Hemodynamics is associated with vessel wall remodeling in patients with middle cerebral artery stenosis.

OBJECTIVES: To evaluate the relationship between hemodynamics and vessel wall remodeling patterns in middle cerebral artery (MCA) stenosis based on high-resolution magnetic resonance imaging and computational fluid dynamics (CFD). METHODS: Forty consecutive patients with recent ischemic stroke or transient ischemic attack attributed to unilateral atherosclerotic MCA stenosis (50-99%) were prospectively recruited. All patients underwent a cross-sectional scan of the stenotic MCA vessel wall. The parameters of the vessel wall, the number of patients with acute infarction, translesional wall shear stress ratio (WSSR), wall shear stress in stenosis (WSSs), and translesional pressure ratio were obtained. The patients were divided into positive remodeling (PR) and negative remodeling (NR) groups. The differences in vessel wall parameters and hemodynamics were compared. Correlations between the parameters of the vessel wall and hemodynamics were calculated. RESULTS: Of the 40 patients, 16 had PR, 19 had NR, and the other 5 displayed non-remodeling. The PR group had a smaller lumen area (p = 0.004), larger plaque area (p < 0.001), normal wall index (p = 0.004), and higher WSSR (p = 0.004) and WSSs (p = 0.023) at the most narrowed site. The PR group had more enhanced plaques (12 vs 6, p = 0.03). The number of patients with acute stroke in the PR group was more than that in the NR group (11 vs 4, p = 0.01). The remodeling index (r = 0.376, p = 0.026) and plaque area (r = 0.407, p = 0.015) showed a positive correlation with WSSR, respectively. CONCLUSIONS: Hemodynamics plays a role in atherosclerotic plaques and vessel wall remodeling. Individuals with greater hemodynamic values might be more prone to stroke. KEY POINTS: • Stenotic plaques in middle cerebral artery with positive remodeling have smaller lumen area and larger resp. higher plaque area, normal wall index, translesional wall shear stress ratio, and wall shear stress than negative remodeling. • The remodeling index and plaque area are positively correlated with translesional wall shear stress ratio. • Hemodynamic may help to understand the role of positive remodeling in the development of acute stroke.

Euzebyella marina sp. nov., isolated from seawater.

A Gram-stain-negative, aerobic, yellow-pigmented, non-flagellated, non-gliding, oxidase- and catalase-positive bacterium, designated CY01T, was isolated from seawater of the Yellow Sea. CY01T grew at 15-37 °C (optimum, 30 °C), pH 5-8 (optimum, 6.5-7.5) and with 0.5-12 % (w/v) NaCl (optimum, 0.5-3.5 %). It could not produce flexirubin-type pigment or reduce nitrate to nitrite. CY01T showed the highest 16S rRNA gene sequence similarity to the type strain of Euzebyella saccharophila (97.0 %) and clustered tightly with the species of the genus Euzebyella in the phylogenetic trees based on the 16S rRNA gene sequences. The major cellular fatty acids of CY01T were iso-C15 : 0, iso-C15 : 1G and iso-C17 : 0 3-OH and the major respiratory quinone was menaquinone MK-6. Polar lipids included phosphatidylethanolamine (PE), four unidentified lipids and one unidentified aminolipid. The genomic DNA G+C content was 38.2 mol%. Based on the results of the polyphasic characterization of CY01T, it represents a novel species of the genus Euzebyella, for which the name Euzebyella marina sp. nov. is proposed. The type strain is CY01T (=CCTCC AB 2014348T=KCTC 42440T).

Digital subtraction CT angiography for the detection of posterior inferior cerebellar artery aneurysms: comparison with digital subtraction angiography.

OBJECTIVE: To evaluate the diagnostic accuracy of digital subtraction CT angiography (DS-CTA) in detecting posterior inferior cerebellar artery (PICA) aneurysms with digital subtraction angiography (DSA) as reference standard. METHODS: A total of 115 patients, including 56 patients diagnosed with PICA aneurysms by CTA or DSA and 59 non-PICA-aneurysm patients were included in this retrospective study. All patients underwent DS-CTA and DSA. The site of PICA aneurysms and the pattern of haemorrhage were analysed. Sensitivity and specificity of DS-CTA without and with combining haemorrhage pattern in diagnosing PICA aneurysms were evaluated on a per patient and per aneurysm basis with DSA. RESULTS: Of 115 patients, 56 patients (48.7%) had 61 PICA aneurysms (size range, 1.1-13.5 mm; mean size, 4.9 ± 2.8 mm) on DSA. The sensitivity and specificity in depicting PICA aneurysms were 89.3% and 96.6% on a per patient basis and 90.2% and 93.4% on a per aneurysm basis, while the corresponding values were 94.6% and 96.6% on a per patient basis and 95.1% and 93.4% on a per aneurysm basis when combining with haemorrhage site. CONCLUSION: DS-CTA has a high sensitivity and specificity in detecting PICA aneurysms compared with DSA. It may be helpful for clinical diagnosis of PICA aneurysms to combine with haemorrhage sites. KEY POINTS: • CT angiography has a good diagnostic performance in detecting PICA aneurysms. • The haemorrhage location is helpful to detect PICA aneurysms. • Digital subtraction CTA is a preferable diagnostic means for PICA aneurysms.

Image quality, radiation dose and diagnostic accuracy of 70 kVp whole brain volumetric CT perfusion imaging: a preliminary study.

PURPOSE: To evaluate image quality and diagnostic accuracy for acute infarct detection and radiation dose of 70 kVp whole brain CT perfusion (CTP) and CT angiography (CTA) reconstructed from CTP source data. METHODS: Patients were divided into three groups (n = 50 each): group A, 80 kVp, 21 scanning time points; groups B, 70 kVp, 21 scanning time points; group C, 70 kVp, 17 scanning time points. Objective and subjective image quality of CTP and CTA were compared. Diagnostic accuracy for detecting acute infarct and cerebral artery stenosis ≥ 50 % was calculated for CTP and CTA with diffusion weighted imaging and digital subtraction angiography as reference standards. Effective radiation dose was compared. RESULTS: There were no differences in any perfusion parameter value between three groups (P > 0.05). No difference was found in subjective image quality between three groups (P > 0.05). Diagnostic accuracy for detecting acute infarct and vascular stenosis showed no difference between three groups (P > 0.05). Compared with group A, radiation doses of groups B and C were decreased by 28 % and 37 % (both P < 0.001), respectively. CONCLUSION: Compared with 80 kVp protocol, 70 kVp brain CTP allows comparable vascular and perfusion assessment and lower radiation dose while maintaining high diagnostic accuracy in detecting acute infarct. KEY POINTS: • 70 kVp whole brain CTP can provide diagnostic image quality. • 70 kVp CTP diagnostic accuracy was maintained vs. 80 kVp protocol. • 70 kVp CTP radiation doses were lower than 80 kVp protocol.

Reproducibility of image-based computational models of intracranial aneurysm: a comparison between 3D rotational angiography, CT angiography and MR angiography.

BACKGROUND: Reconstruction of patient-specific biomechanical model of intracranial aneurysm has been based on different imaging modalities. However, different imaging techniques may influence the model geometry and the computational fluid dynamics (CFD) simulation. The aim of this study is to evaluate the differences of the morphological and hemodynamic parameters in the computational models reconstructed from computed tomography angiography (CTA), magnetic resonance angiography (MRA) and 3D rotational angiography (3DRA). METHODS: Ten patients with cerebral aneurysms were enrolled in the study. MRA, CTA and 3DRA were performed on all patients. For each patient, three patient-specific models were reconstructed respectively based on the three sets of imaging data of the patient. CFD simulations were performed on each model. Model geometry and hemodynamic parameters were compared between the three models. RESULTS: In terms of morphological parameters, by comparing CTA based models (CM) and 3DRA based models (DM) which were treated as the "standard models", the aspect ratio had the minimum difference (Δ = 8.3 ± 1.72 %, P = 0.953) and the surface distance was 0.25 ± 0.07 mm. Meanwhile, by comparing MRA based models (MM) and DM, the size had the minimum difference (Δ = 6.6 ± 1.85 %, P = 0.683) and the surface distance was 0.36 ± 0.1 mm. In respect of hemodynamic parameters, all three models showed a similar distribution: low average WSS at the sack, high OSI at the body and high average WSSG at the neck. However, there was a large variation in the average WSS (Δ = 34 ± 5.13 % for CM, Δ = 40.6 ± 9.21 % for MM). CONCLUSION: CTA and MRA have no significant differences in reproducing intracranial aneurysm geometry. The CFD results suggests there might be some significant differences in hemodynamic parameters between the three imaging-based models and this needs to be considered when interpreting the CFD results of different imaging-based models. If we only need to study the main flow patterns, three types of image-based model might be all suitable for patient-specific computational modeling studies.

Radiation dose and image quality of 70 kVp cerebral CT angiography with optimized sinogram-affirmed iterative reconstruction: comparison with 120 kVp cerebral CT angiography.

OBJECTIVES: To evaluate radiation dose, image quality, and optimal level of sinogram-affirmed iterative reconstruction (SAFIRE) of cerebral CT angiography (CTA) at 70 kVp. METHODS: One hundred patients were prospectively classified into two groups: Group A (n = 50), 70 kVp cerebral CTA with 5 levels of SAFIRE reconstruction (S1-S5); and Group B (n = 50), 120 kVp with filtered back projection (FBP) reconstruction. CT attenuation values, noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the internal carotid artery (ICA) and middle cerebral artery (MCA) were measured. Subjective image quality was evaluated. Effective dose (ED) was estimated. RESULTS: CT attenuation and noise of the ICA and MCA in Group A were higher than those of Group B (all P < 0.001) while the SNRICA, SNRMCA, CNRICA, and CNRMCA of Group A at S4-5 were comparable to (P > 0.05) or higher than in Group B (P < 0.05). There was no difference in overall image quality between Group A S3-5 and Group B (P > 0.05). ED was 0.2 ± 0.0 mSv for Group A with 85 % ED reduction in comparison to Group B (1.3 ± 0.2 mSv). CONCLUSION: Cerebral CTA at 70 kVp is feasible, allowing for substantial radiation dose reduction. SAFIRE S4 level is recommended for obtaining optimal image quality. KEY POINTS: • 70 kVp cerebral CTA is feasible and provides diagnostic image quality. • 70 kVp cerebral CTA resulted in 85% effective dose reduction. • S4 level of SAFIRE is recommended for 70 kVp cerebral CTA.

Rheum palmatum L. and Salvia miltiorrhiza Bge. Alleviates Acute Pancreatitis by Regulating Th17 Cell Differentiation: An Integrated Network Pharmacology Analysis, Molecular Dynamics Simulation and Experimental Validation.

OBJECTIVE: To identify the core targets of Rheum palmatum L. and Salvia miltiorrhiza Bge., (Dahuang-Danshen, DH-DS) and the mechanism underlying its therapeutic efficacy in acute pancreatitis (AP) using a network pharmacology approach and validate the findings in animal experiments. METHODS: Network pharmacology analysis was used to elucidate the mechanisms underlying the therapeutic effects of DH-DS in AP. The reliability of the results was verified by molecular docking simulation and molecular dynamics simulation. Finally, the results of network pharmacology enrichment analysis were verified by immunohistochemistry, Western blot analysis and real-time quantitative PCR, respectively. RESULTS: Sixty-seven common targets of DH-DS in AP were identified and mitogen-activated protein kinase 3 (MAPK3), Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), protein c-Fos (FOS) were identified as core targets in the protein interaction (PPI) network analysis. Gene ontology analysis showed that cellular response to organic substance was the main functions of DH-DS in AP, and Kyoto Encyclopedia of Genes and Genomes analysis showed that the main pathway included Th17 cell differentiation. Molecular docking simulation confirmed that DH-DS binds with strong affinity to MAPK3, STAT3 and FOS. Molecular dynamics simulation revealed that FOS-isotanshinone II and STAT3-dan-shexinkum d had good binding capacity. Animal experiments indicated that compared with the AP model group, DH-DS treatment effectively alleviated AP by inhibiting the expression of interleukin-1ß, interleukin-6 and tumor necrosis factor-α, and blocking the activation of Th17 cell differentiation (P<0.01). CONCLUSION: DH-DS could inhibit the expression of inflammatory factors and protect pancreatic tissues, which would be functioned by regulating Th17 cell differentiation-related mRNA and protein expressions.

Magnetic chitin beads (MCB) coated with Vibrio cholerae reveals transcriptome dynamics in adult mice with a complex gut microbiota.

Vibrio cholerae adapts to the host environment by altering gene expression. Because of the complexity of the gut microbiome, current in vivo V. cholerae transcriptome studies have focused on microbiota-undeveloped conditions, neglecting the interaction between the host's commensal gut microbiota and V. cholerae. In this study, we analyzed the transcriptome of fully colonized adult mice in vivo using V. cholerae coated-magnetic chitin beads (vcMCB). This provides a simple yet powerful method for obtaining high-quality RNA from V. cholerae during colonization in mice. The transcriptome of V. cholerae recovered from adult mice infected with vcMCB shows differential expression of several genes when compared to V. cholerae recovered from the infant mouse and infant rabbit model. Some of these genes were also observed to be differentially expressed in previous studies of V. cholera recovered from human infection when compared to V. cholerae grown in vitro. In particular, we confirmed that V. cholerae resists the inhibitory effects of low pH and formic acid from gut microbiota, such as Anaerostipes caccae and Dorea formicigenerans, by downregulating vc1080. We propose that the vc1080 product may protect V. cholerae from formic acid stress through a novel acid tolerance response mechanism. Transcriptomic data obtained using the vcMCB system provide new perspectives on the interaction between V. cholerae and the gut microbiota, and this approach can also be applied to studies of other pathogenic bacteria.

Cross-Platform Transcriptomic Data Integration, Profiling, and Mining in Vibrio cholerae.

A large number of transcriptome studies generate important data and information for the study of pathogenic mechanisms of pathogens, including Vibrio cholerae. V. cholerae transcriptome data include RNA-seq and microarray: microarray data mainly include clinical human and environmental samples, and RNA-seq data mainly focus on laboratory processing conditions, including different stresses and experimental animals in vivo. In this study, we integrated the data sets of both platforms using Rank-in and the Limma R package normalized Between Arrays function, achieving the first cross-platform transcriptome data integration of V. cholerae. By integrating the entire transcriptome data, we obtained the profiles of the most active or silent genes. By transferring the integrated expression profiles into the weighted correlation network analysis (WGCNA) pipeline, we identified the important functional modules of V. cholerae in vitro stress treatment, gene manipulation, and in vitro culture as DNA transposon, chemotaxis and signaling, signal transduction, and secondary metabolic pathways, respectively. The analysis of functional module hub genes revealed the uniqueness of clinical human samples; however, under specific expression patterning, the Δhns, ΔoxyR1 strains, and tobramycin treatment group showed high expression profile similarity with human samples. By constructing a protein-protein interaction (PPI) interaction network, we discovered several unreported novel protein interactions within transposon functional modules. IMPORTANCE We used two techniques to integrate RNA-seq data for laboratory studies with clinical microarray data for the first time. The interactions between V. cholerae genes were obtained from a global perspective, as well as comparing the similarity between clinical human samples and the current experimental conditions, and uncovering the functional modules that play a major role under different conditions. We believe that this data integration can provide us with some insight and basis for elucidating the pathogenesis and clinical control of V. cholerae.

The haplotype of the TGFß1 gene associated with cerebral infarction in Chinese.

BACKGROUND: Transforming growth factor beta1 (TGFß1) is a multifunctional cytokine involved in inflammation and pathogenesis of atherosclerosis. The aim of the present study was to investigate the relationship between human TGFß1 gene +869T>C (rs1800470), -509C>T (rs1800469) single nucleotide polymorphisms (SNPs) and haplotypes and cerebral infarction (CI) in a Chinese population. METHODS: The genetic association study was performed in 450 Chinese patients (306 male and 144 female) with CI and 450 control subjects (326 male and 124 female). TGFß1 gene +869T>C and -509C>T polymorphisms were identified with amplification refractory mutation system polymerase chain reaction and DNA sequencing method. RESULTS: The individual SNPs analysis showed the +869T and -509C in an additive model (+869T vs +869C; -509 C vs T), +869TT genotype in a recessive model (TT vs TC+CC) and 509CC genotype in a dominant model (CC+ CT vs TT) were identified to be related to CI (P<0.05). +869T>C and -509C>T SNPs were in strong linkage disequilibrium (d'=0.87, R2=0.75). Haplotype analysis showed that +869C/-509T haplotype was associated with a significant decreased risk of CI (OR= 0.86, 95%CI, 0.70-0.92; P=0.007). Furthermore,+869T/-509C haplotype was associated with a significant increased risk of CI (OR=1.31, 95%CI, 1.10-2.03; P=0.019). CONCLUSIONS: The results of this study indicate that polymorphisms and the haplotypes in the TGFß1 gene might be genetic markers for CI in the Chinese population.

Ropivacaine-induced seizures evoked pain sensitization in rats: Participation of 5-HT/5-HT3R.

Due to the increasing use of local anesthetic techniques in various healthcare settings, local anesthetic toxicity still occurs. Seizures are the most common symptom of local anesthetic toxicity. The relationship between local anesthetic-induced seizures and the sensation of pain has not been established till now. Here, we assessed the development of pain hypersensitivity after ropivacaine-induced seizures (RIS) and the influence of RIS on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. In addition, the involvement of spinal 5-HT/5-HT3R in RIS-induced pain sensitization was investigated. According to a sequential exploratory experimental strategy, we first calculated the 50% seizure dosage of ropivacaine to be 42.66 mg/kg (95% confidence interval: 40.19-45.28 mg/kg). We showed that RIS induced significant bilateral mechanical pain hypersensitivity that lasted around 5 days, accompanied by an increase in spinal 5-HT. Moreover, RIS considerably protracted postsurgical pain and enhanced formalin-induced spontaneous flinching in the second phase. Depletion of spinal 5-HT with intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT) reduced RIS-induced pain hypersensitivity and prevented the prolonging of postsurgical pain following RIS. Likewise, blocking spinal 5-HT3R by intrathecal administration of ondansetron reversed RIS-induced pain hypersensitivity and attenuated the pronociception of RIS in the formalin test. Our findings revealed that acute RIS led to pain hypersensitivity and had pronociceptive effects on incision-induced postsurgical pain and formalin-induced acute inflammatory pain. Moreover, our data implied that RIS-induced pain sensitization depends on spinal 5-HT/5-HT3R signaling. Thus, targeting the descending serotonergic facilitation system should be an important element of the precise treatment for local anesthetic toxicity.

TGF-beta 1 codon 10 polymorphism is associated with cerebral SVD.

BACKGROUND: To clarify the role of inflammation in the pathogenesis of cerebral small vessel disease (SVD), we investigated whether the gene encoding transforming growth factor-beta 1(TGF-beta 1) is a risk factor for cerebral SVD as a whole, and for two different SVD subtypes. METHODS: TGF-beta 1 codon10 (T+29C) genotype was determined in 441 Chinese patients (313 male and 128 female) with cerebral SVD and 450 control subjects (326 male and 124 female). Cerebral SVD patients were retrospectively classified into two groups based on neuroimaging findings: lacunar infarction group with 112 patients and ischaemic leukoaraiosis group with 329 patients. RESULTS: Subjects carrying TT homozygote were susceptible to cerebral SVD [adjusted odds ratio (OR) =1.44, 95% confidence interval (CI), 1.05-1.98; P=0.026]. Further analysis of SVD subtypes revealed a moderate association with the ischaemic leukoaraiosis group [OR= 1.60, 95% CI, 1.14-2.25; P=0.007]. CONCLUSIONS: Codon 10 of TGF-beta 1 might be a risk factor for SVD, specifically in ischaemic leukoaraiosis phenotype.

Intervertebral foramen injection of plerixafor attenuates neuropathic pain after chronic compression of the dorsal root ganglion: Possible involvement of the down-regulation of Nav1.8 and Nav1.9.

Neuropathic pain is a common chronic pain condition with major impact on quality of life. However, its physiopathologic mechanism remains unknown and pain management is still a challenge. Accumulating evidence indicated that C-X-C chemokine receptor type 4 (CXCR4) played a critical role in the process of pain. Thus, the present study aimed to investigate whether intervertebral foramen injection of CXCR4 antagonist, plerixafor, was able to relieve neuropathic pain and explore the possible underlying mechanism. Chronic compression of the dorsal root ganglion (CCD) was established as a typical model of neuropathic pain. The results indicated that CCD induced multiple pain-related behaviors and the expression of CXCR4, Nav1.8 and Nav1.9 was significantly increased in compressed dorsal root ganglion (DRG) neurons. Knocking down CXCR4 expression could significantly reduce neuropathic pain and intervertebral foramen plerixafor injection (IVFP) dramatically decreased the up-regulation of Nav1.8 and Nav1.9 and attenuated neuropathic pain. The analgesic duration of IVFP was maintained at least for 24 h which was much longer than intervertebral foramen injection of Nav1.8 blocker and local anesthetics. Therefore, our study provided evidence that IVFP could reduce the expression of Nav1.8 and Nav1.9 in DRG neurons which might contribute to, at least in part, the analgesic effect of plerixafor on CCD-induced neuropathic pain. It is concluded that IVFP was an effective and applicable treatment approach for neuropathic pain.

The analgesic effects of ulinastatin either as a single agent or in combination with sufentanil: A novel therapeutic potential for postoperative pain.

Ulinastatin is a broad-spectrum protease inhibitor widely used for the treatment of various inflammation-related diseases owing to its recognized excellent anti-inflammatory and cytoprotective properties. However, whether ulinastatin can relieve postoperative pain remains unclear. In this study, we evaluated the analgesic effects of ulinastatin administered either as a single agent or in combination with sufentanil in a validated preclinical rat model of postoperative pain induced by plantar incision. We found that incisional surgery on the hind paw of these rats induced sustained ipsilateral mechanical pain hypersensitivity that lasted for at least 10 days. A single intraperitoneal (i.p.) injection of ulinastatin prevented the development and reversed the maintenance of incision-induced mechanical pain hypersensitivity in a dose-dependent manner. However, ulinastatin had no effect on the baseline nociceptive threshold. Moreover, repeated i.p. injections of ulinastatin persistently attenuated incision-induced mechanical pain hypersensitivity and promoted recovery from the surgery. The rats did not develop any analgesic tolerance over the course of repeated injections of ulinastatin. A single i.p. injection of ulinastatin was also sufficient to inhibit the initiation and maintenance of incision-induced hyperalgesic priming when the rats were subsequently challenged with an ipsilateral intraplantar prostaglandin E2 injection. Furthermore, the combined administration of ulinastatin and sufentanil significantly enhanced the analgesic effect of sufentanil on postoperative pain, which involved mechanisms other than a direct influence on opioid receptors. These findings demonstrated that ulinastatin had a significant analgesic effect on postoperative pain and might be a novel pharmacotherapeutic agent for managing postoperative pain either alone or as an adjuvant.

Trichoderma: A Treasure House of Structurally Diverse Secondary Metabolites With Medicinal Importance.

Fungi play an irreplaceable role in drug discovery in the course of human history, as they possess unique abilities to synthesize diverse specialized metabolites with significant medicinal potential. Trichoderma are well-studied filamentous fungi generally observed in nature, which are widely marketed as biocontrol agents. The secondary metabolites produced by Trichoderma have gained extensive attention since they possess attractive chemical structures with remarkable biological activities. A large number of metabolites have been isolated from Trichoderma species in recent years. A previous review by Reino et al. summarized 186 compounds isolated from Trichoderma as well as their biological activities up to 2008. To update the relevant list of reviews of secondary metabolites produced from Trichoderma sp., we provide a comprehensive overview in regard to the newly described metabolites of Trichoderma from the beginning of 2009 to the end of 2020, with emphasis on their chemistry and various bioactivities. A total of 203 compounds with considerable bioactivities are included in this review, which is worth expecting for the discovery of new drug leads and agrochemicals in the foreseeable future. Moreover, new strategies for discovering secondary metabolites of Trichoderma in recent years are also discussed herein.

New Enantiomers of a Nor-Bisabolane Derivative and Two New Phthalides Produced by the Marine-Derived Fungus Penicillium chrysogenum LD-201810.

Marine-derived fungi are a treasure house for the discovery of structurally novel secondary metabolites with potential pharmaceutical value. In this study, a pair of new nor-bisabolane derivative enantiomers (±)-1 and two new phthalides (4 and 5), as well as four known metabolites, were isolated from the culture filtrate of the marine algal-derived endophytic fungus Penicillium chrysogenum LD-201810. Their structures were established by detailed interpretation of spectroscopic data (1D/2D NMR and ESI-MS). The optical resolution of compound (±)-1 by chiral HPLC successfully afforded individual enantiomers (+)-1 and (-)-1, and their absolute configurations were determined by TDDFT-ECD calculations. Compound (±)-1 represents the first example of bisabolane analogs with a methylsulfinyl substituent group, which is rare in natural products. All of the isolated compounds 1-7 were evaluated for their cytotoxic activity against A549, BT-549, HeLa, HepG2, MCF-7, and THP-1 cell lines, as well as for antifungal activity against four plant pathogenetic fungi (Alternaria solani, Botrytis cinerea, Fusarium oxysporum, and Valsa mali). Compound 2, a bisabolane-type sesquiterpenoid, was shown to possess excellent activity for control of B. cinerea with half-maximal inhibitory concentration (IC50) of 13.6 µg/mL, whereas the remaining investigated compounds showed either weak or no cytotoxic/antifungal activity in this study.

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation.

INTRODUCTION: Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain. METHODS: The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining. RESULTS: We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin. CONCLUSION: Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.

TGF-ß1 869T/C polymorphism and ischemic stroke: sex difference in Chinese.

BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and of cerebrovascular complications. Transforming growth factor-ß (TGF-ß) is a pleiotropic cytokine with a central role in inflammation. To investigate whether polymorphisms of the TGF-ß1 gene can modify the risk of ischemic stroke (IS) in Chinese population, we conduct this hospital-based, case-control study. METHODS: Transforming growth factor-ß1 genotype was determined in 450 Chinese patients (306 male and 144 female) with IS and 450 control subjects (326 male and 124 female). RESULTS: Subjects carrying 869TT were susceptible to IS (odds ratio [OR] =1.58; P=0.003). Further analysis of IS data partitioned by gender revealed the female-specific association with 869T/C (OR=2.64; P=0.001). CONCLUSIONS: Findings suggest that the TT genotype of 869T/C might be a risk factor of IS in Chinese, especially in females.

Meta-analysis of the ACE gene polymorphism in cerebral infarction.

BACKGROUND: The angiotensin-1 converting enzyme (ACE) gene is known to have two polymorphic alleles insertion/deletion (I/D). People with the DD genotype have been shown to be at greater risk of cerebral infarction, but only in some studies. Identification of cerebral infarction susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. This meta-analysis was made to look specifically into the genetics of cerebral infarction among Han Chinese population. METHODS: Genetic associations studies published from January 1, 1990 to December 30, 2007 were collected from databases of MEDLINE, EMBASE, CBM and CNKI. Data were extracted using standardised forms and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-nine original case-control studies of Han Chinese population, comprising 3654 patients with cerebral infarction and 3058 controls were included in the meta-analysis. Using the random effects model, the pooled ORs of ACE DD genotype VS ID+ II was 1.91 (95% CI 1.56 to 2.34, P<0.00001). CONCLUSIONS: These data suggest that the ACE DD genotype may be a risk factor for cerebral infarction in Han Chinese population. A large scale case-control study is needed to clarify the functional effect of the polymorphism of the ACE I/D gene in the pathogenesis of cerebral infarction in Han Chinese population.

[Effects of high thoracic epidural anesthesia on ventricular remodeling and expression of beta(3)-adrenoceptor in rats with heart failure induced by acute myocardial infarction].

OBJECTIVE: To investigate the effect of high thoracic epidural anesthesia on ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction, and to investigate their mechanism. METHODS: Rats that had been established successively model were randomly divided into S group (n = 12), HTEA group and CHF group (24/group). 9.0 g/L normal sodium 100 microl/kg was injected to epidural cavity twice a day separately in group S and group CHF. 1.25 g/L bupivacaine 100 microl/kg was injected to epidural cavity twice a day in group HTEA. Epidural injection was started 24 hrs after the epidural surgery and continued 4 weeks. Then the change of cardiac function was observed by using echocardiogram. The ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW) were measured. Noninfarct ventricular tissue were stained with hematoxylin-eosin (HE) and Masson's trichrome respectively. beta(3)-adrenoceptor levels and eNOS levels were detected with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: LVEDD and LVESD were significantly decreased in the group HTEA compared with group CHF (P < 0.01), while LVEF% and LVFS% were significantly increased (P < 0.01). The ratios HW/BW and LVW/BW were significantly increase in the group CHF compared with the group S (P < 0.01), but they were limited in the group HTEA (P < 0.01). Hypertrophy and edema, degeneration and necrosis of myocytes can be seen in rats with CHF, as well as muscle fibers disruption and collagen fiber increase, while the pathological amorphous were attenuated in HTEA rats. beta(3)AR and eNOS mRNA levels were significantly decreased in the group THEA compared with the group CHF. CONCLUSIONS: These results indicate that HTEA could ameliorate ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction. The mechanism could involve decreases of beta(3)AR expression in rats of heart failure.