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Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

The clinical utilization of doxorubicin (Dox) in various malignancies is restrained by its major adverse effect: irreversible cardiomyopathy. Extensive studies have been done to explore the prevention of Dox cardiomyopathy. Currently, ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy. Sorting Nexin 3 (SNX3), the retromer-associated cargo binding protein with important physiological functions, was identified as a potent therapeutic target for cardiac hypertrophy in our previous study. However, few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy. In this study, a decreased level of SNX3 in Dox-induced cardiomyopathy was observed. Cardiac-specific Snx3 knockout (Snx3-cKO) significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly. SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro, and cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to Dox-induced ferroptosis and cardiomyopathy. Mechanistically, SNX3 facilitated the recycling of transferrin 1 receptor (TFRC) via direct interaction, disrupting iron homeostasis, increasing the accumulation of iron, triggering ferroptosis, and eventually exacerbating Dox-induced cardiomyopathy. Overall, these findings established a direct SNX3–TFRC–ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRC-dependent ferroptosis.

This study seeks to develop a fundamental comprehension of the noise challenges encountered by commercial aircraft fuselage surface attachments, such as blade antennas and pitot tubes. The study examines the flow characteristics and far-field noise directivity of a wall-mounted NACA0012 airfoil with various sweep angles (−35°, −15°, 0°, +15°, and +35°) and an aspect ratio of 1.5. The Mach numbers of the incoming flow range from 0.8 to 0.9 with a Reynolds number of about 7 × 105. Delayed Detached Eddy Simulation (DDES) and the Ffowcs Williams–Hawkings (FW-H) equation are utilized. The results show that the shock wave intensity at the junction between the airfoil and the bottom wall is enhanced by the forward-swept angle. The shock wave moves and changes into a λ-type structure, while the boundary layer separates and produces shedding vortices in the junction at a smaller Mach number on the forward-swept airfoil compared to the straight airfoil and the backward-swept airfoil. These phenomena cause significant surface pressure fluctuations in the junction and result in a significant dipole noise in the far field, which is the primary source of noise in the far field. In addition, the normal Mach number and the absolute sweep angle also contribute to the far-field noise.

Electronic cigarettes (e-cigarettes) have rapidly gained popularity as alternatives to traditional combustible cigarettes. However, their long-term health impact remains uncertain. This study aimed to investigate the effects of chronic exposure to e-cigarette aerosol (ECA) in mice compared to conventional cigarette smoke (CS) exposure. The mice were exposed to air (control), low, medium, or high doses of ECA, or a reference CS dose orally and nasally for eight months. Various cardiovascular and pulmonary assessments have been conducted to determine the biological and prosthetic effects. Histopathological analysis was used to determine structural changes in the heart and lungs. Biological markers associated with fibrosis, inflammation, and oxidative stress were investigated. Cardiac proteomic analysis was applied to reveal the shared and unique protein expression changes in ECA and CS groups, which related to processes such as immune activation, lipid metabolism, and intracellular transport. Overall, chronic exposure to ECA led to adverse cardiovascular and pulmonary effects in mice, although they were less pronounced than those of CS exposure. This study provides evidence that e-cigarettes may be less harmful than combustible cigarettes for the long-term health of the cardiovascular and respiratory systems in mice. However, further human studies are needed to clarify the long-term health risks associated with e-cigarette use.

Existing research has neglected to explain why freemium business models lead to differentiated performance or what accounts for the difference in their revenue models. This study investigates how the configuration effect of freemium business models promotes performance and explores the different ways through which freemium business models, their dynamic capabilities, and environmental uncertainty interact to achieve high performance. The fuzzy set qualitative comparative analysis (fsQCA) approach was used to test the conceptual model with data from 45 freemium business model apps. From empirical evidence on the relationship between freemium business models, dynamic capabilities, and environmental uncertainty, the study finds that (1) bundled and fragmented freemium business models are fundamental performance drivers. However, they work only in combination with dynamic capabilities and environmental uncertainty. Moreover, the bundled and fragmented freemium business models have complementary rather than substitution relationships. (2) For companies with bundled and fragmented freemium business models, high sensing and seizing capabilities are critical to achieving high performance. A high bundled freemium business model, high sensing capability, and a lack of fragmented freemium business models and seizing capability can lead to high performance, regardless of reconfiguration capabilities and environmental uncertainty. (3) Under high environmental uncertainty, offering fragmented freemium business models with or without a bundled freemium business model will lead to high performance if they have high sensing, seizing, and reconfiguring capabilities. This study can provide systematic decision support for achieving high performance through freemium business models and the configuration of dynamic capabilities under environmental uncertainty.

Abstract Electronic cigarette (EC) has been suggested to be less harmful than cigarette smoking, but the research on the full extent of their harm reduction potential is still lacking. This study aimed to evaluate the influence of EC aerosol and cigarette smoke (CS) on cardiovascular, gastrointestinal, and renal functions in mice after prolonged exposure. Forty-eight C57BL/6J male mice were randomly grouped and then exposed to fresh air (control), mung bean-flavored EC aerosol with low and high dose (EC1L, 6 mg/kg; EC1H, 12 mg/kg), watermelon-flavored EC aerosol with low and high dose (EC2L, 6 mg/kg; EC2H, 12 mg/kg), and finally a cigarette smoke (CS, 6 mg/kg), respectively. After 10 weeks of exposure, the heart rate increased for both the EC and CS groups, and the effect of CS on blood oxygen saturation was significantly higher than that of the EC group (P

For noise reduction at a low-to-moderate Reynolds number, airfoil trailing-edge tonal noise has multiple prominent tones. Among these tones, secondary tones are greatly influenced by external disturbances such as oscillations commonly in the environment. In previous experiments, the spatial movement of sources was found to be related to an inherent high-frequency oscillation. Therefore, the spatial influence of external low-frequency oscillations was investigated in this study. By using tripping tapes to construct different symmetry source regions on the pressure side with side secondary tones, a transient spatial analysis of an NACA0012 airfoil at 2 degrees was performed by microphone arrays when a 10 Hz pressure oscillation was significant at 24 m/s. Temporally, this 10 Hz periodic strength change became more intense at a broader frequency bandwidth for a longer source region. Furthermore, a substantial time delay, significantly larger than the sound propagating time difference between microphones, was observed exclusively along the spanwise direction. This delay led to a periodic directivity pattern, particularly when two 0.2 m source regions were separated by a 0.2 m or 0.4 m tripping region. This low-frequency oscillation introduces an asymmetric transient switching pattern for symmetric spanwise source regions. Consequently, the response of airfoils to external oscillations in field tests should be considered.

This paper investigates the impact of varying the part geometric complexity and 3D printing process setup on the resulting structural load bearing capacity of fiber composites. Three levels of geometric complexity are developed through 2.5D topology optimization, 3D topology optimization, and 3D topology optimization with directional material removal. The 3D topology optimization is performed with the SIMP method and accelerated by high-performance computing. The directional material removal is realized by incorporating the advection-diffusion partial differential equation-based filter to prevent interior void or undercut in certain directions. A set of 3D printing and mechanical performance tests are performed. It is interestingly found that, the printing direction affects significantly on the result performance and if subject to the uni direction, the load-bearing capacity increases from the 2.5D samples to the 3D samples with the increased complexity, but the load-bearing capacity further increases for the 3D simplified samples due to directional material removal. Hence, it is concluded that a restricted structural complexity is suitable for topology optimization of 3D-printed fiber composites, since large area cross-sections give more degrees of design freedom to the fiber path layout and also makes the inter-layer bond of the filaments firmer.

Abstract. Background:. Three-dimensional shear wave elastography (3D-SWE) is a promising method in distinguishing benign and malignant thyroid nodules. By combining with conventional method, it may further improve the diagnostic value. The study aimed to assess the diagnostic value of American College of Radiology (ACR) thyroid imaging reporting and data system (TI-RADS) combined with 3D-SWE in ACR TI-RADS 4 and 5 thyroid nodules. Methods:. All nodules were examined by conventional ultrasonography, ACR TI-RADS classification, and 3D-SWE examination. Conventional ultrasonography was used to observe the location, size, shape, margin, echogenicity, taller-than-wide sign, microcalcification, and blood flow of thyroid nodules, and then ACR TI-RADS classification was performed. The Young's modulus values (3D-C-Emax, 3D-C-Emean, and elastography standard deviation [3D-C-Esd]) were measured on the reconstructed coronal plane images. According to the receiver operating characteristic (ROC) curve, the best diagnostic efficiency among 3D-C-Emax, 3D-C-Emean, and 3D-C-Esd was selected and the cut-off threshold was calculated. According to the surgical pathology, they were divided into benign group and malignant group. And appropriate statistical methods such as t-test and Mann–Whitney U test were used to compare the difference between the two groups. On this basis, 3D-SWE combined with conventional ACR TI-RADS was reclassified as combined ACR TI-RADS to determine benign or malignant thyroid nodules. Results:. Of the 112 thyroid nodules, 62 were malignant and 50 were benign. The optimal cut-off value of three-dimensional maximum Young's modulus in coronal plane (3D-C-Emax) was 51.5 kPa and the area under the curve (AUC) was 0.798. The AUC, sensitivity, specificity, and accuracy of conventional ACR TI-RADS were 0.828, 83.9%, 66.0%, and 75.9%, respectively. The AUC, sensitivity, specificity, and accuracy of combined ACR TI-RADS were 0.845, 90.3%, 66.0%, and 79.5%, respectively. The difference between the two AUC values was statistically significant. Conclusions:. Combined ACR TI-RADS has higher diagnostic efficiency than conventional ACR TI-RADS. The sensitivity and accuracy of combined ACR TI-RADS showed significant improvements. It can be used as an effective method in the diagnosis of thyroid nodules.

Abstract Background There is an increase in the use of cigarettes and e-cigarettes worldwide, and the similar trends may be observed in young adults. Since 2014, e-cigarettes have become the most commonly used nicotine products among young adults (Sun et al., JAMA Netw Open 4:e2118788, 2021). With the increase in e-cigarette use and the decrease in use of cigarettes and other tobacco products, however, there is limited information about Chinese smokers, e-cigarettes users and trends in cigarettes and e-cigarettes use among university students. Therefore, our objective was to investigate the using status of cigarettes, e-cigarettes and smoking behavior among the students from 7 universities in Guangzhou, China. Methods Students at 7 different universities in Guangzhou were investigated online in 2021 through a cross-sectional survey. A total of 10,008 students were recruited and after screening, 9361 participants were adopted in our statistics. Descriptive analysis, Chi-square analysis, and multiple logistic regression analysis were used to explore the smoking status and influencing factors. Results The average age of the 9361 university students was 22.4 years (SD = 3.6). 58.3% of participants were male. 29.8% of the participants smoked or used e-cigarettes. Among the smokers and users of e-cigarettes, 16.7% were e-cigarettes only users, 35.0% were cigarettes only users, and 48.3% were dual users. Males were more likely to smoke or use e-cigarettes. Medical students, students from prestigious Chinese universities, and students with higher levels of education were less likely. Students with unhealthy lifestyles (e.g., drinking alcohol frequently, playing video games excessively, staying up late frequently) were more likely to smoke or use e-cigarettes. Emotion can have significant impacts on both cigarettes and e-cigarettes dual users when choosing cigarettes or e-cigarettes to use. More than half of dual users said they would choose cigarettes when they were depressed and e-cigarettes when they were happy. Conclusion We identified factors influencing the use of cigarettes and e-cigarettes among university students in Guangzhou, China. Gender, education level background, specialization, lifestyle habits and emotion all influenced the use of cigarettes and e-cigarettes among university students in Guangzhou, China. Male, low education level, from non-prestigious Chinese universities or vocational schools, non-medical specialization, and presence of unhealthy lifestyles were influencing factors for the use of cigarettes and e-cigarettes among university students in Guangzhou and students with these factors were more likely to smoke or use e-cigarettes. Besides, emotions can influence dual users' choice of products. This study provides more information to better understand young people's preferences for cigarettes and e-cigarettes by elucidating the characteristics of cigarettes and e-cigarettes use, as well as related influencing factors, among university students in Guangzhou. Further research involving more variables connected to the use of cigarettes and e-cigarettes will be required in our future study.

Downy blight, caused by Peronophythora litchii, is a destructive disease that impacts lychee fruit throughout the pre-harvest, post-harvest, and transportation phases. Therefore, the prompt and precise identification of P. litchii is crucial for the effective management of the disease. A novel gene encoding a Rh-type ammonium transporter, Pl_101565, was identified in P. litchii through bioinformatic analysis in this study. Based on this gene, a coupled recombinase polymerase amplification–lateral flow (RPA-LF) assay for the rapid visual detection of P. litchii was developed. The assay has been shown to detect P. litchii accurately, without cross-reactivity to related pathogenic oomycetes or fungi. Moreover, it can be performed effectively within 15 to 25 min at temperatures ranging from 28 to 46 °C. Under optimized conditions, the RPA-LF assay could detect as low as 1 pg of P. litchii genomic DNA in a 25 μL reaction system. Furthermore, the RPA-LF assay successfully detected P. litchii in infected lychee samples within a 30 min timeframe. These attributes establish the RPA-LF assay as a rapid, sensitive, and specific method for diagnosing P. litchii early; it is particularly suitable for applications in resource-limited settings.

Electronic cigarettes have become increasingly popular, but the results of previous studies on electronic cigarette exposure in animals have been equivocal. This study aimed to evaluate the effects of electronic cigarette smoke (ECS) and cigarette smoke (CS) on lung function and pulmonary inflammation in mice to investigate whether electronic cigarettes are safer when compared to cigarettes. 32 specific pathogen-free BALB/c male mice were randomly grouped and exposed to fresh air (control), mint-flavored ECS (ECS1, 6 mg/kg), cheese-flavored ECS (ECS2, 6 mg/kg), and CS (6 mg/kg). After 3 weeks exposure to ECS or CS, we measured lung function (PIF and Penh) and blood oxygen saturation. The levels of TNF-α and IL-6 in the bronchoalveolar lavage fluid (BALF) and serum were measured using ELISA. HE staining was performed to observe the pathological changes in the lung tissues. The levels of IL-6 in BALF and serum, and TNF-α in BALF, were elevated similarly in the ECS and CS groups compared to the control group. Significant elevation was observed in serum TNF-α levels in the CS group. The total count of cells in BALF were increased after ECS1 exposure and CS exposure. PIF and oxygen saturation decreased, and Penh increased markedly in the CS group but not in the ECS groups. Compared with the ECS groups, mice in the CS group had widened lung tissue septa and increased inflammatory cell infiltration. However, we did not detect significant differences between mint-flavored and cheese-flavored e-cigarettes in our study. Overall, our findings suggested that both ECS and CS impair lung function and histopathology while promoting inflammation. In contrast, ECS has a less negative impact than CS.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity worldwide. Cigarette smoking, which leads to abnormalities in the airways or alveoli and persistent obstruction of the airway's flow, is a significant risk factor of COPD. Cryptotanshinone (CTS) is the active ingredient in Salvia miltiorrhiza (Danshen) and has many pharmacological properties including anti-inflammatory, antitumor, and antioxidant properties, but its impact on COPD is uncertain. In the present study, the potential effect of CTS on COPD was investigated in a modified COPD mice model induced with cigarette smoke (CS) and lipopolysaccharide (LPS) exposure. CTS significantly reversed the decline in lung function, emphysema, inflammatory cell infiltration, small airway remodeling, pulmonary pathological damage, and airway epithelial cell proliferation in CS- and LPS-exposed mice. Additionally, CTS decreased inflammatory cytokines such as tumor necrosis factor α (TNF α), interleukins IL-6 and IL-1β, and keratinocyte chemoattractant (KC), increased the activities of superoxide dismutase (SOD), Catalase (CAT) and L-Glutathione (GSH), and repressed the expression of protein hydrolases matrix metalloprotein (MMP)− 9 and − 12 in pulmonary tissue and bronchoalveolar lavage fluid (BALF). The protective effects of CTS were also observed in human bronchial epithelial cell line BEAS-2B simulated with cigarette smoke condensate (CSC) and LPS. Mechanistically, CTS can repress the protein level of Keap1, resulting to activation of erythroid 2-related factor (Nrf2), finally alleviating COPD. In summary, the present findings demonstrated that CTS dramatically ameliorates COPD induced by CS and LPS via activating Keap1/Nrf2 pathway.

Highlights 1. High-throughput screening of ATG4B inhibitors based on FDA-approved drug library 2. Ebselen can covalently bind to ATG4B at Cys74 3. Ebselen can promote ATG4B oligomerization at Cys292 and Cys361 4. Ebselen suppresses the growth of colorectal cancer cells and xenograft tumors via ATG4B inhibition

Abstract Huntington’s disease (HD) is a neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein encoded from extra tracts of CAG repeats in exon 1 of the HTT gene. mHTT proteins are neurotoxic to render the death of neurons and a series of disease-associated phenotypes. The mHTT is degraded through autophagy pathway and ubiquitin–proteasome system (UPS). This study identified a small molecule, J3, as an autophagy inducer by high-content screening. The results revealed that J3 could inhibit mTOR, thus promoting autophagic flux and long-lived protein degradation. Further, J3 selectively lowered the soluble and insoluble mHTT but not wild type HTT levels in cell models. The HdhQ140 mice showed reduced HD-associated activity and loss of motor functions. However, administration of J3 showed increased activity and a slight improvement in the motor function in the open-field test, balance beam test, and rotarod tests. Furthermore, in vivo studies revealed that J3 decreased T-HTT and misfolded protein levels in the striatum and increased the levels of the medium spiny neuron marker DARPP-32. In addition, J3 showed good permeability across the brain-blood barrier efficiently, suggesting that J3 was a promising candidate for the treatment of HD.

The present study identified a novel mechanism underlying the protective effect of Sirtuin 3 (SIRT3) against pathological cardiac hypertrophy, beyond its well-accepted role as a deacetylase in mitochondria. SIRT3 modulates the peroxisomes-mitochondria interplay by preserving the expression of peroxisomal biogenesis factor 5 (PEX5), thereby improving mitochondrial function. Downregulation of PEX5 was observed in the hearts of Sirt3−/− mice and angiotensin II-induced cardiac hypertrophic mice, as well as in cardiomyocytes with SIRT3 silencing. PEX5 knockdown abolished the protective effect of SIRT3 against cardiomyocyte hypertrophy, whereas PEX5 overexpression alleviated the hypertrophic response induced by SIRT3 inhibition. PEX5 was involved in the regulation of SIRT3 in mitochondrial homeostasis, including mitochondrial membrane potential, mitochondrial dynamic balance, mitochondrial morphology and ultrastructure, as well as ATP production. In addition, SIRT3 alleviated peroxisomal abnormalities in hypertrophic cardiomyocytes via PEX5, as implied by improvement of peroxisomal biogenesis and ultrastructure, as well as increase of peroxisomal catalase and repression of oxidative stress. Finally, the role of PEX5 as a key regulator of the peroxisomes-mitochondria interplay was confirmed, since peroxisomal defects caused by PEX5 deficiency led to mitochondrial impairment. Taken together, these observations indicate that SIRT3 could maintain mitochondrial homeostasis by preserving the peroxisomes-mitochondria interplay via PEX5. Our findings provide a new understanding of the role of SIRT3 in mitochondrial regulation via interorganelle communication in cardiomyocytes.

As one of the most destructive bacterial phytopathogens, Ralstonia solanacearum causes substantial annual yield losses of many important crops. Deciphering the functional mechanisms of type III effectors, the crucial factors mediating R. solanacearum-plant interactions, will provide a valuable basis for protecting crop plants from R. solanacearum. Recently, the NEL (novel E3 ligase) effector RipAW was found to induce cell death on Nicotiana benthamiana in a E3 ligase activity-dependent manner. Here, we further deciphered the role of the E3 ligase activity in RipAW-triggered plant immunity. We found that RipAWC177A, the E3 ligase mutant of RipAW, could not induce cell death but retained the ability of triggering plant immunity in N. benthamiana, indicating that the E3 ligase activity is not essential for RipAW-triggered immunity. By generating truncated mutants of RipAW, we further showed that the N-terminus, NEL domain and C-terminus are all required but not sufficient for RipAW-induced cell death. Furthermore, all truncated mutants of RipAW triggered ETI immune responses in N. benthamiana, confirming that the E3 ligase activity is not essential for RipAW-triggered plant immunity. Finally, we demonstrated that RipAW- and RipAWC177A-triggered immunity in N. benthamiana requires SGT1 (suppressor of G2 allele of skp1), but not EDS1 (enhanced disease susceptibility), NRG1 (N requirement gene 1), NRC (NLR required for cell death) proteins or SA (salicylic acid) pathway. Our findings provide a typical case in which the effector-induced cell death can be uncoupled with immune responses, shedding new light on effector-triggered plant immunity. Our data also provide clues for further in-depth study of mechanism underlying RipAW-induced plant immunity.

The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.

Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor (Anf) and β-myosin heavy chain (β-Mhc) in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3′ untranslated region of Atg4b mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

Abstract Background To evaluate the diagnostic performance of multiparametric transrectal ultrasound (TRUS) and to design diagnostic scoring systems based on four modes of TRUS to predict peripheral zone prostate cancer (PCa) and clinically significant prostate cancer (csPCa). Methods A development cohort involved 124 nodules from 116 patients, and a validation cohort involved 72 nodules from 67 patients. Predictors for PCa and csPCa were extracted to construct PCa and csPCa models based on regression analysis of the development cohort. An external validation was performed to assess the performance of models using area under the curve (AUC). Then, PCa and csPCa diagnostic scoring systems were established to predict PCa and csPCa. The diagnostic accuracy was compared between PCa and csPCa scores and PI-RADS V2, using receiver operating characteristics (ROC) and decision curve analysis (DCA). Results Regression models were established as follows: PCa = − 8.284 + 4.674 × Margin + 1.707 × Adler grade + 3.072 × Enhancement patterns + 2.544 × SR; csPCa = − 7.201 + 2.680 × Margin + 2.583 × Enhancement patterns + 2.194 × SR. The PCa score ranged from 0 to 6 points, and the csPCa score ranged from 0 to 3 points. A PCa score of 5 or higher and a csPCa score of 3 had the greatest diagnostic performance. In the validation cohort, the AUC for the PCa score and PI-RADS V2 in diagnosing PCa were 0.879 (95% confidence interval [CI] 0.790–0.967) and 0.873 (95%CI 0.778–0.969). For the diagnosis of csPCa, the AUC for the csPCa score and PI-RADS V2 were 0.806 (95%CI 0.700–0.912) and 0.829 (95%CI 0.727–0.931). Conclusions The multiparametric TRUS diagnostic scoring systems permitted better identifications of peripheral zone PCa and csPCa, and their performances were comparable to that of PI-RADS V2.

Introduction: Cryptotanshinone(CTS), a compound derived from the root of Salvia miltiorrhiza, has been linked to various of diseases, particularly pulmonary fibrosis. In the current study, we investigated the benefit of CTS on Sprague-Dawley (SD) rats induced by bleomycin (BLM) and established high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods to compare pharmacokinetics and tissue distribution in subsequent normal and modulated SD rats.Methods: The therapeutic effect of CTS on BLM-induced SD rats was evaluated using histopathology, lung function and hydroxyproline content measurement, revealing that CTS significantly improved SD rats induced by BLM. Additionally, a simple, rapid, sensitive and specific HPLC-MS/MS method was developed to determine the pharmacokinetics of various components in rat plasma.Results: Pharmacokinetic studies indicated that CTS was slowly absorbed by oral administration and had low bioavailability and a slow clearance rate. The elimination of pulmonary fibrosis in 28-day rats was slowed down, and the area under the curve was increased compared to the control group. Long-term oral administration of CTS did not accumulate in vivo, but the clearance was slowed down, and the steady-state blood concentration was increased. The tissue distribution study revealed that CTS exposure in the lungs and liver.Discussion: The lung CTS exposure was significantly higher in the model group than in the control group, suggesting that the pathological changes of pulmonary fibrosis were conducive to the lung exposure of CTS and served as the target organ of CTS.

BackgroundAcute lung injury (ALI) is a life-threatening inflammatory disease without effective therapeutic regimen. Macrophage polarization plays a key role in the initiation and resolution of pulmonary inflammation. Therefore, modulating macrophage phenotype is a potentially effective way for acute lung injury. Cryptotanshinone (CTS) is a lipophilic bioactive compound extracted from the root of Salvia miltiorrhiza with a variety of pharmacological effects, especially the anti-inflammatory role. In this study, we investigated the therapeutic and immunomodulatory effects of CTS on ALI.Materials and methodsThe rat model of ALI was established by intratracheal instillation of LPS (5 mg/kg) to evaluate the lung protective effect of CTS in vivo and to explore the regulation of CTS on the phenotype of lung macrophage polarization. LPS (1 μg/mL) was used to stimulate RAW264.7 macrophages in vitro to further explore the effect of CTS on the polarization and metabolic reprogramming of RAW264.7 macrophages and to clarify the potential mechanism of CTS anti-ALI.ResultsCTS significantly improved lung function, reduced pulmonary edema, effectively inhibited pulmonary inflammatory infiltration, and alleviated ALI. Both in vivo and in vitro results revealed that CTS inhibited the differentiation of macrophage into the M1 phenotype and promoted polarization into M2 phenotype during ALI. Further in vitro studies indicated that CTS significantly suppressed LPS-induced metabolic transition from aerobic oxidation to glycolysis in macrophages. Mechanistically, CTS blocked LPS-induced metabolic transformation of macrophages by activating AMPK.ConclusionThese findings demonstrated that CTS regulates macrophage metabolism by activating AMPK, and then induced M1-type macrophages to transform into M2-type macrophages, thereby alleviating the inflammatory response of ALI, suggesting that CTS might be a potential anti-ALI agent.

Abstract Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients’ poor prognosis. Knockdown of ATG4B significantly inhibited GCa cell survival and tumor growth. To further probe the role of ATG4B in GCa by pharmacological means, we screened an in-house marine natural compound library against ATG4B and identified Azalomycin F4a (Am-F4a) as a novel and potent ATG4B inhibitor. Am-F4a directly bound to ATG4B with high affinity and effectively suppressed GCa cell autophagy via inhibition of ATG4B both in vitro and in vivo. Moreover, Am-F4a or ATG4B knockdown significantly suppressed tumor growth as well as GCa cell migration and invasion. Am-F4a effectively blocked the metastatic progression of primary GCa and sensitized tumors to chemotherapy. Taken together, our findings indicate that ATG4B is a potential therapeutic target against GCa and the natural product Am-F4a is a novel ATG4B inhibitor that can be further developed for the treatment of GCa.

Abstract Background Combining targeted biopsy (TB) with systematic biopsy (SB) is currently recommended as the first-line biopsy method by the European Association of Urology (EAU) guidelines in patients diagnosed with prostate cancer (PCa) with an abnormal magnetic resonance imaging (MRI). The combined SB and TB indeed detected an additional number of patients with clinically significant prostate cancer (csPCa); however, it did so at the expense of a concomitant increase in biopsy cores. Our study aimed to evaluate if ipsilateral SB (ipsi-SB) + TB or contralateral SB (contra-SB) + TB could achieve almost equal csPCa detection rates as SB + TB using fewer cores based on a different csPCa definition. Methods Patients with at least one positive prostate lesion were prospectively diagnosed by MRI. The combination of TB and SB was conducted in all patients. We compared the csPCa detection rates of the following four hypothetical biopsy sampling schemes with those of SB + TB: SB, TB, ipsi-SB + TB, and contra-SB + TB. Results The study enrolled 279 men. The median core of SB, TB, ipsi-SB + TB, and contra-SB + TB was 10, 2, 7 and 7, respectively (P

Ralstonia solanacearum causes devastating diseases in a wide range of economically important crops. It secretes a large number of virulence factors, also known as effectors, to promote its infection, and some of them are recognized when the host plant contains corresponding resistance genes. In this study we showed that a type III effector RipTPS from the avirulent R. solanacearum strain GMI1000 (RipTPSG) specifically induced cell death in Nicotiana tabacum, but not in Nicotiana benthamiana, whereas the RipTPS homolog in the virulent strain CQPS-1 (RipTPSC) induced cell death in neither N. tabacum nor N. benthamiana. These results indicated that RipTPSG is recognized in N. tabacum. Expression of RipTPSG induced upregulation of hypersensitive response (HR) -related genes in N. tabacum. The virulence of CQPS-1 was reduced when RipTPSG was genetically introduced into CQPS-1, further confirming that RipTPSG functions as an avirulence determinant. Protein sequence alignment indicated that there are only three amino acid polymorphisms between RipTPSG and RipTPSC. Site-directed mutagenesis analyses confirmed that the three amino acid residues are jointly required for the recognition of RipTPSG in N. tabacum. Expression of either RipTPSG or RipTPSC suppressed flg22-triggered reactive oxygen species (ROS) burst in N. benthamiana, suggesting that RipTPS contributes to pathogen virulence. Mutating the conserved residues in RipTPS’s trehalose-phosphate synthase (TPS) domain did not block its HR induction and defense suppression activity, indicating that the TPS activity is not required for RipTPS’s avirulence and virulence function.

Citri Reticulatae Pericarpium (CRP) has been utilized as a versatile medicinal herb with wide cardiovascular benefits in Asian nations for centuries. Accumulating evidence suggests that CRP and its components are effective in preventing cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, myocardial ischemia, arrhythmia, cardiac hypertrophy, heart failure, and hypertension. Studies show that the two most bioactive components of CRP are flavonoids and volatile oils. The cardiovascular protective effects of CRP have attracted considerable research interest due to its hypolipidemic, antiplatelet activity, antioxidant and anti-inflammatory effects. Hereby, we provide a rigorous and up-to-date overview of the cardiovascular protective properties and the potential molecular targets of CRP, and finally highlight the pharmacokinetics and the therapeutic potential of the main pharmacologically active components of CRP to treat CVDs.

Abstract Heme oxygenase-1 (HO-1) has attracted accumulating attention for its antioxidant enzymatic activity. However, the exact regulatory role of its non-enzymatic activity in the cardiovascular system remains unaddressed. Here, we show that HO-1 was accumulated in the nuclei of stress-induced senescent endothelial cells, and conferred protection against endothelial senescence independent of its enzymatic activity. Overexpression of ΔHO-1, a truncated HO-1 without transmembrane segment (TMS), inhibited H2O2-induced endothelial senescence. Overexpression of ΔHO-1H25A, the catalytically inactive form of ΔHO-1, also exhibited anti-senescent effect. In addition, infection of recombinant adenovirus encoding ΔHO-1 with three nuclear localization sequences (NLS), alleviated endothelial senescence induced by knockdown of endogenous HO-1 by CRISPR/Cas9. Moreover, repression of HO-1 nuclear translocation by silencing of signal peptide peptidase (SPP), which is responsible for enzymatic cleavage of the TMS of HO-1, exacerbated endothelial senescence. Mechanistically, nuclear HO-1 interacted with NPM1 N-terminal portion, prevented NPM1 translocation from nucleolus to nucleoplasm, thus disrupted NPM1/p53/MDM2 interactions and inhibited p53 activation by NPM1, finally resisted endothelial senescence. This study provides a novel understanding of HO-1 as a promising therapeutic strategy for vascular senescence-related cardiovascular diseases.

Peronophythora litchii is an oomycete pathogen that exclusively infects litchi, with infection stages affecting a broad range of tissues. In this study, we obtained a near chromosome-level genome assembly of P. litchii ZL2018 from China using Oxford Nanopore Technologies long-read sequencing and Illumina short-read sequencing. The genome assembly was 64.15 Mb in size and consisted of 81 contigs with an N50 of 1.43 Mb and a maximum length of 4.74 Mb. Excluding 34.67% of repeat sequences, 14,857 protein-coding genes were identified, among which 14,447 genes were annotated. We also predicted 306 candidate RxLR effectors in the assembly. The high-quality genome assembly and annotation resources reported in this study will provide new insight into the infection mechanisms of P. litchii.

Background: Ulcerative colitis (UC) is one type of inflammatory bowel disease, characterized by inflammation with infiltration and activation of macrophages in colonic tissue. LH011 is a trypsin inhibitor with potential anti-inflammatory effect.Purpose: Here, we aim to assay the effects of LH011 on UC and further investigate the potential mechanisms in vitro and in vivo.Methods: Dextran sulfate sodium (DSS, 3.5%, w/v) was used to induce UC, and lipopolysaccharide (LPS) was used to induce inflammation in RAW 264.7 cells. LH011 was administrated to mice in vivo or to RAW 264.7 cells in vitro at different concentrations. The cytokines (IL-1β, IL-6, and TNF-α) and the changes of NF-κB and Nrf2 pathways were detected.Results: The results showed that LH011 improved DSS-induced mice colitis, including loss of weight, disease activity index (DAI), and colonic pathological damage. In addition, LH011 inhibited the expressions of IL-1β, IL-6, and TNF-α and strengthened the anti-oxidative capacity. Mechanically, LH011 downregulated the nuclear localization of NF-κB p65 and upregulated the protein expression of Nrf2.Conclusion: These results demonstrated that LH011 alleviated inflammation and oxidative stress during UC by inhibiting TLR4/NF-κB and activating Nrf2/Keap1/HO-1 signaling pathways.

The cytochrome P450 (CYP) enzymes play a pivotal role in drug metabolism. LC-MS/MS-based targeting technology has been applied to the analysis of CYP enzymes, promoting drug development and drug-drug interaction studies. Rat is one of the most commonly used models for drug metabolism assessment, but LC-MS/MS assay quantifying the abundance of CYP enzymes in rats is rarely reported. Herein, an accurate and stable LC-MS/MS based method was developed and validated for the simultaneous quantification of seven major rat CYP isoforms (CYP1A2, 2B1, 2C6, 2C11, 2D1, 2E1, and 3A1) in liver microsomes. The careful optimization of trypsin digestion and chromatography combined with isotope-labeled peptide as internal standard improved the efficiency and accuracy of the analysis. Highly specific surrogate peptides were obtained by a procedure including trypsin digestion for six hours and separated on a Hypersil Gold C18 column (100 × 2.1 mm, 3 μm) using gradient elution for 15 min with a mobile phase of water containing 0.1% formic acid and acetonitrile. In the method validation, linearity, matrix effect, recovery, stability, accuracy, and precision all meet the requirements. Subsequently, this method was applied to detect seven enzymes in rat liver microsomes from four different sources, and the correlation between the abundance and activity of CYP enzymes was further analyzed. The high-throughput detection method provided in this study will provide support for pertinent pharmaceutical research based on rat models.

The flap side-edge is a vital contributor to airframe noise. In this study, we propose a novel flap side-edge noise reduction method based on the concept of active blowing air. A long slot is opened from the flap’s lower surface to the tip surface to induce a secondary jet flow, which is driven by the local pressure difference between the flap’s lower surface and the tip surface. The unsteady flow field around the flap side-edge was computed by the lattice Boltzmann solver PowerFLOW, and the far-field noise was predicted by the FW-H equation. It is demonstrated that the dominant features of the flap side-edge flow are the double vortex structures, and the new passive blowing air reduction method can achieve about 3.3 dB noise reduction. Moreover, the underlying noise reduction mechanism has been analyzed and revealed. It is shown that the secondary jet flow from the long slot on the flap side-edge would dissipate the flap side-edge vortex and displace the flap side-edge vortical structure away from the flap surface, thus resulting in a decrease in the pressure fluctuations on the flap side-edge surface. As a result, the flap side-edge noise was reduced. In contrast to the current active air blowing technique, the newly proposed blowing air technique is passive and quite simple and does not require an extra air source or control system. This novel flap side-edge noise reduction technology provides a new flow control strategy and noise reduction methodology and can be further optimized.

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer. FNR associated genes (GPX4, SLC7A11, and FTH1) and STAT3 are upregulated in 5-FU resistant cells and xenografts. Further evidence demonstrates that STAT3 binds to consensus DNA response elements in the promoters of the FNR associated genes (GPX4, SLC7A11, and FTH1) and regulates their expression, thereby establishing a negative STAT3-ferroptosis regulatory axis in gastric cancer. Genetic inhibition of STAT3 activity triggers ferroptosis through lipid peroxidation and Fe2+ accumulation in gastric cancer cells. We further develop a potent and selective STAT3 inhibitor, W1131, which demonstrates significant anti-tumor effects in gastric cancer cell xenograft model, organoids model, and patient-derived xenografts (PDX) model partly by inducing ferroptosis, thus providing a new candidate compound for advanced gastric cancer. Moreover, targeting the STAT3-ferroptosis circuit promotes ferroptosis and restores sensitivity to chemotherapy. Our finding reveals that STAT3 acts as a key negative regulator of ferroptosis in gastric cancer through a multi-pronged mechanism and provides a new therapeutic strategy for advanced gastric cancer and chemotherapy resistance.

Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.

Phytophthora capsici is an important plant pathogenic oomycete with multiple hosts. The P4-ATPases, aminophospholipid translocases (APTs), play essential roles in the growth and pathogenesis of fungal pathogens. However, the function of P4-ATPase in P. capsici remains unclear. This study identified and characterized PcApt1, a P4-ATPase Drs2 homolog, in P. capsici. Deletion of PcAPT1 by CRISPR/Cas9 knock-out strategy impaired hyphal growth, extracellular laccase activity. Cytological analyses have shown that PcApt1 participates in phosphatidylserine (PS) transport across the plasma membrane. Also, we showed that targeted deletion of PcAPT1 triggered a significant reduction in the virulence of P. capsici. Secretome analyses have demonstrated that secretion of hydrolytic enzymes decreased considerably in the PcAPT1 gene deletion strains compared to the wild-type. Overall, our results showed that PcApt1 plays a pivotal role in promoting morphological development, phospholipid transport, secretion of hydrolytic enzymes, and the pathogenicity of the polycyclic phytopathogenic oomycete P. capsici. This study underscores the need for comprehensive evaluation of subsequent members of the P-type ATPase family to provide enhanced insights into the dynamic contributions to the pathogenesis of P. capsici and their possible deployment in the formulation of effective control strategies.

The bromodomain and extra-terminal domain proteins (BETs) family serve as epigenetic “readers”, which recognize the acetylated histones and recruit transcriptional regulator complexes to chromatin, eventually regulating gene transcription. Accumulating evidences demonstrate that pan BET inhibitors (BETi) confer protection against pathological cardiac hypertrophy, a precursor progress for developing heart failure. However, the roles of BET family members, except BRD4, remain unknown in pathological cardiac hypertrophy. The present study identified BRD2 as a novel regulator in cardiac hypertrophy, with a distinct mechanism from BRD4. BRD2 expression was elevated in cardiac hypertrophy induced by β-adrenergic agonist isoprenaline (ISO) in vivo and in vitro. Overexpression of BRD2 upregulated the expression of hypertrophic biomarkers and increased cell surface area, whereas BRD2 knockdown restrained ISO-induced cardiomyocyte hypertrophy. In vivo, rats received intramyocardial injection of adeno-associated virus (AAV) encoding siBRD2 significantly reversed ISO-induced pathological cardiac hypertrophy, cardiac fibrosis, and cardiac function dysregulation. The bioinformatic analysis of whole-genome sequence data demonstrated that a majority of metabolic genes, in particular those involved in TCA cycle, were under regulation by BRD2. Real-time PCR results confirmed that the expressions of TCA cycle genes were upregulated by BRD2, but were downregulated by BRD2 silencing in ISO-treated cardiomyocytes. Results of mitochondrial oxygen consumption rate (OCR) and ATP production measurement demonstrated that BRD2 augmented cardiac metabolism during cardiac hypertrophy. In conclusion, the present study revealed that BRD2 could facilitate cardiac hypertrophy through upregulating TCA cycle genes. Strategies targeting inhibition of BRD2 might suggest therapeutic potential for pathological cardiac hypertrophy and heart failure.

Reprogramming of cellular energy metabolism is considered an emerging feature of cancer. Mitochondrial metabolism plays a crucial role in cancer cell proliferation, survival, and metastasis. As a major mitochondrial NAD+-dependent deacetylase, sirtuin3 (SIRT3) deacetylates and regulates the enzymes involved in regulating mitochondrial energy metabolism, including fatty acid oxidation, the Krebs cycle, and the respiratory chain to maintain metabolic homeostasis. In this article, we review the multiple roles of SIRT3 in various cancers, and systematically summarize the recent advances in the discovery of its activators and inhibitors. The roles of SIRT3 vary in different cancers and have cell- and tumor-type specificity. SIRT3 plays a unique function by mediating interactions between mitochondria and intracellular signaling. The critical functions of SIRT3 have renewed interest in the development of small molecule modulators that regulate its activity. Delineation of the underlying mechanism of SIRT3 as a critical regulator of cell metabolism and further characterization of the mitochondrial substrates of SIRT3 will deepen our understanding of the role of SIRT3 in tumorigenesis and progression and may provide novel therapeutic strategies for cancer targeting SIRT3.

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin (Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Dox-induced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor (30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been widely used in the quantitative analysis of drugs. The ubiquitous concomitant drug scenario in the clinic has spawned a large number of co-analyses based on this technique. However, signal suppression caused by concomitant drugs during electrospray ionization may affect the quantification accuracy of analytes, which has not received enough attention. In this study, metformin (MET) and glyburide (GLY) were co-eluted by the conventional optimization of chromatographic conditions to illustrate the effect of signal suppression caused by the combined drugs on the quantitative analysis. The response of MET was not affected by GLY over the investigated concentration range. However, the GLY signal could be suppressed by about 30% in the presence of MET, affecting its pharmacokinetic analysis in simulated samples. As an attempt to solve the suppression of GLY by co-eluting MET, dilution can alleviate the suppression. However, this method still has limitations due to the sacrifice of sensitivity. The stable isotope-labeled internal standard could play a role in correction and improve the quantitative accuracy of GLY, which was further confirmed in the pharmacokinetic study of simulated samples. This study provided an example model to illustrate the possible effect of clinical drug combination on LC-MS/MS drug quantitative analysis and investigated the effective methods to solve this problem.

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor RORγ as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from Actinomycete streptomyces, is a novel RORγ antagonist and showed potent antitumor activity against CRPC in vitro and in vivo. We demonstrated that Elai selectively binded to RORγ protein and potently blocked RORγ transcriptional regulation activities. Structure–activity relationship studies showed that Elai occupied the binding pocket with several key interactions. Furthermore, Elai markedly reduced the recruitment of RORγ to its genomic DNA response element (RORE), suppressed the expression of RORγ target genes AR and AR variants, and significantly inhibited PCa cell growth. Importantly, Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models. Taken together, these results suggest that Elai is novel therapeutic RORγ inhibitor that can be used as a drug candidate for the treatment of human CRPC.

A 30°/30° S-duct is often employed by a modern civil and military aircraft. Due to the vortex generators have poor control effect on the flow separation in the large curvature S-duct, so a new method adjusting the direction of the main flow in the transition zone for S-duct is proposed in the present study. These studies are carried out by solving Navier-Stokes equations with SST k-ω turbulence model. In order to explore the control mechanism of guide vanes on the flow field for S-duct, the internal flow field of S-duct with/without guide vanes is analyzed and compared in detail, including the velocity distribution on the symmetry plane, the secondary vortex intensity at different cross sections, turbulent kinetic energy on different cross sections, total pressure distribution on different cross sections, three-dimensional streamline, and so on. The results show that guide vanes can not only effectively adjust the direction of the main flow, but also restrain the flow separation, reduce the total pressure loss, and improve the uniformity of flow field.

Cigarette seriously affects human health, and electronic cigarette (e-cigarette), considered as cigarette substitutes, become popular as its contribution to quit smoking. But scientific evidence about the absolute safety of e-cigarette is insufficient. Previous studies also have indicated that different dosages of cigarette can lead to different biological effects. Thus, the impact of cigarette at toxicological dose such as IC50 compared with that of e-cigarette are highly needed. In this study, we investigated the effects of cigarette smoke condensate (CSC) at toxicological dose compared with e-cigarette smoke condensate (ECSC) in equivalent nicotine level. Nicotine content of CSC and ECSC were determined by UPLC. Human lung epithelial cells (BEAS-2B) were exposed to 0–32 μg/ml of CSC and ECSC for 24 h to determine IC50 of cell viability and morphological assessment. Inflammation, apoptosis, cell cycle analysis and RNA-Seq transcriptome analysis were performed to characterize the differences between CSC and ECSC. We found that acute exposure of BEAS-2B cells to CSC at IC50 leaded to morphological change, inflammatory cytokines production and cell apoptosis, while ECSC did not exert such cell effects in equivalent nicotine level. The transcriptome analysis showed that differentially expressed genes in CSC were far more than that in ECSC, and mainly enriched in the category of cell cycle, DNA repair, cancer, and metabolic related pathways. Such cell cycle arrest was further experimentally confirmed. These results suggested that toxicological dose of ECSC might be much higher than that of CSC. Based on equivalent nicotine content, an acute exposure to CSC had significant impacts on cell effects and gene expression profile compared to ECSC. Our results provided a reference for the safety studies of conventional cigarette and e-cigarette.

The clinical application of doxorubicin (DOX) in cancer chemotherapy is limited by its life-threatening cardiotoxic effects. Chrysophanol (CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes. However, the effects of CHR׳s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide (3AB) and ABT888. Ectopic expression of PARP1 effectively blocked this CHR׳s cardioprotection against DOX-induced cardiomyocyte injury in H9C2 cells. Furthermore, pre-administration with both CHR and 3AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy. KEY WORDS: Chrysophanol, Doxorubicin, PARylation, Cardiotoxicity, Apoptosis, Mitochondria

Electronic cigarettes (e-cigarettes) have attracted much attention as a new substitute for conventional cigarettes. E-cigarettes are first exposed to the respiratory system after inhalation, and studies on the toxicity mechanisms of e-cigarettes have been reported. Current research shows that e-cigarette exposure may have potentially harmful effects on cells, animals, and humans, while the safety evaluation of the long-term effects of e-cigarette use is still unknown. Similar but not identical to conventional cigarettes, the toxicity mechanisms of e-cigarettes are mainly manifested in oxidative stress, inflammatory responses, and DNA damage. This review will summarize the toxicity mechanisms and signal pathways of conventional cigarettes and e-cigarettes concerning the respiratory system, which could give researchers a better understanding and direction on the effects of e-cigarettes on our health.

Phytophthora capsici causes a severe soil-borne disease in a wide variety of vegetables; to date, no effective strategies to control P. capsici have been developed. Liquiritin (LQ) is a natural flavonoid found in licorice (Glycyrrhiza spp.) root, and it is used in pharmaceuticals. However, the antifungal activity of LQ against P. capsici remains unknown. In the present study, we demonstrated that LQ inhibits P. capsici mycelial growth and sporangial development. In addition, the EC50 of LQ was 658.4 mg/L and LQ caused P. capsici sporangia to shrink and collapse. Next, LQ severely damaged the cell membrane integrity, leading to a 2.0–2.5-fold increase in relative electrical conductivity and malondialdehyde concentration, and a 65–70% decrease in sugar content. Additionally, the H2O2 content was increased about 2.0–2.5 fold, but the total antioxidant activity, catalase activity and laccase activity were attenuated by 40–45%, 30–35% and 70–75%. LQ also induced autophagy, apoptosis, and reduction of intracellular Ca2+ content. Furthermore, LQ inhibited P. capsici pathogenicity by reducing the expression of virulence genes PcCRN4 and Pc76RTF, and stimulating the plant defense (including the activated transcriptional expression of defense-related genes CaPR1, CaDEF1, and CaSAR82, and the increased antioxidant enzyme activity). Our results not only elucidate the antifungal mechanism of LQ but also suggest a promising alternative to commercial fungicides or a key compound in the development of new fungicides for the control of the Phytophthora disease.

For turboprop engine, the S-shaped intake affects the engine performance and the propeller is not far in front of the inlet of the S-shaped intake, so the slipstream inevitably affects the flow field in the S-shaped intake and the engine performance. Here, an S-shaped intake with/without propeller is studied by solving Reynolds-averaged Navier-Stokes equation employed SST k-ω turbulence model. The results are presented as time-averaged results and transient results. By comparing the flow field in S-shaped intake with/without propeller, the transient results show that total pressure recovery coefficient and distortion coefficient on the AIP section vary periodically with time. The time-averaged results show that the influence of propeller slipstream on the performance of S-shaped intake is mainly circumferential interference and streamwise interference. Circumferential interference mainly affects the secondary flow in the S-shaped intake and then affects the airflow uniformity; the streamwise interference mainly affects the streamwise flow separation in the S-shaped intake and then affects the total pressure recovery. The total pressure recovery coefficient on the AIP section for the S-shaped intake with propeller is 1%-2.5% higher than that for S-shaped intake without propeller, and the total pressure distortion coefficient on the AIP section for the S-shaped intake with propeller is 1%-12% higher than that for the S-shaped intake without propeller. However, compared with the free stream flow velocity (Ma=0.527), the influence of the propeller slipstream belongs to the category of small disturbance, which is acceptable for engineering applications.

The present study reveals a link between protein arginine methyltransferase 5 (PRMT5) and Homebox A9 (HoxA9) in the regulation of cardiomyocyte hypertrophy. In cardiomyocyte hypertrophy induced by β-adrenergic receptor agonist isoprenaline (ISO), PRMT5 expression was decreased while HoxA9 was upregulated. Silencing of PRMT5 or inhibition of PRMT5 by its pharmacological inhibitor EPZ augmented the expressions of cardiomyocyte hypertrophic genes brain natriuretic peptide (BNP) and β-Myosin Heavy Chain (β-MHC), whereas overexpression of PRMT5 inhibited ISO-induced cardiomyocyte hypertrophy, suggesting that PRMT5 ameliorates cardiomyocyte hypertrophy. On the contrary, HoxA9 promoted cardiomyocyte hypertrophy, as implied by the gain-of-function and loss-of-function experiments. HoxA9 was involved in the regulation of PRMT5 in cardiomyocyte hypertrophy, since HoxA9 knockdown prevented si-RPMT5-induced cardiomyocyte hypertrophy, and HoxA9 expression impaired the anti-hypertrophic effect of PRMT5. Co-immunoprecipitation experiments revealed that there were physical interactions between PRMT5 and HoxA9. The symmetric dimethylation level of HoxA9 was decreased by ISO or EPZ treatment, suggesting that HoxA9 is methylated by PRMT5. Additionally, PRMT5 repressed the expression of HoxA9. Chromatin immunoprecipitation (ChIP) assay demonstrated that HoxA9 could bind to the promoter of BNP, and that this binding affinity was further enhanced by ISO or EPZ. In conclusion, this study suggests that PRMT5 symmetric dimethylates HoxA9 and represses HoxA9 expression, thus impairing its binding to BNP promoter and ultimately protecting against cardiomyocyte hypertrophy. These findings provide a novel insight of the mechanism underlying the cardiac protective effect of PRMT5, and suggest potential therapeutic strategies of PRMT5 activation or HoxA9 inhibition in treatment of cardiac hypertrophy.