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Background Systemic sclerosis (SSc) is a multisystem rheumatic disease. Orofacial manifestations are commonly in SSc but maybe usually ignored and overshadowed by other systemic complications. Multiple comparative studies have been conducted to investigate the possible links between SSc and oral manifestations. The present study aimed to investigate the oral health status in patients with SSc. Methods Pubmed, Embase, Web of Science, and Scopus were searched up to July 2020. Following outcomes were evaluated: Probing depth (PD), Attachment loss (AL), Bleeding on probing (BOP), Number or percentage of Sites with PD ≥ 4 mm, Prevalence of periodontitis, Number of teeth, Decayed Teeth, Missing teeth, Filled teeth, DMFT index, and the interincisal distance. Newcastle-Ottawa Scale (NOS) were applied for quality assessment. The statistical analysis was processed using the software STATA. Results 11 eligible studies were included. The maximum interincisor distance was significantly restricted in SSc patients (SMD − 1.061; 95 %CI [− 1.546, − 0.576]; Z = 4.29, P = 0.000).The prevalence of Periodontitis (OR 7.007; 95 %CI [3.529, 13.915]; Z = 5.56, P = 0.000), PD (SMD 3.101; 95 %CI [1.374, 4.829]; Z = 3.52, P = 0.000), AL(SMD 2.584; 95 %CI [0.321, 4.846]; Z = 2.24, P = 0.025), sites with PD ≥ 4mm (SMD 2.071 ; 95 %CI [0.267, 3.875]; Z = 2.25, P = 0.024) and the number of decayed teeth (SMD, 0.186; 95 %CI [0.007, 0.365]; Z = 2.04, P = 0.041) were increased significantly in SSc population in comparison with the controls. Conclusions SSc patients have limited mouth opening, higher periodontitis prevalence, and worse periodontal status, as well as an increased number of decayed teeth. Routinely oral hygiene instruction and initial periodontal treatment is recommended for SSc patients.

Background and Objectives: Kangaroo mother care (KMC) benefits preterm infants' health through increasing breastfeeding, but the longitudinal effects of KMC remain unknown. This study investigates ...

The HAIYPRH (T7) peptide has been widely used as a ligand for constructing tumor-targeted nanodrug delivery systems since it can target the transferrin receptor (TfR) and then enter cells easily with the help of transferrin (Tf). However, the dynamic mechanism by which transferrin promotes the entry of T7-conjugated nanostructures into cells remains unclear. Herein, a force tracing technique based on atomic force microscopy (AFM) was used to track the ultrafast dynamic process of a T7-conjugated gold nanoparticle (AuNP-T7) entering a cell at the single-particle level in real time. Tf helped decrease the endocytosis force and increase the endocytosis speed of AuNP-T7 in A549 cells. However, Tf only increased the endocytosis speed of AuNP-T7 in HeLa cells. In contrast, in Vero cells without TfR overexpression, Tf decreased the endocytosis speed. This report provides important insights for redesigning and developing T7-conjugated nanodrug carriers in targeted nanodrug delivery systems.

Because of structural complexity, a “biosimilar” will not be exactly the same as its reference biologic treatment, but is required to be equivalent in all relevant attributes, including efficacy. T...

The construction of the evaluation index system of employee satisfaction level is the basis for an enterprise to measure the level of employee satisfaction. In this paper, the author analyzes the employee incentive in supply chain network based on asymmetric information game analysis and fuzzy model. Through the correction of network weight and threshold value, the error function decreases along the gradient direction. The construction and training of the network can be realized by MATLAB. The newff function in the software is used to construct the network, and the train function is used to train. This evaluation index system is a multi-level target evaluation system based on asymmetric information game, and its basic principle is to simplify complex problems. Long term effort is bigger when the salesperson’s risk averse parameter is more than a certain value or risk averse parameter is less but discount factor is more than a threshold; short term effort is bigger when risk averse parameter and discount factor is both less. For both information scenarios, the compensation contracts are designed and comparison analyses are conducted.

Purpose This study aimed to explore the potential role and mechanism of garlic-derived S-allylmercaptocysteine (SAMC), the major water-soluble fraction of garlic, in osteoarthritis (OA) both in vivo and in vitro. Methods The effect of SAMC in a surgical-induced OA model was examined by X-ray, staining, ELISA, and immunoblotting. Then the key role of Nrf2 by SAMC treatment in IL-1β stimulated chondrocytes in vitro was determined by gene-knockdown technique. Results SAMC could stabilize the extracellular matrix (ECM) by decreasing metalloproteinase (MMPs) expression to suppress type II collagen degradation in OA rats. The inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, were elevated in OA, which could be down-regulated by SAMC treatment. This effect was parallel with NF-κB signaling inhibition by SAMC. As oxidative stress has been shown to participate in the inflammatory pathways in OA conditions, the key regulator Nrf2 in redox-homeostasis was evaluated in SAMC-treated OA rats. Nrf2 and its down-stream gene NQO-1 were activated in the SAMC-treated group, accompanied by NAD(P)H oxidases 4 (NOX4) expression down-regulated. As a result, the toxic lipid peroxidation byproduct 4-hydroxynonenal (4HNE) was reduced in articular cartilage. In IL-1β-stimulated primary rat chondrocytes, which could mimic OA in vitro, SAMC could ameliorate collagen destruction, inhibit inflammation, and maintain redox-homeostasis. Interestingly, after Nrf2 gene knockdown by adenovirus, the protective effect of SAMC in IL-1β-stimulated chondrocytes disappeared. Conclusion Overall, our study demonstrated that SAMC targeted Nrf2 to protect OA both in vivo and in vitro, which would be a new pharmaceutical way for OA therapy.

Many clinical trials of treatments for patients hospitalised for COVID-19 use an ordinal scale recommended by the World Heath Organisation. The scale represents intensity of medical intervention, with higher scores for interventions more burdensome for the patient, and highest score for death. There is uncertainty about use of this ordinal scale in testing hypotheses. With the objective of assessing the power and Type I error of potential endpoints and analyses based on the ordinal scale, trajectories of the score over 28 days were simulated for scenarios based closely on results of two trials recently published. The simulation used transition probabilities for the ordinal scale over time. No one endpoint was optimal across scenarios, but a ranked measure of trajectory fared moderately well in all scenarios. Type I error was controlled at close to the nominal level for all endpoints. Because not tied to a particular population with regard to baseline severity, the use of transition probabilities allows plausible assessment of endpoints in populations with configurations of baseline score for which data is not yet published, provided some data on the relevant transition probabilities are available. The results could support experts in the choice of endpoint based on the ordinal scale.

Objective Urinary incontinence is highly prevalent among women, with a substantial effect on health-related quality of life. This article aimed to investigate the independent factors for urinary incontinence (UI) and the relative importance of each factor. Methods This study was a cross-sectional survey of Chinese women in Guangzhou. Female 20 years and older were invited to participate. The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form was used to determine whether respondents are experiencing UI. Univariate and multivariate unconditional logistic regression analyses were performed to determine the significant risk factors associated with UI. Results A total of 2626 women were invited to participate in the survey. The response rate was 80.5% (2114/2626). The prevalence of UI among the study population was 31.2%. Old age, increased body mass index, childbirth, family history of any female pelvic floor disorders, symptoms of chronic cough or rhinitis, wearing a corset, and often drinking were independent risk factors for UI. Conclusions Urinary incontinence is common among Chinese women in Guangzhou. Among the factors that we are concerned with, old age and vaginal delivery are the two with greatest impact. Moreover, wearing a corset and drinking are the 2 lifestyle factors associated with UI.

Most conventional drugs accumulate in non-target areas in the body of patients and are responsible for adverse side effects due to poor solubility and poor selectivity after injection, with only a tiny portion of drugs reaching their targets (cells or tissues). Drug delivery is believed to overcome this challenge by allowing control over drug distribution, metabolism, and excretion, which also improves drug safety and efficacy. Nano-drugs (nanoscale particles and vehicles) have attracted great interest because of the enhanced permeation and retention (EPR) effect for tumors. In this review, we summarized the types of nano-drug carriers, described the advantages and adverse effects of the carriers, and discussed the mechanism of single nano-drug transport in living cells. Better understanding the nano-drug delivery mechanism is necessary to ensure the potential chemotherapy of nano-drugs.

Under adverse conditions, such as sustained or chronic hyperglycemia or hyperlipidemia, ROS (reactive oxygen species) or/and ER-stress (endoplasmic reticulum stress) will be induced in pancreatic β cells. ROS or ER-stress damages β-cells even leads to apoptosis. Previously we found ROS or ER-stress resulted in JNK activation in β cells and overexpressing NR4A1 in MIN6 cells reduced JNK activation via modulating cbl-b expression and subsequent degrading the upstream JNK kinase (MKK4). To search other possible mechanisms, we found the mRNA level and protein level of MKP7 (a phosphatase for phospho-JNK) were dramatic reduced in pancreatic β cells in the islets from NR4A1 KO mice compared with that from wild type mice. To confirm what we found in animals, we applied pancreatic β cells (MIN6 cells) and found that the expression of MKP7 was increased in NR4A1-overexpression MIN6 cells. We further found that knocking down the expression of MKP7 increased the p-JNK level in pancreatic β cells upon treatment with TG or H2O2. After that, we figured out that NR4A1 did enhance the transactivation of the MKP7 promoter by physical association with two putative binding sites. In sum, NR4A1 attenuates JNK phosphorylation incurred by ER-stress or ROS partially via enhancing MKP7 expression, potentially decreases pancreatic β cell apoptosis induced by ROS or ER-stress. Our finding provides a clue for diabetes prevention.

The influence of neuroinflammation in the development and progression of Parkinson's disease (PD) remains unknown. Macrophage migration inhibitory factor (MIF) is a multipotent and key cytokine involved in the pathogenesis of acute and chronic inflammatory and immune disorders. The aim of this study was to investigate the neuroprotective effects mediated by MIF in PD. Cellular apoptosis was measured by RT-qPCR analysis, fluorescence-activated cell sorting (FACS) analysis and western blotting. JC-1 staining was used to analyze the mitochondrial membrane potential (MMP). The formation of autophagosomes was detected by western blot analysis. Autophagic flux was assessed by tandem mRFP-GFP-LC3 fluorescence microscopy. Expression of MIF, cleaved-PARP and LC3B-II was increased significantly in both acute and chronic PD animal models. MIF was positively associated with IL-10 (P 0.001), but inversely with TNF-α (P 0.05). The PD cells (1 mM MPP+ treated group) showed an increase in early-apoptotic cells by FACS. Upregulating MIF expression resulted in a lower concentration of cleaved-PARP than the control group (P 0.001). The MMP was higher in the MIF upregulated group than in the MIF knockdown group (P 0.001). Upregulating MIF expression resulted in a higher concentration of LC3B-II than the control group (P 0.001). Finally, LC3 puncta were markedly increased in the MIF upregulated group and in the MIF + MPP+ group. This study indicates that MIF mediates a neuroprotective effect via suppressing inflammatory responses, inhibiting apoptosis and inducing autophagy in PD.

Background Radix Salviae Miltiorrhizae (RSM), a well-known traditional Chinese medicine, has been shown to inhibit tumorigenesis in various human cancers. However, the anticancer effects of RSM on human hepatocellular carcinoma (HCC) and the underlying mechanisms of action remain to be fully elucidated. Methods In this study, we aimed to elucidate the underlying molecular mechanisms of RSM in the treatment of HCC using a network pharmacology approach. In vivo and in vitro experiments were also performed to validate the therapeutic effects of RSM on HCC. Results In total, 62 active compounds from RSM and 72 HCC-related targets were identified through network pharmacological analysis. RSM was found to play a critical role in HCC via multiple targets and pathways, especially the EGFR and PI3K/AKT signaling pathways. In addition, RSM was found to suppress HCC cell proliferation, and impair cancer cell migration and invasion in vitro. Flow cytometry analysis revealed that RSM induced cell cycle G2/M arrest and apoptosis, and western blot analysis showed that RSM up-regulated the expression of BAX and down-regulated the expression of Bcl-2 in MHCC97-H and HepG2 cells. Furthermore, RSM administration down-regulated the expression of EGFR, PI3K, and p-AKT proteins, whereas the total AKT level was not altered. Finally, the results of our in vivo experiments confirmed the therapeutic effects of RSM on HCC in nude mice. Conclusions We provide an integrative network pharmacology approach, in combination with in vitro and in vivo experiments, to illustrate the underlying therapeutic mechanisms of RSM action on HCC.

Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). CS heightens inflammation, oxidative stress and apoptosis. Ergosterol is the main bioactive ingredient in Cordyceps sinensis (C. sinensis), a traditional medicinal herb for various diseases. The objective of this work was to investigate the effects of ergosterol on anti-inflammatory and antioxidative stress as well as anti-apoptosis in a cigarette smoke extract (CSE)-induced COPD model both in vitro and in vivo. Our results demonstrate that CSE induced inflammatory and oxidative stress and apoptosis with the involvement of the Bcl-2 family proteins via the nuclear factor kappa B (NF-κB)/p65 pathway in both 16HBE cells and Balb/c mice. CSE induced epithelial cell death and increased the expression of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), malondialdehyde (MAD) and the apoptosis-related proteins cleaved caspase 3/7/9 and cleaved-poly-(ADP)-ribose polymerase (PARP) both in vitro and in vivo, whereas decreased the levels of superoxide dismutase (SOD) and catalase (CAT). Treatment of 16HBE cells and Balb/c mice with ergosterol inhibited CSE-induced inflammatory and oxidative stress and apoptosis by inhibiting the activation of NF-κB/p65. Ergosterol suppressed apoptosis by inhibiting the expression of the apoptosis-related proteins both in vitro and in vivo. Moreover, the usage of QNZ (an inhibitor of NF-κB) also partly demonstrated that NF-κB/p65 pathway was involved in the ergosterol protective progress. These results show that ergosterol suppressed COPD inflammatory and oxidative stress and apoptosis through the NF-κB/p65 pathway, suggesting that ergosterol may be partially responsible for the therapeutic effects of cultured C. sinensis on COPD patients.

During COVID-19 outbreak hospitals were congested and infliximab was interrupted. Thus, we performed this observational study to understand the consequent burden of complications in these special cluster of psoriatic patients. We followed up 56 psoriatic patients who were receiving Infliximab treatment by telephone. The majority of patients had lesions exacerbation, accompanied by anxiety emotion. It is suggested that reserving common drugs for psoriasis at home is necessary. Besides, telemedicine should be advocated as a main medical visit mode during the outbreak of COVID-19.

Background The neuroprotective effects of kallidinogenase against acute cerebral infarction have been demonstrated, and the use of microbubbles has been suggested as a therapeutic mechanism for drug delivery. This study was designed to investigate the optimal parameters for preparing kallidinogenase-loaded microbubbles (KLMs) and to evaluate the effects of KLM-targeted therapy on neurogenesis and angiogenesis following experimental acute cerebral infarction in rats. Materials and Methods KLMs were prepared by mechanical shaking. Male Wistar rats were randomly divided into an ultrasound-mediated KLM-treated group and 4 control groups. Treatments were administered via daily tail vein injection on 6 consecutive days, starting at 24 hours after middle cerebral artery occlusion (MCAO). The ultrasound-treated groups were subjected to a 2-MHz pulse of ultrasonic irradiation on the lateral skull of the ischemic side for 10 minutes during injection. Cell proliferation was examined using a 5-bromo-2-deoxyuridine assay. Infarct volume and neurological function were evaluated on days 3 and 7 after MCAO. Results The ultrasound-mediated KLM and kallidinogenase treatments significantly increased the numbers of doublecortin-immunoreactive cells in the subventricular zone (SVZ) and laminin+ cells in the peri-infarction region on day 7 after MCAO, compared with the other 3 groups (all P Conclusions Treatment with the ultrasound-mediated KLMs promoted the proliferation of SVZ neuroblasts and vascular regeneration, which contributed to functional improvement after stroke. These findings provide a novel therapy for ischemic stroke.

Gastric cancer remains as a common lethal malignancy worldwide. Developing novel anti-gastric cancer drugs with minimal side effects is necessary to address this public health issue. S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has been demonstrated as a suppressive agent against tumors. In this study, we examined the effect of SAMC on human gastric carcinoma growth in vivo and explored the underlying mechanism. Human gastric cancer SGC-7901 cells were inoculated subcutaneously in BALB/c nude mice. When xenograft tumors reached about 100 mm3, mice were treated with SAMC for 30 days. We observed that SAMC administration in mice effectively delayed the growth of SGC-7901 xenografts without signs of toxicity. TUNEL staining confirmed that the tumors from SAMC-treated mice exhibited a markedly higher apoptotic index. Mechanistic studies suggested that this activity may arise from its effects on the caspase activation and modulation of MAPK and PI3K/Akt signaling pathways. Taken together, these data support development of SAMC as a potential agent for gastric cancer therapy.

Diallyl trisulfide (DATS), a natural agent derived from garlic, has been tested for its antigastric cancer activities in various preliminary studies. However, more systematic pharmacodymatic (PD) and mechanistic evaluations are clearly needed. The aim of this study was to investigate the antitumor effects of DATS in the treatment of human gastric cancer cell SGC-7901 both in vitro and in vivo using widely recommended study procedures. DATS suppressed cancer cells proliferation and induced cell cycle arrest accompanied by an increase in the expressions of cyclin A2 and cyclin B1 in SGC-7901 cancer cells. DATS also caused an increase in apoptotic cell death, which involved in accumulations of bax, p53, and cytochrome C and reduction of Bcl-2 expressions. Besides, activation of JNK, ERK and p38 phosphorylation in DATS-treated cells suggested that mitogen-activated protein kinase (MAPKs) pathways were involved in DATS-induced apoptosis. Meanwhile, DATS significantly inhibited tumor growth and promoted tumor apoptosis in a xenograft model of gastric cancer cell SGC-7901. DATS inhibited tumor migration and invasion by modulating MMP9 and E-cadherin protein expressions. In addition, DATS treatment evidently increased the cytokine secretions of IL-12, TNF-α and IFN-γ (p

Diallyl trisulfide (DATS), a garlic organosulfide, has shown excellent chemopreventive potential. Cisplatin (DDP) is widely used to treat solid malignant tumors, but causing serious side effects. In the current study, we attempted to elucidate the chemopreventive mechanisms of DATS in human gastric cancer BGC-823 cells in vitro, and to investigate whether DATS could enhance the anti-tumor efficacy of DDP and improve quality of life in BGC-823 xenograft mice in vivo. Treatment with DATS (25–400 μmol/L) dose-dependently inhibited the viability of BGC-823 cells in vitro with an IC50 of 115.2±4.3 μmol/L after 24 h drug exposure. DATS (50–200 μmol/L) induced cell cycle arrest at G2/M phase in BGC-823 cells, which correlated with significant accumulation of cyclin A2 and B1. DATS also induced BGC-823 cell apoptosis, which was accompanied by the modulation of Bcl-2 family members and caspase cascade activation. In BGC-823 xenograft mice, administration of DATS (20–40 mg·kg−1·d−1, ip) dose-dependently inhibited tumor growth and markedly reduced the number of Ki-67 positive cells in tumors. Interestingly, combined administration of DATS (30 mg·kg−1·d−1, ip) with DDP (5 mg/kg, every 5 d, ip) exhibited enhanced anti-tumor activity with fewer side effects. We showed that treatment of BGC-823 cells with DATS in vitro and in vivo significantly activated kinases such as p38 and JNK/MAPK and attenuated the Nrf2/Akt pathway. This study provides evidence that DATS exerts anticancer effects and enhances the antitumor efficacy of DDP, making it a novel candidate for adjuvant therapy for gastric cancer.

A 43-year-old woman presented with a 4-day history of right limb weakness. While biking 4 days earlier, she felt a weakness in her right hand and leg. She had a history of hypertension for more than 2 years, and was taking extended-release nifedipine tablets (40 mg) and perindopril (4 mg) daily, but her blood pressure was difficult to control (fluctuations of 150–180/90–115 mm Hg). The patient did not smoke or drink alcohol, and had no family history of similar diseases. The authors thank Dr. Haiyan Lou and Dr. Xiaodong Teng for their contributions.

S-Allylmercaptocysteine (SAMC), a water-soluble organosulfur garlic derivative, has exhibited potential antitumor activity in various malignancies. Here we explored the effects of SAMC on colon cancer in vitro and in vivo and further elucidated the underlying molecule mechanisms. In this study, we found that SAMC potently suppressed cell viability and induced G2/M phase arrest and apoptosis in colon cancer HCT116 cells. Further studies showed that reactive oxygen species (ROS) attributed to SAMC-induced cell cycle arrest and apoptosis, which was attenuated by N-acetyl cysteine (NAC), an ROS scavenger. Moreover, we found that SAMC activated p38 and c-Jun N-terminal kinase (JNK) signal pathway, which was also blocked by NAC. Finally, SAMC administration in mice effectively delayed the growth of HCT116 xenografts without signs of toxicity. In conclusion, SAMC induced cell cycle G2/M phase arrest and apoptosis via ROS-mediated p38 and JNK signaling pathway in colon cancer HCT116 cells. In light of these results, SAMC may be a promising agent for anticancer therapy against colon cancer.

Ethnopharmacological relevance Traditional Chinese medicine Yifei Tongluo Granules has been employed clinically with the combination of chemotherapy agents to treat patients with multidrug-resistant tuberculosis. However, the mechanisms underlying the therapeutic potential have not been well elucidated. The present study was employed to verify immunomodulatory effect and to investigate the underlying mechanisms which have not been explored. Materials and methods The study samples of total extracts (FB-E) and polysaccharides (FB-P) were prepared by the extraction of the Yifei Tongluo Granules using appropriate techniques. A simple immunodeficient mice model was established by challenging Balb/c mice with cyclophosphamide in order to avoid the handling of tuberculosis viruses. The in vivo study was thus designed to systematically elucidate the immuno-enhancement effects of Yifei Tongluo Granules extracts in immunosuppressed mice induced by cyclophosphamide. Balb/c mice were orally ingested once daily with the low and high doses of two different extracts for ten consecutive days, respectively, accompanied by intraperitoneal injection of cyclophosphamide (60 mg/kg) on days 1–3 and 10. Results Compared with the model group, the treatment of immunodeficient mice with the low and high doses of the extracts FB-E or FB-P enhanced spleen and thymus indices, T- and B-cell proliferation as well as increased the activities of splenic natural killer, lymphokine activated killer, cytotoxic T lymphocyte cells and peritoneal macrophage phagocytosis. In addition, the FB-E or FB-P treatment balanced the ratio of Th1/Th2 and up-regulated the CD4+/CD8+ ratio in the serum. Conclusions These results demonstrate, for the first time, that the treatment of the cyclophosphamide-challenged mice with the Yifei Tongluo Granules extracts resulted in accelerated recovery of immunosuppression, sugguesting that the immunomodulation might be the mechanism for the observed clinical benefits of Yifei Tongluo Granules. Our findings provide preliminary mechanistic study evidences for clinical application of Yifei Tongluo Granules in patients with immunodeficient diseases such as tuberculosis.

The garlic-derived organosulfur compound S-allylmercaptocysteine (SAMC) has been reported to exhibit anti-inflammatory and anti-oxidative activities, whereas its potential therapeutic effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unknown. In this study, we focused on exploring the therapeutic effects of SAMC on LPS-induced ALI mice and the involvement of underlying molecular mechanisms. BalB/c mice were treated with SAMC (10, 30 and 60 mg/kg) or positive control N-acetylcysteine (NAC, 500 mg/kg) by gavage after intratracheal instillation of LPS for 30 min and were sacrificed 24 h after LPS administration. Our results indicate that the treatment with SAMC not only ameliorated the histological changes but also decreased LPS-triggered lung edema. Moreover, SAMC displayed an anti-inflammatory effect through reducing inflammatory cells infiltration, myeloperoxidase (MPO) formation and inhibiting pro-inflammatory cytokines/mediator production including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) via suppressing the activation of nuclear factor-kappaB (NF-κB) signaling pathway. Furthermore, SAMC attenuated oxidative stress evoked by LPS via diminishing malondialdehyde (MDA) formation and reversing glutathione (GSH) and superoxide dismutase (SOD) depletion. Meanwhile, SAMC up-regulated expressions of endogenous antioxidant/detoxifying proteins including heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1(NQO1) through reversing the suppression of Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway. Our results demonstrate that SAMC effectively attenuated LPS-induced ALI which was largely dependent upon inhibition of inflammation and oxidative stress via NF-κB and Keap1/Nrf2 signaling pathways.

The sequential parallel comparison design (SPCD), with sequence groups P:P, P:T, and T:T, together with the exclusion of the second-period information from placebo responders in the first period, can serve usefully for studies with highly favorable placebo response, for example, psychiatric clinical trials. This paper presents a methodology for the first-period treatment difference in the overall population and the second-period treatment difference in the placebo nonresponders for the first period, as well as other available sources of information that could be of potential interest. Without any assumptions, a hypothesis testing method is proposed based on the randomization distribution of comparisons using the covariance structure for the randomized population under the null hypothesis to control type I error. Randomization-based analysis of covariance (ANCOVA) is introduced to adjust for baseline and for the observations that serve as baselines for the second period. Related methods are proposed for the study population as a simple random sample of an almost infinite population. The statistical properties of the proposed methods are described with simulation studies; and the use of the methods is illustrated for an example based on the data from the ADAPT-A clinical trial.

(1) Background: Diabetic nephropathy, a microvascular complication of diabetes, is one of the principal causes of end-stage renal disease worldwide. The aim of this study was to explore the therapeutic effects of ergosterol on diabetic nephropathy. (2) Methods: Streptozotocin (STZ)-induced C57BL/6 diabetic mice were treated with ergosterol (10, 20, 40 mg/kg/day) for 8 weeks by oral gavage. The in vitro study employed rat mesangial cells exposed to 30 mM glucose for 48 h in the presence of 10 or 20 &mu, M ergosterol. (3) Results: Ergosterol treatment improved body weights, ameliorated the majority of biochemical and renal functional parameters and histopathological changes, and reduced extracellular matrix (ECM) deposition in diabetic mice. In vitro, ergosterol suppressed proliferation, reduced the levels of ECM proteins, and increased the expression of matrix metalloproteinase-2 and -9 in high glucose-induced mesangial cells, Furthermore, ergosterol markedly improved transforming growth factor-&beta, 1 (TGF-&beta, 1) expression, enhanced phosphorylation levels of drosophila mothers against decapentaplegic 2 (Smad2), and regulated the downstream factors in vivo and in vitro. (4) Conclusions: Ergosterol alleviated mesangial cell proliferation and the subsequent ECM deposition by regulating the TGF-&beta, 1/Smad2 signaling pathway.

Background Quantitative real-time polymerase chain reaction (RT-qPCR) is a sensitive method for quantifying mRNA abundance. With relative expression analysis, however, reliable data output is dependent on stably expressed reference genes across the samples being studied. In anorectal malformations (ARMs), there is limited data on the selection of appropriate reference genes. Purpose This study was aimed to investigate the optimal reference genes for PCR in ARM rat models. Methods We selected 15 commonly used reference genes (Rps18, Actb, B2m, Gapdh, Ppia, Hprt1, Pgk1, Ywhaz, Tbp, Ubc, Rps16, Rpl13a, Rplp1, Sdha, and Hmbs) as candidate reference genes and detected their mRNA expression in ARM samples by RT-qPCR. The expression stability and variability of these transcripts were subsequently evaluated using four methods (geNorm, NormFinder, comparative ΔCt, and BestKeeper). Results The abundance of the candidate reference genes was qualified by RT-qPCR and the cycle threshold (Ct) values ranged between 14.07 (Rplp1) and 21.89 (Sdha). In the overall candidate genes, different variations existed across the different algorithms. A comprehensive analysis revealed that Rpl13a ranked first among the relatively stable genes, followed by Ywhaz, Rps18, Sdha, and Hmbs. Conclusions The most stable reference genes for RT-qPCR were Rpl13a, Ywhaz, and Rps18 in ETU-induced ARMs in rat fetus. This study provided a foundation for reference gene selection for future gene expression analyses.

Background Wogonin has been reported to exhibit various biological activities such as anti-inflammation, anti-microbial, and anti-tumor. Previous studies have demonstrated that wogonin could down-regulate Cyclin D1 activity on multiple cancers. However, the related mechanisms have not been fully elucidated so far. Purpose The aim of the current study was to explore whether wogonin can suppress hepatocellular carcinoma (HCC) progression and the mechanism of wogonin in inhibiting Cyclin D1 expression. Methods Herein, we assessed the anti-tumor activity of wogonin against hepatocellular carcinoma (HCC) by MTT assay, clonogenic assay, cell cycle analysis and orthotopic xenograft mouse models. Western blot, immunofluoscence assay, co-immunoprecipitation assay, docking program, surface plasmon resonance, site-directed mutagenesis assay and immunohistochemical assay were performed for exploring the underlying mechanisms of wogonin-induced growth inhibition in HCC. Results Our results showed that non-toxic dosage of wogonin (10, 20 µM) could inhibit cells proliferation and suppress cells cycle progression in MHCC97L and HepG2 cell. Moreover, the findings from the western blot and immunofluoscence assay confirmed the inhibition action of wogonin (10, 20 µM) on Cyclin D1 expression in MHCC97L cells, and wogonin (10, 20 µM) pre-treatment was capable of promoting Cyclin D1 ubiquitination and degradation in MHCC97L cell. In addition, wogonin promoted phosphorylation of Cyclin D1 on threonine-286 site, the mutation of threonine-286 to alanine-286A blocked Cyclin D1 proteolysis induced by wogonin. Wogonin-promoted Cyclin D1 phosphorylation and subsequent proteolysis may associate with the activation of GSK3beta in cancer cells. The phosphorylated form of GSK3beta (active form) expression was significantly increased after wogonin (20 µM) exposure. Molecular docking study and Biacore SPR analysis of GSK3beta mutant further validated the high-affinity wogonin binding site on GSK3beta. Moreover, in vivo studies further confirmed that phospho-GSK3beta Tyr216 was over-expressed in HCC specimens after wogonin treatment while the amount of Cyclin D1 was significantly decreased. Conclusion In summary, our data reveal a novel molecular mechanism by which wogonin induces HCC cells cycle arrest and suppresses tumor proliferation.

Macrophages are the most abundant immune cells in the lung, which play an important role in COPD. The anti-inflammatory and anti-oxidation of ergosterol are well documented. However, the effect of ergosterol on macrophage polarization has not been studied. The objective of this work was to investigate the effect of ergosterol on macrophage polarization in CSE-induced RAW264.7 cells and Sprague-Dawley (SD) rats COPD model. Our results demonstrate that CSE-induced macrophages tend to the M1 polarization via increasing ROS, IL-6 and TNF-α, as well as increasing MMP-9 to destroy the lung construction in both RAW264.7 cells and SD rats. However, treatment of RAW264.7 cells and SD rats with ergosterol inhibited CSE-induced inflammatory by decreasing ROS, IL-6 and TNF-α, and increasing IL-10 and TGF-β, shuffling the dynamic polarization of macrophages from M1 to M2 both in vitro and in vivo. Ergosterol also decreased the expression of M1 marker CD40, while increased that of M2 marker CD163. Moreover, ergosterol improved the lung characters in rats by decreasing MMP-9. Furthermore, ergosterol elevated HDAC3 activation and suppressed P300/CBP and PCAF activation as well as acetyl NF-κB/p65 and IKKβ, demonstrating that HDAC3 deacetylation was involved in the effect of ergosterol on macrophage polarization. These results also provide a proof in immunoregulation of ergosterol for therapeutic effects of cultured C. sinensis on COPD patients.

Background Anorectal malformations (ARMs) are common congenital malformations of the terminal digestive tract, but little is known regarding their pathogenesis. Aberrant cell proliferation/apoptosis are believed to be involved in ARMs. However, there are no studies on proliferation/apoptosis-related genes. Purpose We aimed to investigate the spatiotemporal expression patterns of two proliferation/apoptosis-related genes (MYC proto-oncogene and tumor protein p53) and explore their potential functions in the hindguts of ethylene thiourea-induced ARMs rat fetuses. Methods MYC and p53 expression was evaluated using immunohistochemical staining, western blotting, and quantitative real-time polymerase chain reaction (RT-qPCR). Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and p53 costaining were performed to assay the colocalization of apoptotic and p53-expressing cells. Results Rat fetuses with ARMs displayed fusion failure of the urogenital septum and cloacal membrane. In the control group, MYC was persistently expressed from gestational day (GD)14 to GD16 and distributed throughout the hindgut, while p53 was weakly detected in the terminal segment of the urethra and hindgut; in the ARMs group, MYC expression was obviously reduced, while p53 was widely and highly expressed in the urethra and hindgut. Western blotting and RT-qPCR confirmed the decrease in MYC and increase in p53 expression in ARMs. TUNEL and p53 co-staining revealed considerable overlap between apoptotic and p53-expressing cells. Conclusion The expression patterns of c-myc and p53 were disrupted in ARMs rat embryos, and the downregulation of c-myc and upregulation of p53 might be related to the development of ARMs at the key time points of ARMs morphogenesis.

Nocardia usually manifests as opportunistic infections in immunocompromised hosts. Here, we report a rare case of an immunocompetent patient with lymphocutaneous nocardiosis. The patient was a 34-y...

Surgery and chemotherapy are the gold-standard treatments for ovarian cancer. The major cause of treatment failure in patients with ovarian cancer is tumoral heterogeneity and drug resistance. Paclitaxel (PTX) is one of the most commonly used first-line drugs for ovarian cancer chemotherapy. Unfortunately, the mechanisms of PTX chemoresistance remain unclear. Here, we examined the effects of post-translational neddylation on the sensitivity of ovarian cancer cells (OCCs) to PTX-induced apoptosis. Disruption of protein neddylation with the first-in-class inhibitor MLN4924 dramatically neutralized PTX-mediated antiproliferative, antimigration, and apoptotic effects in human OCCs. Moreover, MLN4924 treatment interrupted PTX-induced microtubule polymerization. Importantly, two neddylation conjugating E2 enzymes, UBE2M and UBE2F, were found to play essential roles in PTX-induced cytotoxicity and tubulin polymerization in OCCs. In summary, our findings demonstrated that disruption of protein neddylation by MLN4924 conferred resistance to PTX and provided insights into the potential mechanisms of PTX chemoresistance in ovarian cancer.

SIRT3 is a NAD+-dependent mitochondrial protein deacetylase implicated in the regulation of central metabolism and mitochondrial proteostasis. SIRT3 is downregulated in clear cell renal cell carcinoma (ccRCC), which is the most common form of renal cancer. Although ccRCC is characterized by a typical Warburg-like phenotype, mitochondrial dysfunction and elevated fat deposition, it is unknown whether SIRT3 plays a role in tumorigenesis and the development of this disease. In the present study, we found that SIRT3 overexpression and knockdown had opposing effects on the growth of ccRCC cells, decreasing and increasing the rate of cell proliferation, respectively. SIRT3 overexpression also increased mitochondrial mass in ccRCC cells. Unexpectedly, SIRT3 overexpression increased ROS levels, and sensitized cells to oxidative stress. Metabolomics and quantitative proteomics showed that SIRT3 overexpression alterd cellular metabolism and reversed the Warburg effect in ccRCC cells. Further studies demonstrated that SIRT3 promoted mitochondrial biogenesis by increasing both the expression and deacetylation of TFAM (transcription factor A, mitochondrial). Mutagenesis experiments revealed that acetylation of TFAM at K154 impaired TFAM interaction with mitochondrial DNA, thereby decreasing the activity of the protein and, consequently, mitochondrial biogenesis. Overall, our results suggest that SIRT3 regulates mitochondrial biogenesis and that its downregulation promotes a Warburg phenotype in ccRCC.

ObjectiveThe effect of polyomavirus infection in HSCT recipients is poorly understood.MethodsWe evaluated 38 HSCT recipients. Polyomavirus was detected by nested qualitative polymerase chain reaction (PCR) assays of urine. The risk factors for BK virus and JC virus were analysed. The kidney and liver functions of infected and uninfected patients were compared.ResultsBK virus, JC virus, and simian virus 40 were detected in 21%, 42%, and 0% of HSCT recipients respectively. HCMV infection was found to be an independent risk factor for JC virus infection (odds ratio (OR): 8.528), while transplants with mismatched HLA are more susceptible to BK virus infection (OR: 12.000). Liver function of JC virus-infected subjects was worse than that of uninfected subjects.ConclusionWe must be vigilant for opportunistic polyomavirus infections in HSCT recipients, especially those with HCMV co-infection or a mismatched HLA transplant. When unexplained liver function deterioration is observed, JC virus infection should be considered.

Dichotomous endpoints in clinical trials have only two possible outcomes, either directly or via categorization of an ordinal or continuous observation. It is common to have missing data for one or more visits during a multi-visit study. This paper presents a closed form method for sensitivity analysis of a randomized multi-visit clinical trial that possibly has missing not at random (MNAR) dichotomous data. Counts of missing data are redistributed to the favorable and unfavorable outcomes mathematically to address possibly informative missing data. Adjusted proportion estimates and their closed form covariance matrix estimates are provided. Treatment comparisons over time are addressed with Mantel-Haenszel adjustment for a stratification factor and/or randomization-based adjustment for baseline covariables. The application of such sensitivity analyses is illustrated with an example. An appendix outlines an extension of the methodology to ordinal endpoints.

Cisplatin is a potent chemotherapeutic agent, but its clinical usage is limited by nephrotoxicity. S‐allylmercaptocysteine (SAMC), one of the water‐soluble organosulfur garlic derivatives, has antioxidant and anti‐inflammatory properties and plays an important role in protecting cells from apoptosis. This study aims to examine the protective effects of SAMC on cisplatin nephrotoxicity and to explore the mechanism of its renoprotection. Rats were treated with cisplatin with or without pre‐treatment with SAMC. Renal function, histological change, oxidative stress markers and antioxidant enzyme activities were investigated. Apoptotic marker, nuclearfactor (NF)‐κB activity, expression of nuclear factor erythroid 2‐related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1) and inflammatory cytokines were also examined. The effect of SAMC on cell viability and apoptosis was examined in cultured human kidney (HK‐2) cells. SAMC was confirmed to significantly attenuate cisplatin‐induced renal damage by using histological pathology and molecular biological method. Pre‐treatment with SAMC reduced NF‐κB activity, up‐regulated Nrf2 and NQO1 expression and down‐regulated inflammatory cytokine levels after cisplatin administration. Cisplatin‐induced apoptosis in HK‐2 cells was significantly attenuated by SAMC. Thus our results suggest that SAMC could be a potential therapeutic agent in the treatment of the cisplatin‐induced nephrotoxicity through its anti‐apoptotic, anti‐oxidant and anti‐inflammatory effects.

The natural plant-derived product S-allylmercapto-cysteine (SAMC) has been studied in cancer therapy as a single and combination chemotherapeutic agent. The present study was employed to verify the combination use of SAMC and rapamycin that is the mTOR inhibitor with anticancer ability but has limited efficacy due to drug resistance, and to explore the underlying mechanisms. We combined rapamycin and SAMC for colorectal cancer treatment in the HCT‑116 cancer cells and a xenograft murine model. The in vivo study was established by xenografting HCT‑116 cells in BALB/c nude mice. It was found that the combination therapy had enhanced tumor-suppressing ability with the upregulation of the Bax/Bcl-2 ratio as a consequence of activated apoptosis, inhibition of autophagic activity and prevention of Akt phosphorylation. The rapamycin and SAMC combination activated antioxidant transcription expressions of Nrf2 and downstream gene NQO1. Concomitantly, autophagosome cargo p62 was downregulated, indicating that the p62 played a negative-regulatory role between Nrf2 and autophagy. Our results show that the combination of SAMC and rapamycin enhanced the anticancer ability, which could be used for the treatment of colorectal cancer. The underling mechanism of autophagy/p62/Nrf2 pathway discovered may provide a new direction for drug development, especially for traditional Chinese medicines.

Background. Garlic-derived S-allylmercaptocysteine (SAMC) has widely been used in many disease therapies. However, the potential effects and mechanism of SAMC on IL-1β-stimulated chondrocytes are unclear. Methods. Chondrocytes were isolated, and 5 ng/mL of IL-1β was added to mimic the in vitro osteoarthritis (OA) model. SAMC (20 and 60 μM) was used for the treatment in OA model. Cell viability was assessed by MTT method. Western blotting, Quantitative RT-PCR, and ELISA were performed to evaluate the mechanisms in SAMC treated OA model. Results. Following 48 h of IL-1β exposure, SAMC exhibited protection effect on IL-1β-injured chondrocyte viability. Type II collagen was elevated with reduced degradation products, as a consequence of altered MMPs/TIMP-1 ratio after SAMC treatment in IL-1β-treated chondrocytes. The protein and mRNA level of TNF-α in cellular supernatant and cells were downregulated in a dose-dependent manner. Besides, IκBα in cytoplasmic fraction was increased, while p65 level in nuclear fraction was decreased after SAMC treatment in OA. Conclusions. This study showed that SAMC may play a protective role in IL-1β induced osteoarthritis (OA) model. This effect may be through inhibiting the NF-κB signaling pathway, therefore altering the MMPs/TIMP-1 ratio change which induced type II collagen destruction and decreasing inflammatory cytokine secretion such as TNF-α.

This study was aimed to investigate the anti-tumor, anti-metastasis and immunomodulatory effects of Yifei Tongluo (YFTL), a Chinese herbal formula, in Lewis lung carcinoma mice and to explore the underlying mechanisms. LLC cells were inoculated subcutaneously in C57BL/6 mice to establish the Lewis lung carcinoma model. We observed that YFTL effectively inhibited tumor growth and prolonged the overall survival of tumor-bearing mice. Additionally, YFTL treatment resulted in a significantly decreased number of surface lung metastatic lesions compared with the model control group. Meanwhile, TUNEL staining confirmed that the tumors from YFTL-treated mice exhibited a markedly higher apoptotic index. The results suggest that Akt and mitogen-activated protein kinase (MAPKs) pathways may be involved in YFTL-induced apoptosis. The results show that YFTL also inhibited the vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2, MMP-9, N-cadherin, and Vimentin expression, but increased E-cadherin expression. Mechanistic studies indicated that YFTL could suppress the angiogenesis and the epithelial-mesenchymal transition (EMT) of the tumor through Akt/ERK1/2 and TGF&beta, 1/Smad2 pathways. In addition, YFTL also showed immunomodulatory activities in improving the immunosuppressive state of tumor-bearing mice. Therefore, our findings could support the development of YFTL as a potential antineoplastic agent and a potentially useful anti-metastatic agent for lung carcinoma therapy.

Garlic has shown versatile medicinal activities in the prevention and treatment of diseases such as chronic obstructive pulmonary disease (COPD). However, no individual garlic bioactive components have yet been determined in the COPD treatment effects. In this work, S-allylmercapto-l-cysteine (SAMC) identified in the aged garlic was selected as a model compound to determine its COPD therapeutic potential. The COPD model was established by using lipopolysaccharides (LPS) to stimulate the human airway submucosal gland cell line SPC-A1. Previous studies show that both MUC5AC up-regulation and AQP5 down-regulation play an important role in viscous COPD mucus secretions. The modulation effects of SAMC on LPS-induced MUC5AC and AQP5 productions in SPC-A1 cells were then evaluated. Pretreatment of the SPC-A1 cells with SAMC attenuated MUC5AC secretion and increased AQP5 expression in a dose-dependent manner in the non-cytotoxic concentration range of 20 to 100μM. Mechanistic studies suggested that SAMC could suppress the accumulation of MUC5AC mRNA and inhibit IкBα degradation and NF-кB p65 translocation. These results suggest that SAMC could be a promising candidate in the prevention and treatment of MUC5AC-associated disorders such as COPD.

Background Research suggests physical activity is linked to obesity. Further, the physical activity of healthy parents and their children is associated with each other. However, this relationship has not been examined in obese parents and their obese children. Methods The purpose of this study was to compare the physical activity and sedentary time of obese, low-income, ethnic minority parents and their children on weekdays and weekend days using accelerometry. Data were obtained from eight rural sites in the middle and eastern part of North Carolina (N.C.), United States (U.S.) from 2007-2010 using a rolling enrollment. One hundred and ninety-nine obese parents (94 % female) and their obese children (54 % female) wore accelerometers simultaneously for three weekdays and one weekend day. Total physical activity, moderate-to-vigorous physical activity (MVPA) and sedentary time and proportions were determined. Results Parents’ and children’s total physical activity and MVPA levels were lower on weekend days than weekdays. Total counts per minute for children on weekdays and weekend days were greater than for parents (p 0.13). Discussion Since physical activity levels of obese parents and their obese child are somewhat related, especially on weekend days, combined parent-child obesity programs focused on reducing sedentary time could be beneficial, particularly for the child. Conclusion In conclusion, this study of the physical activity levels of obese parents and their obese children found some relationships between the parents’ and children’s physical activity and sedentary behavior patterns, especially on weekend days. Trial registration NCT01378806 .

This study was aimed to investigate the chemical composition, antioxidant activities and hepatoprotective effect of flavonoids from Ziziphus jujuba cv. Jinsixiaozao (ZJF). The composition of ZJF was analyzed by high performance liquid chromatography (HPLC) and Liquid chromatography–mass spectrometry (LC–MS), and antioxidant properties were investigated by biological assays in vitro. The hepatoprotective activity of ZJF was evaluated in acetaminophen (APAP)-treated BALB/c mice. Results indicate that ZJF displayed significant antioxidant capacity. Pretreatment with ZJF significantly decreased APAP-elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin (TB). Activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were enhanced with ZJF administration, while malondialdehyde (MDA) level and glutathione (GSH) depletion were reduced. Meanwhile, ZJF reversed the suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, and up-regulated the protein expression of NAD(P)H: quinone oxidoreductase 1(NQO1) in liver damage mice. Furthermore, ZJF attenuated APAP-induced inflammatory mediator production, such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β). Expression of p65 showed that ZJF dampened nuclear factor-κB (NF-κB) activation. The results strongly indicate that the hepatoprotective role of ZJF in APAP-induced hepatotoxicity might result from its induction of antioxidant defense via activation of Nrf2 and reduction of inflammation via inhibition of NF-κB.

Background Rapid diagnostic tests (RDTs) have become an essential tool in the contemporary malaria control and management programmes in the world. This study aims to evaluate the performance of two commonly used RDTs for malaria diagnosis in the China-Myanmar border area. Methods A total 606 febrile patients in the China-Myanmar border were recruited to this study and were diagnosed for malaria infections by microscopy, two RDTs tests (Pf/Pan device, and Pv/Pf device) and nested PCR. Results Malaria parasites were found in 143 patients by microscopy, of which 51, 73, and 19 were Plasmodium falciparum, Plasmodium vivax and P. falciparum/P. vivax mixed infections, respectively. Compared to microscopy, the sensitivity of the Pf/Pan device was 88.6% for P. falciparum and 69.9% for P. vivax with the specificity of 90.4%. For a subset of 350 patients, the sensitivity of the Pf/Pan device and Pv/Pf device for detection of P. falciparum was 87.5% and 91.7%, respectively; and for detection of P. vivax was 72.0% and 73.8%, respectively. The specificity of the Pf/Pan device and Pv/Pf device was 94.3% and 96.5%, respectively. Nested PCR detected malaria parasites in 174 of 606 samples, of which 67, 79, two and 26 were P. falciparum, P. vivax, P. ovale and P. falciparum/P. vivax mixed infections, respectively. Compared to nested PCR, all other methods had sensitivity below 80%, suggesting that a significant number of cases were missed. Conclusions Compared to PCR, both microscopy and RDTs had lower sensitivities. RDTs had similar performance to microscopy for P. falciparum diagnosis, but performed worse for P. vivax diagnosis. Other RDT products should be selected with higher sensitivity (and good specificity) for both P. falciparum and P. vivax diagnosis.

Background and Aims Nuclear factor E2-related factor 2 (Nrf2) appears to be an attractive therapeutic target for the treatment of cardiac disease. We investigated whether a synthetic triterpenoid derivative of dihydro-CDDO-trifluoroethylamide (dh404), a novel Nrf2 activator, protects against pathological cardiac responses to hemodynamic stress in mice. Methods Cardiac maladaptive remodeling and dysfunction were established by transverse aortic constriction (TAC) in mice. Hypertrophic growth of rat neonatal cardiomyocytes was induced by angiotensin II (Ang II). Cell death of rat neonatal cardiomyocytes was induced with hydrogen peroxide (H2O2). Cellular proliferation of rat neonatal cardiac fibroblasts was induced by Ang II, norepinephrine (NE) and phenylephrine (PE). Protein expression was assessed by immunochemical staining and Western blots. Gene expression was determined by real time reverse transcription-polymerase chain reaction (Q-PCR). Results TAC suppressed myocardial Nrf2 expression, increased myocardial 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine levels, and induced cardiac hypertrophy, fibrosis and apoptosis, and overt heart failure and death in mice. Administration of dh404 inhibited the pathological cardiac remodeling and dysfunction, and reduced the mortality. Moreover, dhd404 elevated myocardial levels of Nrf2 and Nrf2 nuclear translocation with a dramatic suppression of the oxidative stress in the heart. Dh404 inhibited hypertrophic growth and death in primary culture of rat neonatal cardiomyocytes and suppressed proliferation in primary culture of rat neonatal cardiac fibroblasts. However, these effects of dh404 were blunted by knocking down of Nrf2. Conclusion These findings demonstrate that dh404 prevents pathological cardiac remodeling and dysfunction by activating Nrf2, indicating a therapeutic potential of dh404 for cardiac disease.