblasts by transcription factors, with an emphasis on their potential roles in the development and prognosis of cardiac remodeling.

Effect of Triptolide on Temporal Expression of Cell Cycle Regulators During Cardiac Hypertrophy.

Adult mammalian cardiomyocytes may reenter the cell cycle and cause cardiac hypertrophy. Triptolide (TP) can regulate the expressions of various cell cycle regulators in cancer cells. However, its effects on cell cycle regulators during myocardial hypertrophy and mechanism are unclear. This study was designed to explore the profile of cell cycle of cardiomyocytes and the temporal expression of their regulators during cardiac hypertrophy, as well as the effects of TP. The hypertrophy models employed were neonatal rat ventricular myocytes (NRVMs) stimulated with angiotensin II (Ang II) for scheduled times (from 5 min to 48 h) in vitro and mice treated with isoprenaline (Iso) for from 1 to 21 days, respectively. TP was used in vitro at 1 µg/L and in vivo at 10 µg/kg. NRVMs were analyzed using flow cytometry to detect the cell cycle, and the expression levels of mRNA and protein of various cell cycle regulators were determined using real-time PCR and Western blot. It was found NRVM numbers in phases S and G2 increased, while that in the G1 phase decreased significantly after Ang II stimulation. The mRNA expression levels of p21 and p27 increased soon after stimulation, and thereafter, mRNA expression levels of all cell cycle factors showed a decreasing trend and reached their lowest levels in 1-3 h, except for cyclin-dependent kinase 1 (CDK1) and CDK4 mRNA. The mRNA expression levels of CDK1, p21, and p27 increased markedly after stimulation with Ang II for 24-48 h. In myocardium tissue, CDK and cyclin expression levels peaked in 3-7 days, followed by a decreasing trend, while those of p21 and p27 mRNA remained at a high level on day 21. Expression levels of all protein were consistent with the results of mRNA in NRVMs or mice. The influence of Ang II or Iso on protein expression was more obvious than that on mRNA. TP treatment effectively prevented the imbalance in the expression of cell cycle regulators in the hypertrophy model group. In Conclusion, an imbalance in the expression of cell cycle regulators occurs during cardiac hypertrophy, and triptolide corrects these abnormal expression levels and attenuates cardiac hypertrophy.

Vigilance on New-Onset Atherosclerosis Following SARS-CoV-2 Infection.

The pandemic of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has become a global challenge to public health. While its typical clinical manifestations are respiratory disorders, emerging evidence of cardiovascular complications indicates the adverse interaction between SARS-CoV-2 infection and cardiovascular outcomes. Given that viral infection has emerged as an additional risk factor for atherosclerosis, in this paper, we attempt to clarify the susceptibility to new-onset atherosclerosis in individuals infected with SARS-CoV-2. Mechanistically, serving as functional receptors for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) mediates SARS-CoV-2 infection of endothelial cells (ECs) directly, leading to endothelial dysfunction and dysregulation of the renin-angiotensin system (RAS). In addition, high expression of CD147, an alternative receptor, and activation of the NLRP3 inflammasome may also contribute to atherosclerosis in the context of COVID-19. More importantly, SARS-CoV-2 attacks the immune system, which results in excessive inflammation and perpetuates a vicious cycle of deteriorated endothelial dysfunction that further promotes inflammation. The alterations in the blood lipid profile induced by COVID-19 should not be ignored in assessing the predisposition toward atherosclerosis in victims of COVID-19. A better understanding of the underlying mechanisms of SARS-CoV-2 infection and the long-term monitoring of inflammatory factors and endothelial function should be considered in the follow-up of patients who have recovered from COVID-19 for early detection and prevention of atherosclerosis.

Dual Role of Triptolide in Interrupting the NLRP3 Inflammasome Pathway to Attenuate Cardiac Fibrosis.

In a previous paper, we reported that triptolide (TP), a commonly used immunomodulator, could attenuate cardiac hypertrophy. This present study aimed to further explore the inhibition of cardiac fibrosis by TP and the possible mechanism from the perspective of the NOD-like receptor protein 3 (NLRP3) inflammasome. Hematoxylin-eosin and Masson's staining, immunohistochemistry, and immunofluorescence were performed to observe cardiac fibrotic changes in mice and mouse cardiac fibroblasts (CFs). The Western blot, colocalization, and immunoprecipitation were applied to detect protein expression and interactions. Results suggested that TP dose-dependently inhibited cardiac fibrosis induced by isoproterenol and collagen production of CFs induced by angiotensin II. TP exhibited an antifibrotic effect via inhibiting activation of the NLRP3 inflammasome, which sequentially decreased IL-1ß maturation, myeloid differentiation factor 88 (MyD88)-related phosphorylation of c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase 1/2 (ERK1/2), and TGF-ß1/Smad signaling, and ultimately resulted in less collagen production. Moreover, TP showed no antifibrotic effect in Nlrp3-knockout CFs. Notably, TP inhibited the expression of NLRP3 and apoptosis-associated speck-like proteins containing a caspase recruitment domain (ASC) as well as inflammasome assembly, by interrupting the NLRP3-ASC interaction to inhibit inflammasome activation. Finally, TP indeed inhibited the NLRP3-TGFß1-Smad pathway in vivo. Conclusively, TP was found to play a dual role in interrupting the activation of the NLRP3 inflammasome to attenuate cardiac fibrosis.

Cyclin-Dependent Kinase Inhibitor p21WAF1/CIP1 Facilitates the Development of Cardiac Hypertrophy.

BACKGROUND/AIMS: Adult cardiomyocytes can re-enter cell cycle as stimulated by prohypertrophic factors although they withdraw from cell cycle soon after birth. p21WAF1/CIP1, a cyclin-dependent kinase inhibitor, has been implicated in cardiac hypertrophy, however, its precise contribution to this process remains largely unclear. METHODS: The gene expression profile in left ventricle (LV) of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was determined using quantitative PCR array and verified by real-time PCR and Western blotting. Hypertrophic response of H9c2 cells and neonatal rat ventricular myocytes (NRVM) were induced by angiotensin II (1 µmol/L). Cardiac hypertrophy of mice was elicited by isoproterenol (ISO) infusion (40 mg/kg per day for 14 days). p21-adenovirus and p21-siRNA were employed to transfect NRVM, and sterigmatocystin (STE, 3 mg/kg, ip, qd) was used to inhibit p21 activity. mRNA and protein expression levels of α- and ß-myosin heavy chain (MHC), p21WAF1/CIP1, calcineurin (CaN) and atrial natriuretic peptide (ANP) were assayed by realtime PCR and WB, respectively. RESULTS: Sixteen genes showed two-fold or greater changes between SHR and WKY rats, in which the expression of p21WAF1/CIP1 was upregulated by 4.15-fold (P=0.002) and reversed by losartan. Surface area, protein content, mRNA and protein expressions of ß-MHC, ANP and p21WAF1/CIP1 in H9c2 cells treated with AngII elevated significantly compared with control group. p21-Ad transfection markedly increased the surface area and ß-MHC mRNA expression of normal NRVMs, and p21-siRNA transfection decreased them in AngII-treated NRVMs. STE treatment decreased HW/BW and cross-sectional area, expression levels of ß-MHC, ANP and p21 significantly in ISO-treated mice. CONCLUSION: Our findings suggest that p21 facilitates the development of cardiac hypertrophy, and regulating the expression of p21 may be an approach to attenuate hypertrophic growth of cardiomyocytes.

Triptolide Upregulates Myocardial Forkhead Helix Transcription Factor p3 Expression and Attenuates Cardiac Hypertrophy.

The forkhead/winged helix transcription factor (Fox) p3 can regulate the expression of various genes, and it has been reported that the transfer of Foxp3-positive T cells could ameliorate cardiac hypertrophy and fibrosis. Triptolide (TP) can elevate the expression of Foxp3, but its effects on cardiac hypertrophy remain unclear. In the present study, neonatal rat ventricular myocytes (NRVM) were isolated and stimulated with angiotensin II (1 µmol/L) to induce hypertrophic response. The expression of Foxp3 in NRVM was observed by using immunofluorescence assay. Fifty mice were randomly divided into five groups and received vehicle (control), isoproterenol (Iso, 5 mg/kg, s.c.), one of three doses of TP (10, 30, or 90 µg/kg, i.p.) for 14 days, respectively. The pathological morphology changes were observed after Hematoxylin and eosin, lectin and Masson's trichrome staining. The levels of serum brain natriuretic peptide (BNP) and troponin I were determined by enzyme-linked immunosorbent assay and chemiluminescence, respectively. The mRNA and protein expressions of α- myosin heavy chain (MHC), ß-MHC and Foxp3 were determined using real-time PCR and immunohistochemistry, respectively. It was shown that TP (1, 3, 10 µg/L) treatment significantly decreased cell size, mRNA and protein expression of ß-MHC, and upregulated Foxp3 expression in NRVM. TP also decreased heart weight index, left ventricular weight index and, improved myocardial injury and fibrosis; and decreased the cross-scetional area of the myocardium, serum cardiac troponin and BNP. Additionally, TP markedly reduced the mRNA and protein expression of myocardial ß-MHC and elevated the mRNA and protein expression of α-MHC and Foxp3 in a dose-dependent manner. In conclusion, TP can effectively ameliorate myocardial damage and inhibit cardiac hypertrophy, which is at least partly related to the elevation of Foxp3 expression in cardiomyocytes.

Gαq protein carboxyl terminus imitation polypeptide GCIP-27 improves cardiac function in chronic heart failure rats.

BACKGROUND: Gαq protein carboxyl terminus imitation polypeptide (GCIP)-27 has been shown to alleviate pathological cardiomyocyte hypertrophy induced by various factors. Pathological cardiac hypertrophy increases the morbidity and mortality of cardiovascular diseases while it compensates for poor heart function. This study was designed to investigate the effects of GCIP-27 on heart function in rats with heart failure induced by doxorubicin. METHODS AND RESULTS: Forty-eight rats were randomly divided into the following six groups receiving vehicle (control), doxorubicin (Dox), losartan (6 mg/kg, i.g.) and three doses of GCIP-27 (10, 30, 90 µg/kg; i.p., bid), respectively. Heart failure was induced by Dox, which was administered at a 20 mg/kg cumulative dose. After 10 weeks of treatment, we observed that GCIP-27 (30, 90 µg/kg) significantly increased ejection fraction, fraction shortening, stroke volume and sarcoplasmic reticulum Ca2+ ATPase activity of Dox-treated hearts. Additionally, GCIP-27 decreased myocardial injury, heart weight index and left ventricular weight index, fibrosis and serum cardiac troponin-I concentration in Dox-treated mice. Immunohistochemistry, western blotting and real-time PCR experiments indicated that GCIP-27 (10-90 µg/kg) could markedly upregulate the protein expression of myocardial α-myosin heavy chain (MHC), Bcl-2, protein kinase C (PKC) ε and phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 as well as the mRNA expression of α-MHC, but downregulated the expression of ß-MHC, Bax and PKC ßII, and the mRNA expression levels of ß-MHC in Dox-treated mice. It was also found that GCIP-27 (30, 90 µg/L) decreased cell size and protein content of cardiomyocytes significantly in vitro by comparison of Dox group. CONCLUSIONS: GCIP-27 could effectively ameliorate heart failure development induced by Dox. PKC-ERK1/2 signaling might represent the underlying mechanism of the beneficial effects of GCIP-27.

Transmembrane transport of the Gαq protein carboxyl terminus imitation polypeptide GCIP-27.

The Gαq protein carboxyl terminus imitation polypeptide (GCIP)-27 has been shown to affect cardiac hypertrophy and vascular remodeling in various models both in vitro and in vivo. Transport across the plasma membrane is a critical step in regulating the action of this peptide drug. This study was designed to explore the mechanisms underlying the transmembrane transport of GCIP-27. The peptide drug was labeled with fluorescein isothiocyanate (FITC), and measured in a time- and concentration-dependent manner using laser confocal microscopy. Various transport inhibitors, including energy and endocytosis inhibitors, were used to identify the factors that regulate its transmembrane transport. GCIP-27 transport was examined in cardiomyocytes, cardiac fibroblasts, vascular endothelial cells, vascular smooth muscle cells (VSMCs) and hepatocytes. Atomic force microscopy and scanning electron microscopy were used to determine the ultrastructure of the cardiomyocyte membranes. The results showed that GCIP-27 was transported through the plasmalemma in a time- and concentration-dependent manner. The rate of uptake and the level of GCIP-27 in the cells decreased significantly after treatment with energy inhibitors, methyl-ß-cyclodextrin chlorpromazine or heparin. GCIP-27 levels in VSMCs and cardiomyocytes were significantly greater than the levels observed in hepatocytes, cardiac fibroblasts and vascular endothelial cells. Treatment with GCIP-27 led to a marked increase in the surface roughness of the cellular membrane. In conclusion, the transmembrane transport of GCIP-27 is mediated by endocytosis, which requires energy, and GCIP-27 preferentially enters myocardial cells and VSMCs.

Panax notoginseng saponins attenuate atherosclerosis via reciprocal regulation of lipid metabolism and inflammation by inducing liver X receptor alpha expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax notoginseng (Burk.) F.H. Chen has been used as a health product and natural remedy in traditional medicine for cardiovascular diseases for more than 1000 years in Asia, including China, Japan, and Korea. Panax notoginseng saponins (PNS) are the major effective ingredients extracted from Panax notoginseng. AIM OF THE STUDY: The purpose of this study was to investigate whether Panax notoginseng saponins (PNS) attenuated atherosclerosis by inducing liver X receptor alpha (LXRα) expression and to elucidate the mechanisms responsible for the effects. MATERIALS AND METHODS: The AS rats were treated once daily with PNS (100 mg/kg, i.p.), and pathological changes in the aorta were observed using Sudan IV staining. The expression of LXRα in the aortic wall was measured by Western blot analysis. THP-1 macrophages were cultured with PNS in the presence or absence of geranylgeranyl pyrophosphate ammonium salt (GGPP), an LXRα antagonist. The expression of LXRα and its target genes ATP-binding cassette A1 and G1 (ABCA1, ABCG1) were determined by qRT-PCR. The transcriptional activation of the LXRα gene promoter was analyzed by a reporter assay. The NF-κB DNA binding activity and the expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1) was evaluated respectively by Trans-AM NF-κB ELISA and ELISA in THP-1 macrophages that were stimulated with LPS after treatment with PNS and GGPP. RESULTS: PNS treatment alleviated the typical pathological changes associated with atherosclerosis in rats. The expression of LXRα was increased in rat aortas after treatment with PNS. In vitro, PNS increased LXRα mRNA levels in THP-1 macrophages. The reporter assays showed that PNS enhanced transcriptional activation of the LXRα gene promoter and led to the upregulation of ABCA1 and ABCG1 expression. This upregulation could be reversed by treatment with GGPP. Additionally, PNS inhibited NF-κB DNA binding activity and reduced secretion of IL-6 and MCP-1 in LPS-stimulated THP-1 macrophages. These effects could be reversed by GGPP. CONCLUSIONS: The results indicated that the PNS-mediated attenuation of AS may, at least partly, due to LXRα uprergulation. The mechanisms of action included enhancement transcriptional activation of the LXRα gene promoter by PNS and subsequent upregulation of ABCA1 and ABCG1 and inhibition of NF-κB DNA binding activity.

Gαq-protein carboxyl terminus imitation polypeptide GCIP-27 attenuates proliferation of vascular smooth muscle cells and vascular remodeling in spontaneously hypertensive rats.

Gq-protein is located at the convergent point in signal transduction pathways leading to vascular remodeling. The carboxyl terminus of Gα-subunit plays a vital role in G-protein-receptor interaction. The present study was designed to explore the effects of a synthetic Gαq carboxyl terminus imitation peptide, namely GCIP-27, on vascular smooth muscle cells (VSMC) in vitro and vascular remodeling in spontaneous hypertensive rats (SHR). Hyperplasia and hypertrophy of VSMC wre determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, [(3)H]-thymidine and [(3)H]-leucine incorporation, and [Ca(2+)](i) was measured with Fluo-3/AM staining. Systolic blood pressure (SBP), the ratio of media thickness to lumen diameter (MT/LD) of aorta, collagen content, and phospholipase C activity in aorta were measured in SHR. GCIP-27 (3-100 µg/l) significantly decreased proliferation activity, protein content, incorporation of [(3)H]-thymidine and [(3)H]-leucine, and [Ca(2+)](i) level in VSMC. SBP, MT/LD, collagen content, and phospholipase C activity in aorta of SHR were decreased significantly in GCIP-27 (7, 20, 60 µg/kg)-treated groups and losartan (6 mg/kg) group compared with vehicle group. In conclusion, GCIP-27 could inhibit vascular remodeling effectively in vitro and in vivo.

A Chinese herbal decoction, Danggui Buxue Tang, improves chronic fatigue syndrome induced by food restriction and forced swimming in rats.

Danggui Buxue Tang (DBT), a Chinese medicinal decoction that contains Radix Angelicae sinensis (Danggui) and Radix Astragali (Huangqi) at a ratio of 1:5, is used commonly for treating women's ailments. The present study explored the effects of this preparation on chronic fatigue syndrome (CFS). Rats were subjected to a combination of food restriction and forced swimming to induce CFS, and rats were gavaged once daily with either 12 or 24 g/kg DBT for 28 days. Body weights, T-cell subset counts, (3) H-TdR incorporation measurements and mRNA levels of IL-1ß, TNF-α, NF-кB, p38MAPK and JNK were determined on days 14 and 28. The swimming endurance capacity was measured on day 28. Rats that received DBT exhibited increased body weight and endurance capacity, corrected T cell subsets counts, increased (3) H-TdR incorporation and decreased mRNA levels of IL-1ß, TNF-α, NF-кB, p38MAPK and JNK compared with rats that did not receive DBT. The results indicate that DBT can ameliorate CFS through immune modulation and may act to normalize cytokines and their related signaling pathways.

Panax notoginseng saponins attenuate atherogenesis accelerated by zymosan in rabbits.

Panax notoginseng saponins (PNS) are highly valued traditional Chinese medicine. The effects of PNS (120 mg/kg, once daily administrated intragastrically (i.g.)) on atherosclerosis induced by a high-cholesterol diet and chronic inflammation, which was derived through zymosan (10 mg/kg, once every 2 d) administration intraperitoneally, were evaluated in rabbits for 8 weeks. A normal group, a simple high-fat diet group, and a zymosan plus high-cholesterol diet group (Zym) were used as controls. Typical pathologic changes associated with atherosclerosis in rabbits following induction by zymosan were alleviated by PNS treatment. After 2, 4, 6, and 8 weeks of treatment, PNS decreased the serum levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, interleukin-6 and C-reactive protein as well as increased high-density lipoprotein cholesterol level significantly in comparison with those in the Zym group, except for triglycerides at week 2. In addition, PNS treatment significantly decreased the mRNA expression levels of monocyte chemoattactant protein-1 and nuclear factor-kappaB/p65 in the aorta wall after 8 weeks of treatment compared with the Zym group. In conclusion, PNS attenuates atherogenesis through an antiinflammatory action and regulation of the blood lipid profile.

Panax notoginseng saponins decrease cholesterol ester via up-regulating ATP-binding cassette transporter A1 in foam cells.

AIM: Accumulating evidence has indicated that Panax notoginseng saponins (PNS), the major ingredients in Panax notoginseng (Burk.) F.H. Chen which could be found widely in Asia, can attenuate atherogenesis in vivo. This study was designed to examine the relationship of PNS with cholesterol ester in foam cells sourced from macrophages and the effect of PNS on the expression of ATP-binding cassette transporter A1 (ABCA1). MATERIALS AND METHODS: Foam cells sourced from macrophages were cultured with PNS. The content of cholesterol ester in foam cells was analyzed and expressions of ABCA1 and liver X receptor α (LXRα) in foam cells were measured by real-time PCR and western blotting methods. RESULTS: The results showed that PNS could significantly decrease the level of cholesterol ester in foam cells at middle and high dosages. The real-time PCR and western blotting assays indicated that the expression of ABCA1 was up-regulated by PNS in a dose-dependent manner. Analysis based on these results showed that the cholesterol ester level was negatively correlated with ABCA1 expression. CONCLUSIONS: As a result, we conclude that by up-regulating the expression of ABCA1, PNS could lower the cholesterol ester level, which resulted in the attenuation of the foam cell formation. This bioactivity might be associated with the special chemical structures of PNS that are similar to the natural agonist of LXRα.

Prenatal exposure to inflammation induced by zymosan results in activation of intrarenal renin-angiotensin system in adult offspring rats.

Prenatal exposure to inflammation produces offspring that are hypertensive in adulthood. The present study was to explore the role of intrarenal renin-angiotensin (Ang) system in the development of hypertension programmed by prenatal exposure to zymosan. Pregnant rats were randomly divided into control group and zymosan group (n = 6). Rats in these two groups were administered intraperitoneally with 0.5 ml vehicle and 2.37 mg/kg zymosan, respectively, on the eighth, tenth, and 12th day during gestation. The results showed the glomerular number and creatinine clearance rate decreased significantly in offspring of zymosan-treated rats. The renal cortex renin mRNA expression, Ang II-positive cells in renal cortex, and Ang II expression in renal medulla increased significantly in offspring of zymosan-treated rats at 7, 16, and 25 weeks of age. The plasma renin activity and Ang II concentration were unchanged. In conclusion, prenatal exposure to zymosan resulted in the activation of intrarenal renin-Ang system in adult offspring rats.