A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the epidermal growth factor precursor homologous domain A (EGF-A) of low-density lipoprotein receptor (LDLR) in the liver and triggers the degradation of LDLR via the lysosomal pathway, consequently leading to an elevation in plasma LDL-C levels. Inhibiting PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the body. Thus, PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and atherosclerosis. In this study, we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds. E28362 (5, 10, 20 µM) dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells, and enhanced the uptake of DiI-LDL in AML12 cells. MTT assay showed that E28362 up to 80 µM had no obvious toxicity in HepG2, AML12, and HEK293a cells. The effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal models. In high-fat diet-fed golden hamsters, administration of E28362 (6.7, 20, 60 mg·kg-1·d-1, i.g.) for 4 weeks significantly reduced plasma total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and PCSK9 levels, and reduced liver TC and TG contents. In Western diet-fed ApoE-/- mice (20, 60 mg·kg-1·d-1, i.g.) and human PCSK9 D374Y overexpression mice (60 mg·kg-1·d-1, i.g.), administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic roots. Moreover, E28362 significantly increased the protein expression level of LDLR in the liver. We revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells, blocked the interaction between LDLR and PCSK9, and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway, which finally resulted in increased LDLR protein levels. In conclusion, E28362 can block the interaction between PCSK9 and LDLR, induce the degradation of PCSK9, increase LDLR protein levels, and alleviate hyperlipidemia and atherosclerosis in three distinct animal models, suggesting that E28362 is a promising lead compound for the treatment of hyperlipidemia and atherosclerosis.

Acupuncture in treating obesity combined with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled clinical trials.

BACKGROUND: and purpose: Most type 2 diabetes mellitus (T2DM) patients are accompanied by overweight or obesity, and it is difficult to concurrently solve these two issues with conventional treatment regimens without experiencing adverse effects. While clinical practice demonstrates that acupuncture is beneficial in treating obesity combined with T2DM, there is a lack of evidence-based medicine to support this claim. The study aims to systematically evaluate the efficacy and safety of acupuncture in treating obesity combined with T2DM. METHODS: By searching eight electronic databases, we collected randomized controlled trials on acupuncture in treating obesity combined with T2DM. Two reviewers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. Meta-analysis was then performed using RevMan 5.4 software. RESULTS: A total of 13 randomized controlled trials (RCTs) involving 993 patients were eventually included. Meta-analysis results demonstrated the effective rate of clinical symptoms: [RR = 1.19, 95% CI: 1.11, 1.28, P < 0.00001]; body mass index: [MD = -2.11, 95% CI: -2.56, -1.66, P < 0.00001]; fasting plasma glucose: [MD = -1.09, 95% CI: -1.60, -0.59, P < 0.00001]; haemoglobin A1c: [MD = -0.58, 95% CI: -0.95, -0.20, P = 0.002]; triglyceride: [MD = -0.29, 95% CI: -0.46, -0.11, P = 0.001]; waist circumference: [MD = -5.36, 95% CI: -8.68, -2.05, P = 0.002]; body fat rate: [MD = -3.59, 95% CI: -4.28, -2.90, P < 0.00001]. CONCLUSION: Current evidence suggests that acupuncture has advantages in treating obesity combined with T2DM. However, due to low-quality evidence of included research, additional large-sample and high-quality research are required to validate the findings of this study.

Atorvastatin reduces IOP in ocular hypertension in vivo and suppresses ECM in trabecular meshwork perhaps via FGD4.

To explore the role of atorvastatin in regulating intraocular pressure (IOP) in glaucoma in vivo, and to investigate its related molecular pathway in vitro, an ocular hypertension model was generated by intravitreal injection of an adenoviral vector encoding transforming growth factor (TGF)­ß2 in the right eye of BALB/cJ mice, while the left was treated with an empty control adenovirus. To determine its anti­intraocular hypertension role, these induced hyper­IOP mice were gavaged with atorvastatin (20 mg/kg/day). Furthermore, extracellular matrix (ECM) factors were examined in the primary human trabecular meshwork (HTM) cells followed atorvastatin (0~200 µM) treatment in vitro. Whole genome microarray was employed to identify potential therapeutic target molecules associated with ECM regulation. Unilateral murine ocular hypertension was induced, via intravitreal injection of the adenoviral vector carrying the human TGF­ß2 gene (Ad.hTGF­ß2226/228), raising IOP from 12±1.6 to 32.3±0.7 mmHg (n=6, P<0.05) at day 15, which plateaued from day 15 to 30. Atorvastatin administration from day 15 to 30 decreased IOP from 32.3±0.7 to 15.4±1.1 mmHg (n=6, P<0.05) at day 30. Additionally, atorvastatin administration changed the morphology of cultured HTM cells from an elongated and adherent morphology into rounded, less elongated and less adherent cells, accompanied with suppressed expression of ECM. Gene Ontology and Genome analysis revealed that FGD4 (FYVE, RhoGEF and PH domain containing 4) might be a key factor contributing to these changes. Our data demonstrated that atorvastatin reduced TGF­ß2­induced ocular hypertension in vivo, perhaps via modifying cellular structure and decreasing ECM, using the FGD4 signaling pathway, as demonstrated in HTM cells. Our findings provide some useful information for the management of glaucoma, with statin therapy revealing a potential novel therapeutic pathway for glaucoma treatment.

The NAM/ATAF1/2/CUC2 transcription factor PpNAC.A59 enhances PpERF.A16 expression to promote ethylene biosynthesis during peach fruit ripening.

Peach is a typical climacteric fruit that releases ethylene during fruit ripening. Several studies have been conducted on the transcriptional regulation of ethylene biosynthesis in peach fruit. Herein, an ethylene response factor, PpERF.A16, which was induced by exogenous ethylene, could enhance ethylene biosynthesis by directly inducing the expression of 1-aminocyclopropane-1-carboxylic acid synthase (PpACS1) and 1-aminocyclopropane-1-carboxylic acid oxidase (PpACO1) genes. Moreover, the NAM/ATAF1/2/CUC2 (NAC) transcription factor (TF) PpNAC.A59 was coexpressed with PpERF.A16 in all tested peach cultivars. Interestingly, PpNAC.A59 can directly interact with the promoter of PpERF.A16 to induce its expression but not enhance LUC activity driven by any promoter of PpACS1 or PpACO1. Thus, PpNAC.A59 can indirectly mediate ethylene biosynthesis via the NAC-ERF signaling cascade to induce the expression of both PpACS1 and PpACO1. These results enrich the genetic network of fruit ripening in peach and provide new insight into the ripening mechanism of other perennial fruits.

Aorto-esophageal fistula caused by fishbone ingestion: a case report on staged endovascular and endoscopic treatment.

BACKGROUND: Aorto-esophageal fistula (AEF) caused by foreign bodies ingestion is a rare but devastating disorder. Thoracic endovascular aortic repair (TEVAR) has become a widely accepted intervention for treating aorto-esophageal fistulas. As for post-TEVAR esophageal defect, secondary esophagectomy has been the recommended choice for most of the AEFs, but there is no general consensus with regard to the need of secondary surgeries for patients in the absence of clear signs of reinfection or bleeding. We herein presented a case of an AEF caused by fishbone ingestion, after successful TEVAR, the esophageal lesion was closed endoscopically. CASE PRESENTATION: A 38-year-old male presented with esophageal fistula for 4 months. He was diagnosed with AEF because of Chiari's triad after fishbone ingestion 4 months ago. Emergency thoracic aortic stent implantation was done, and given broad spectrum antibiotics and blood transfusion. His symptoms were improved, and discharged with an esophageal fistula left to heal itself. Nevertheless, after 4 months, re-examination of esophago-gastro-duodenoscopy revealed that the diameter of the fistula was changed from 3 to 6 mm. He was then admitted to our hospital for esophageal fistula repair. Laboratory examinations and chest computed tomography showed no signs of active infection, and endoscopic closure of the fistula was achieved with 4 clips. After that, he was discharged and gradually returned to normal diet. CONCLUSION: For AEFs in the absence of active infection with repaired aorta but persistent esophageal fistula, endoscopic closure by endoclips might be an effective treatment choice.

A simple and quick method to detect adulterated sesame oil using 3D fluorescence spectra.

Adulterated sesame oil seriously damages the interests of consumers and the health of market. In this paper, a simple, fast and real-time model for identifying adulterated sesame oil (ASO) was proposed by combining 3D fluorescence spectra with wavelet moments (WMs). First, noise and data volume of the experimental data were reduced by wavelet multiresolution decomposition (WMRSD), which improved the stability and real-time of the model. Next, WMs were used to extract the features of the 3D fluorescence spectra and proved to be effective by hierarchical clustering results. Then, the qualitative quality of WMs of the same orders, different orders and the combinations were evaluated by Dunn's validity index (DVI), and the rules were given, respectively. Finally, the target WMs for identifying ASO were determined. This model is simple and fast, and expandable to online measurement, providing a reference for identification and adulteration of vegetable oils.

The relationship between elevated serum uric acid and arterial stiffness in a healthy population.

OBJECTIVE: This study aims to investigate the relationship between serum uric acid and arterial stiffness in a healthy population. METHODS: Among the 979 participants, baPWV was non-invasively measured, the circulating levels of uric acid were tested, and the uric acid polymorphisms (rs2231142 and rs11722228) were genotyped. Then, the Mendelian randomization method was employed to test the relationship between serum uric acid and arterial stiffness in a healthy population. RESULTS: After adjusting for age, gender, antihypertensive medication, body mass index, waist-to-hip ratio, urea nitrogen, creatinine and diabetic mellitus, there was a significant allelic difference in uric acid levels for each genotype (P < 0.0001 for rs2231142; P = 0.007 for rs11722228). However, there were no differences on the potential confounders between the genotypes of rs2231142 and rs11722228 (P > 0.05). The baPWV was significantly associated with circulating levels of uric acid after adjusting for cardiovascular risk factors and other potential confounders (P = 0.002). However, neither the single polymorphism, nor the accumulation of culprit alleles was associated with baPWV (P = 0.92 for rs2231142; P = 0.60 for rs11722228; P for trend = 0.77 for the combined analysis of culprit alleles). CONCLUSION: These results do not support the causal role of circulating levels of uric acid in the development of arterial stiffness.

Risk factors for distal migration of biliary plastic stents and related duodenal injury.

BACKGROUND: The risk factors of duodenal injury from distal migrated biliary plastic stents remain uncertain. The aim of this study was to determine the risk factors of distal migration and its related duodenal injury in patients who underwent placement of a single biliary plastic stent for biliary strictures. METHODS: We retrospectively reviewed all patients with biliary strictures who underwent endoscopic placement of a single biliary plastic stent from January 2006 to October 2017. RESULTS: Two hundred forty-eight patients with 402 endoscopic retrograde cholangiopancreatography procedures were included. The incidence of distal migration was 6.2%. The frequency of duodenal injury was 2.2% in all cases and 36% in cases with distal migration. Benign biliary strictures (BBS), length of the stent above the proximal end of the stricture (> 2 cm), and duration of stent retention (< 3 months) were independently associated with distal migration (p = 0.018, p = 0.009, and p = 0.016, respectively). Duodenal injury occurred more commonly in cases with larger angle (≥ 30°) between the distal end of the stent and the centerline of the patient's body (p = 0.018) or in cases with stent retention < 3 months (p = 0.031). CONCLUSIONS: The risk factors of distal migration are BBS and the length of the stent above the proximal end of the stricture. The risk factor of duodenal injury due to distal migration is large angle (≥ 30°) between the distal end of the stent and the centerline of the patient's body. Distal migration and related duodenal injury are more likely to present during the early period after biliary stenting.

New antireflux plastic stent for patients with distal malignant biliary obstruction.

BACKGROUND: Endoscopic biliary stenting is a well-established palliative treatment for patients with unresectable distal malignant biliary obstruction (MBO). However, the main problem with stent placement is the relatively short duration of stent patency. Although self-expanding metal stents (SEMSs) have a longer patency period than plastic stents (PSs), the higher costs limit the wide use of SEMSs. A PS with an antireflux valve is an attractive idea to prolong stent patency, but no ideal design for an antireflux PS (ARPS) has been proposed. We developed a new ARPS with a "duckbilled" valve attached to the duodenal end of the stent. AIM: To compare the patency of ARPSs with that of traditional PSs (TPSs) in patients with unresectable distal MBO. METHODS: We conducted a single-center, prospective, randomized, controlled, double-blind study. This study was conducted at the West China Hospital of Sichuan University. Consecutive patients with extrahepatic MBO were enrolled prospectively. Eligible patients were randomly assigned to receive either an ARPS or a TPS. Patients were followed by clinic visits or telephone interviews every 1-2 mo until stent exchange, death, or the final study follow-up in October 2018. The primary outcome was the duration of stent patency. Secondary outcomes included the rate of technical success, the rate of clinical success, adverse events, and patient survival. RESULTS: Between February 2016 and December 2017, 38 patients were randomly assigned to two groups, with 19 patients in each group, to receive ARPSs or TPSs. Stent insertion was technically successful in all patients. There were no significant differences between the two groups in the rates of clinical success or the rates of early or late adverse events (P = 0.660, 1.000, and 1.000, respectively). The median duration of stent patency in the ARPS group was 285 d [interquartile range (IQR), 170], which was significantly longer than that in the TPS group (median, 130 d; IQR, 90, P = 0.005). No significant difference in patient survival was noted between the two groups (P = 0.900). CONCLUSION: The new ARPS is safe and effective for the palliation of unresectable distal MBO, and has a significantly longer stent patency than a TPS.

Novel inflammatory cytokines (IL-36, 37, 38) in the aqueous humor from patients with chronic primary angle closure glaucoma.

Glaucoma eventually leads to optic nerve damage and vision loss without medical intervention. More than 50% of glaucoma caused blindness are attributed to primary angle closure glaucoma, particularly in Asians. It is reported that immune inflammation is involved in the progress of glaucoma. Increased inflammation cytokines are detected in the aqueous humor of chronic primary angle closure glaucoma (CPACG). IL-36, IL-37 and IL-38, are novel cytokines and are involved in many inflammatory diseases, including inflammatory bowel diseases and acute anterior uveitis, but the possible contributing role in the pathogenesis of CPACG is unclear. In our current study, increased IL-36, IL-37 and IL-38 were detected in the aqueous humor of CPACG compared with age-related cataract (ARC). Furthermore, a significant correlation was detected between mean deviation of visual field (MDVF) of CPACG and IL-36, IL-37 or IL-38, respectively. Our data suggest IL-36, IL-37 and IL-38 might contribute to the immunological mediated pathogenesis of CPACG, despite the eye being an immune-privileged organ under normal conditions. The precise underlying mechanism of these cytokines during the development of CPACG remains to be explored. Our findings may be useful in therapeutic targeting of specific pathology.

Increased serum levels of macrophage migration inhibitory factor in autism spectrum disorders.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) has been suggested as a pivotal regulator of innate immunity and inflammatory. The aim of this study was to measure serum circulating levels of MIF in relation to the degree of the severity of autism spectrum disorders (ASD). METHODS: One hundred and two Chinese children with ASD and same their age-sex matched typical development children were included. Concentrations of MIF were tested by Quantikine Human MIF Immunoassay. Serum levels of homocysteine (HCY), C-reactive protein (CRP) and serum Interleukin 6 (IL-6) were also tested. The influence of serum levels of MIF on ASD risk and ASD severity were performed by binary logistic regression analysis. RESULTS: The serum levels of MIF in the children with ASD (24.7 ± 08.9 ng/ml) were significantly higher than those of control subjects (18.3 ± 5.5 ng/ml) (t = 6.134, P < 0.001). Levels of MIF increased with increasing severity of ASD as defined by the CARS score (P < 0.001). In multivariate model, MIF was associated with an increased risk of ASD (OR 1.11, 95% CI: 1.05-1.17; P < 0.001). MIF improved the combined model (HCY/CRP/IL-6) to predict ASD (P < 0.001). At admission, 68 children (66.7%) had a severe autism. In these children, the mean serum level of MIF was higher than in those children with mild to moderate autism (28.1 ± 8.5 ng/ml VS. 17.9 ± 4.7 ng/ml; t = 6.482, P < 0.001). In multivariate model, MIF was still associated with an increased risk of severe ASD (OR: 1.15, 95% CI: 1.04-1.19; P < 0.001). MIF improved the combined model (HCY/CRP/IL-6) to predict severe ASD (P < 0.001). CONCLUSIONS: These results identify high serum MIF levels are associated with severity of ASD. Further study is warranted on the precise involvement of MIF in ASD, and the mechanism by which MIF contributes to ASD pathogenesis.

[Finite element analysis of the influence of anchorage number and location on Bankart repair strength of shoulder joint].

OBJECTIVE: To study the influence of the number and position of anchor nails on the Bankart repair by the finite element analysis. METHODS: The 3D CT data of shoulder joints including normal adult volunteers were imported into Mimics 10.0 and Geomagic 2012 software to reconstruct the related tissues, and then meshed in Hypermesh 13.0 software to give material attributes. The position and number of MPC constraints were adjusted in Abaqus 6.14 to establish finite element model of shoulder joint under 6 working conditions including A model(normal control model), B model (Bankart damage control model), C model (1 anchor), D model (2 anchors), E model (3 anchors), F model (4 anchors). The humerus external rotation and forward load were added to simulate the fear test of the shoulder joint forward instability. RESULTS: (1)Normally, the inferior glenohumeral ligament complex accompanied by the external rotation of the humerus head has a wrinkle and a significant stress concentration around its anterior and posterior bundle terminations.(2)The stress of the anterior bundle and posterior bundle of the inferior glenohumeral ligament were increased by 52.33% and 45.67% respectively after Bankart's injury.(3)In each model of anchor repair, the stress concentration was obvious at the anchor site, and the stress of anterior and posterior bundle ligaments could be reduced; there were no obvious differences between C, D models and B model(P>0.05), and there were significant differences between E, F models and B model(P<0.05). CONCLUSIONS: One or two anchors can reduce the stress of the anterior and posterior bundles of the inferior glenohumeral ligament in the repair of Bankart's injury, but when the angle of rotation is large, the stress concentration in the anchor position increases significantly, leading to the increases of the risk of failure. The application of three or four anchors can enhance the constraints on the inferior glenohumeral ligament and reduce the stress of the anchor itself through the "load sharing" effect between anchors, so as to ensure the stability of the shoulder joint and provide a mechanical environment for the early rehabilitation of patients.

Diffusion Tensor Imaging Detects Microstructural Differences of Visual Pathway in Patients With Primary Open-Angle Glaucoma and Ocular Hypertension.

Ocular hypertension (OHT), the common situation in adult patients in the outpatients, occurs ∼5% worldwide. However, there are still some practical problems in differentiation of OHT with early primary open-angle glaucoma (POAG) using current standard methods. Application of high resolution diffusion tensor imaging (DTI) enables us to the differentiate axonal architecture of visual pathway between POAG and OHT subjects. Among 32 POAG patients recruited (15 OHT and 14 control subjects), 62.5% of glaucoma were in early stage for the current study. All subjects underwent ophthalmological assessments with standard automated perimetry and optical coherence tomography (OCT). DTI was applied to measure fraction anisotropy (FA) and mean diffusivity (MD) of optic tract (OT), lateral geniculate body (LGN) and optic radiation (OR) using voxel-based analysis. Our data demonstrated that FA values of bilateral OR in POAG were significantly lower in the right or left than that of OHT patients (left OR: 0.51 ± 0.04 vs. 0.54 ± 0.03, p < 0.05; right OR: 0.51 ± 0.05 vs. 0.54 ± 0.03, p < 0.05). In right LGN, MD values were higher in POAG patients compared with OHT subjects (9.81 ± 1.45 vs. 8.23 ± 0.62, p < 0.05). However, no significant difference of all of the DTI parameters was observed between OHT and control subjects. DTI parameters in POAG patients were positively correlated with morphological and functional measurements (p < 0.05). Vertical cup to disc ratio (VCDR) was correlated with ipsilateral FA of OT (p < 0.05), ipsilateral MD of OT (p < 0.05), ipsilateral MD of LGN (p < 0.05), and contralateral MD of OT (p < 0.05). Mean deviation of visual field (MDVF) was correlated with ipsilateral FA of OT (p < 0.05), ipsilateral MD of OT (p < 0.05), and ipsilateral FA of LGN (p < 0.05). Our study demonstrated that DTI can differentiate POAG from OHT subjects in optic pathway, particularly in early POAG, and DTI parameters can quantify the progression of POAG.

Favorable response to pemetrexed, cisplatin and bevacizumab in invasive mucinous adenocarcinoma: A case report and literature review.

Invasive mucinous adenocarcinoma (IMA) was formerly referred to as mucinous bronchioloalveolar carcinoma. The lack of effective chemotherapy and comprehensive treatment for this type of tumor poses a great challenge in clinical practice. We herein report the case of a male patient with IMA who was treated with a combination of pemetrexed (500 mg/m2), cisplatin (75 mg/m2) and bevacizumab (15 mg/kg) as first-line chemotherapy. The patient achieved significant radiological improvement with 6 courses of this regimen. After the tumor progressed, the patient again achieved marked improvement with an additional 4 courses of the same regimen. The patient survived for a total of 30 months after the first chemotherapy. Therefore, bevacizumab in combination with pemetrexed/cisplatin may be an effective strategy for the treatment of IMA. The available literature on this chemotherapy regimen was also reviewed and discussed in the present study.

The Protective Effects of Terpinen-4-ol on LPS-Induced Acute Lung Injury via Activating PPAR-γ.

Terpinen-4-ol, the major constituent of tea tree oil, has been reported to have anti-inflammatory effect. However, whether terpinen-4-ol could attenuate LPS-induced inflammation in lung tissues remains unclear. In the present study, we aimed to investigate the protective effects of terpinen-4-ol on LPS-induced acute lung injury (ALI) in mice. Terpinen-4-ol could inhibit LPS-induced ALI as confirmed by the decreased lung histopathological changes, MPO activity, and lung W/D ratio caused by terpinen-4-ol. The production of TNF-α and IL-1ß in the BALF was suppressed by the treatment of terpinen-4-ol. Western blot analysis showed that terpinen-4-ol significantly attenuated LPS-induced phosphorylation of IκBα and NF-κB p65. Furthermore, the expression of PPAR-γ was dose-dependently upregulated by the treatment of terpinen-4-ol. In conclusion, the results of this study indicated that terpinen-4-ol inhibited LPS-induced ALI via activating PPAR-γ, which subsequently attenuated LPS-induced NF-κB activation and inflammatory response.

RNA-Seq analysis unveils gene regulation of fruit size cooperatively determined by velocity and duration of fruit swelling in peach.

Fruit swelling determines fruit size and usually occurs in two distinct time periods in peach. However, little is known about the gene regulation of fruit swelling. In this study, measurements of longitudinal and transverse diameters in developing and ripening peach fruits unveiled two periods of fruit swelling: the first swelling ends at approximately 65 days after flower blooming (DAFB) and the second swelling starts at approximately 75 DAFB. Comparisons of diameters sizes and development periods among cultivars and accessions revealed a cooperative regulation of swelling velocity and swelling duration, which leads to final determination of fruit size. Furthermore, RNA-sequencing was conducted for fruits at the initial swelling, non-swelling interval between the two swellings (hereafter, 'the interval'), second swelling and ripening stages. A total of 110 and 128 differentially expressed genes were screened from fruits in the first and second swelling, respectively. Besides, the nine most differentially expressed genes located within the reported quantitative trait locations (QTLs) of fruit size in peach were detected in both the first and second swelling stages. Those genes have been reported to be involved in mediating cell size, which indicates the occurrence of both cell proliferation and cell expansion in each of the two major periods of fruit swelling. In addition, a potential gene regulation network is proposed herein and could be used to elucidate the molecular mechanism of peach fruit swellings mediated by multiple key genes.

[Pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia].

To study the pharmacokinetics-pharmacodynamics correlation of protocatechuic aldehyde and hydroxysafflor yellow A alone or their combination use in rats with hyperlipidemia. In this study, the hyperlipidemia model was established by intravenous injection of protocatechuic aldehyde (20 mg•kg⁻¹) and hydroxysafflor yellow A (12 mg•kg⁻¹). The HPLC-DAD method was applied to determine the plasma concentration of protocatechuic aldehyde and hydroxysafflor yellow A at different time points and draw the drug effect-time curve. Meanwhile, the platelet activating factors (PAF) and plasma a granule membrane protein (GMP-140) contents were determined at different time points to draw the time-effect curve. Then DAS 3.2.6 software was used to process the data, analyze their correlation, and compare the difference of pharmacokinetics and pharmacodynamics of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combined application, so as to evaluate the effect of protocatechuic aldehyde and hydroxysafflor yellow A on hyperlipidemia rats. According to the result, the pharmacokinetics and pharmacodynamics process of protocatechuic aldehyde and hydroxysafflor yellow A in hyperlipidemia rats after alone or their combination were consistent to the three-compartment model. In model group, the plasma PAF and GMP-140 were significantly increased, and the PAF and GMP-140 in vivo contents were decreased in a certain time after treatment. The effects of protocatechuic aldehyde and hydroxysafflor yellow A against the pharmacodynamic action may be related with their level in vivo, and their plasma concentration was positively related to the PAF and GMP-140 contents. The pharmacodynamic indexes were better after the combined use of protocatechuic aldehyde and hydroxysafflor yellow A, with certain influence on each other in hyperlipidemia rats; at the same time, it also reflected the rationality of protocatechuic aldehyde and hydroxysafflor yellow A combined application.

Host Pore-Forming Protein Complex Neutralizes the Acidification of Endocytic Organelles to Counteract Intracellular Pathogens.

Many intracellular pathogens invade cells via endocytic organelles and have adapted to the drop in pH along the endocytic pathway. However, the strategy by which the host cell counteracts this pathogen adaptation remains unclear. ßγ-CAT is an aerolysin-like pore-forming protein and trefoil factor complex in the frog Bombina maxima. We report here that ßγ-CAT, as a host-secreted factor with an intrinsic channel-forming property, is the first example of a molecule that actively neutralizes the acidification of endocytic organelles to counteract Listeria monocytogenes infection. Immunodepletion of endogenous ßγ-CAT largely impaired the control of L. monocytogenes by frog cells. ßγ-CAT elevates the pH of L. monocytogenes-containing vacuoles to limit the vacuole escape of L. monocytogenes to cytosol. Furthermore, ßγ-CAT promotes intracellular L. monocytogenes clearance via autophagy and by that the nonlytic expulsion of the bacteria from host cells. Finally, ßγ-CAT attenuated the dissemination of L. monocytogenes in vivo. These findings reveal a novel host strategy and effectors that combat pathogen adaptation to acidic conditions along the endocytic pathway.