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The rostral agranular insular cortex (RAIC) has been associated with pain modulation. Although the endogenous cannabinoid system (eCB) has been shown to regulate chronic pain, the roles of eCBs in the RAIC remain elusive under the neuropathic pain state. Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve (CPN) ligation. The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice, glutamatergic, or GABAergic neuron cannabinoid receptor 1 (CB1R) knockdown mice with the whole-cell patch-clamp and pain behavioral methods. The E/I ratio (amplitude ratio between mEPSCs and mIPSCs) was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice. Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice. The analgesic effect of ACEA (a CB1R agonist) was alleviated along with bilateral dorsolateral funiculus lesions, with the administration of AM251 (a CB1R antagonist), and in CB1R knockdown mice in GABAergic neurons, but not glutamatergic neurons of the RAIC. Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.
Subject(s)
Mice , Animals , Insular Cortex , Peroneal Nerve , Mice, Inbred C57BL , Neuralgia , GABAergic Neurons , Analgesia , Analgesics , Receptors, CannabinoidABSTRACT
When this paper was first published the following ethical statement was omitted in error: The experiment was conducted in accordance with the welfare and ethical principles of experimental animals and the laws and regulations of experimental animals. Treat animals kindly, respect animal life, no maltreatment and brutality against animals, and take the least painful method to deal with animals. The authors would like to apologise for any inconvenience caused. DOI of original article: https://doi.org/10.1016/j.chmed.2019.03.005
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Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.
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@#AIM: To explore the prevalence of outer retinal tubulation(ORT)in nAMD patients treated with anti-VEGF and the frequency of anti-VEGF therapy before and after ORT appearance.<p>METHODS:Sixty eyes of 54 patients were included in the study(treated with ranibizumab by pro re nata regimen(PRN)and followed up for 24mo. At baseline, patients underwent fluorescein fundus angiography(FFA), fundus color photography(CFP), best corrected visual acuity(BCVA)and macular optical coherence tomography(OCT), and followed up monthly thereafter. The subretinal hyper reflective material(SHRM)and ORT was recorded at baseline, and the time of new appearance of outer retinal tubulation structure during followup also was noted. The average number of intravitreal injections before and after ORT was compared. The BCVA and central retinal thickness(CRT)were compared between ORT eyes and non-ORT eyes. <p>RESULTS: ORT was found in 15.0%, 21.7%, 25.0% and 46.7% of patients at baseline. After ORT appearance, the average number of injections of anti-VEGF per month decreased(Whitman <i>U</i> test, <i>P</i>=0.006), and the difference was statistically significant. At baseline, 78.3% of the eyes had SHRM, 66.0% of which eventually had ORT, while at baseline, there was only 23.1% of the eyes had ORT in no SHRM eyes, with a relative risk of 2.86(<i>P</i><0.01). The BCVA and CRT were worse in ORT eyes than those in non-ORT eyes. <p>CONCLUSION: ORT increases gradually with the prolongation of the course of the disease, and the frequency of anti-VEGF retreatment decreases after the occurrence of ORT.
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@#Objective To evaluate the efficacy and safety of transcatheter closure of patent ductus arteriosus (PDA) with transthoracic echocardiography (TTE). Methods From February 2016 to November 2018, 98 patients of pure PDA were selected, including 43 patients of funnel type and 55 patients of tube type. There were 38 males and 60 females at age of 2-48 (9.8±10.4) years. All patients underwent TTE-guided retrograde closure of the PDA through the femoral artery to establish a femoral-abdominal aorta-thoracic aorta-ductus arteriosus-aorta-right ventricle trajectory.Under the guidance of TTE, a suitable closure umbrella was placed through the femoral artery. One month, 3 months, 6 months, 12 months after the surgery, the patients received out-patient clinical follow-up. Results Ninety eight patients were successfully occluded by TTE. The occluder was replaced many times in an adult PDA patient, but finally it was successfully plugged. The operation time was 33.2±5.8 min. The lumbar diameter was 12±6 mm. And the postoperative murmur disappeared. Ultrasound showed no shunt between the aorta and the pulmonary artery, and the postoperative hospital stay was 3-4 days. No shunt signal was found in 1, 3, 6, 12 months follow-up. Left atrial anteroposterior diameter (25.8±6.1 mm vs. 30.6±8.4 mm) and left ventricular end diastolic diameter (38.5±9.1 mm vs. 45.2±11.5 mm) were significantly smaller (P < 0.05). Conclusion TTE-guided transcatheter closure of PDA via femoral artery is a safe and effective method to avoid the damage of X-ray and contrast medium. The prospect of clinical application is good.
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In order to adapt to the rapid development of brain science and cultivate high-level innovative brain science research talents, combined with the practical teaching experience in the Department of Neurobiology of Air Force Military Medical University in recent years, the article constructs a new system for fundamentals and frontiers of brain science curriculum, which integrates advanced teaching concepts, diverse teaching forms and flexible teaching modes, expecting this new curriculum system will lay a solid foundation for the cultivation of talents in brain science.
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@#【Objective】To investigate the effect of Imatinib（Ima）on the inflammatory phenotype of RAW264.7 mac⁃ rophages induced by lipopolysaccharide（LPS）.【Methods】RAW264.7 cells were treated by LPS（0.1 μg/mL）and/or Ima（1 μmol/L，5 μmol/L）. The mRNA levels of IL-1β，IL-10，CCL2，iNOS，TNF-α and Arg1 in RAW264.7 cells were tested by Q-PCR. The iNOS protein level and the activation of NF-κB and MAPK signal pathways were detected by Western Blot. The protein levels of IL-1β，CCL2，IL-10 and TNF-α in cell supernatant were detected by ELISA. 【Results】Compared with the normal control group，the mRNA levels of IL-1β，CCL2，iNOS，TNF-α and IL-10 were significantly increased in RAW264.7 cells treated with LPS for 8 h（P < 0.001）. In addition，the cell supernatant protein levels of IL-1β，IL-10，CCL2 as well as TNFα and the iNOS protein level were significantly increased in RAW264.7 cells stimulated by LPS for 24 h（P < 0.001）. Moreover，the phosphorylation levels of p65，p38，ERK and AKT were enhanced in RAW264.7 cells after treatment with LPS for 24 h. Compared with LPS group，pretreatment with Ima decreased the mRNA and protein levels of IL-1β，CCL2，iNOS and TNF-α（P < 0.01，P < 0.001），but increased the mRNA and protein level of IL-10（P < 0.001）. And this effect of Ima was dose-dependent. The phosphorylation levels of p65，p38， ERK and AKT were decreased in LPS+Ima group compared with that in LPS group. The functional status of RAW264.7 cells did not change significantly after treatment with Ima alone.【Conclusions】The effect of Imatinib to inhibit the inflammato⁃ ry phenotype of macrophage is related to retarding the overactivation of NF-κB and MAPK signaling pathways.
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@#Objective To introduce the application of transcatheter closure of multi-fenestrated atrial septal defect (ASD) via femoral vein under ultrasound guidance with amplatzer cribriform occluder (ACO) and atrial septal defect occluder (ASDO), as well as to assess its feasibility, effectiveness and safety. Methods The clinical data of 48 patients with fenestrated ASD occluded via femoral vein under ultrasound guidance from December 2015 to May 2018 in our hospital were retrospectively analyzed, including 17 males and 31 females, aged 10 months to 51 years, an average of 11.50±13.86 years, and weighting 6-79 (27.00±20.14) kg. Among 48 patients with fenestrated ASD, 12 patients had double-foramen and 13 atrial septal aneurysm combined with defects and 23 multi-foramen. All patients underwent transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) to complete the closure of fenestrated ASD. Ultrasound, electrocardiogram and chest X-ray were reviewed the next day after surgery to evaluate the curative effect. Results Forty-eight patients with ASD were treated with 49 occluders, due to one patient with two occluders. There were 29 ASDO (8-26 mm) and 20 ACO (18-34 mm). During the operation, TTE/TEE examination showed that 48 patients were completely occluded, 13 patients showed fine bundle shunt in the unreleased push notification rod, and 9 patients had fine bundle shunt after the release of push notification rod. Fine bundle shunt was found in 8 patients 24 hours after operation, and microshunt was found in 3 patients 1 year after operation. All the patients were followed up. The occluder position was good. The right heart was reduced in different degrees, and the X-ray showed that the pulmonary blood was reduced in different degrees. No arrhythmia was found by electrocardiogram after operation. Conclusion It is a safe and effective method to use ACO and ASDO to occlude ASD through femoral approach under ultrasound guidance.
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Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Subject(s)
Animals , Female , Male , Mice , Benzoxazines , Pharmacology , Therapeutic Uses , Chemokine CCL2 , Genetics , Metabolism , Pharmacology , Excitatory Amino Acid Agents , Pharmacology , Excitatory Amino Acid Agonists , Pharmacology , Freund's Adjuvant , Toxicity , Hyperalgesia , Metabolism , Long-Term Potentiation , Physiology , Luminescent Proteins , Genetics , Metabolism , Mice, Inbred C57BL , Mice, Transgenic , Myelitis , Drug Therapy , Metabolism , Neurons , Pain Management , Somatostatin , Genetics , Metabolism , Spinal Cord , Cell Biology , Spiro Compounds , Pharmacology , Therapeutic Uses , Vesicular Glutamate Transport Protein 2 , Genetics , Metabolism , Vesicular Inhibitory Amino Acid Transport Proteins , Genetics , MetabolismABSTRACT
Objective To investigate the clinical significance of the changes of serum level of high mobility group protein B1 (HMGB1) in patients with severe pneumonia complicated with sepsis.Methods Fifty patients with severe pneumonia complicated with sepsisin in Respiratory Intensive Care Unit(RICU) of Xinxiang Central Hospital from April 2014 to March 2017 were selected as observation group;while 50 healthy individuals were selected as control group.The patients in the observation group were divided into death group(n =32) and survival group(n =18) according to the prognosis.The serum levels of procalcitonin(PCT) and HMGB1 of patients in the observation group were detected on the 1st,3rd,7th day of patients hospitalized in the RICU,while the acute physiology and chronic health evaluation Ⅱ (APACHE lⅡ)scores of the patients were evaluated.The serum levels of PCT and HMGB1 of subjects in the control group were detected during physical examination.Results There was no statistic difference in the mean arterial pressure,oxygenation index,body temperature and total white cell count of patients between the death group and survival group(P ＞0.05).On the first day of patients hospitalized in the RICU,the serum levels of PCT and HMGB1 of patients in the observation group were significantly higher than those in the control group (P ＜0.05).The serum levels of HMGB1 and the APACHEⅡ scores of patients in the death group were significantly higher than those in the survival group at each time point(P ＜0.05).On the first day of patients hospitalized in the RICU,there was no statistic difference in the serum level of PCT of patients between the death group and survival group (P ＞ 0.05);the serum level of PCT of patients in the death group was significantly higher than that in the survival group at another time point (P ＜ 0.05).The serum level of HMGB1 of patients in the observation group was positively correlated with the PCT and APACHE Ⅱ score (r =0.562,0.460;P ＜0.05).Conclusion The serum level of HMGB1 in patients with severe pneumonia complicated with sepsis is increased;and the increase of serum level of HMGB1 in the death cases is more obvious than that in the survival cases.So it can be used to evaluate the patient's condition and judge the prognosis.
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Objective@#To investigate the expressions of glutathione S-transferase (GSTP1) and tetra-hydroxynonenal (4-HNE) in prostate cancer (PCa) and their clinical significance.@*METHODS@#We determined the expressions of GSTP1 and 4-HNE in 40 patients with PCa and another 42 with benign prostatic hyperplasia (BPH) by immunohistochemistry and analyzed their relationship with Gleason grades.@*RESULTS@#The expression rate of GSTP1 was 92.9% in the BPH tissue, and those in the highly, moderately, and lowly differentiated PCa tissues were 58.3%, 20.0%, and 16.7%, respectively, significantly higher in the BPH than in the PCa group (P <0.01). However, the positive rate of 4-HNE was only 5.0% in the BPH tissue, markedly lower than 91.6%, 100.0%, and 100.0% in the highly, moderately, and lowly differentiated PCa tissues (P <0.01). There was a negative correlation between the expression of GSTP1 and that of 4-HNE in the PCa tissue (r = －2.73, P <0.01).@*CONCLUSIONS@#Expression deletion of GSTP1 and high expression of 4-HNE may play an important role in the progression of prostate cancer.
Subject(s)
Humans , Male , Aldehydes , Metabolism , Disease Progression , Glutathione S-Transferase pi , Metabolism , Immunohistochemistry , Neoplasm Grading , Neoplasm Proteins , Metabolism , Prostatic Hyperplasia , Metabolism , Pathology , Prostatic Neoplasms , Metabolism , PathologyABSTRACT
<p><b>OBJECTIVE</b>To observe the intervention and mechanism of Qushi Huayu Recipe (QHR) on gene expression profiles in high lipid diet induced fatty liver rats.</p><p><b>METHODS</b>Fatty liver model was prepared in 20 male SD rats using single high fat diet (88% common forage +2% cholesterol +10% lard). Four weeks after modeling they were divided into the model group and the QHR group according to random digit table, 10 in each group. QHR (at 0. 93 g crude drug/100 g body weight) and distilled water was respectively to rats in the QHR group and the model group by gastrogavage while modeling, once per day. Meanwhile, 10 SD male rats were recruited in a normal group, administered with equal volume of distilled water by gastrogavage. At the end of week 8 all rats were sacrificed, and blood and livers were collected for subsequent analysis. Contents of liver triglyceride (TG) and free fatty acid (FFA) , activities of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected using biochemical assay. Pathological changes of liver tissue were observed using H&E and oil red O stain. Liver gene expressions were detected by Affymetrix gene expression profiles. Differentially expressed genes were compared between the QHR group and the model group, functions of differentially expressed genes and signal pathways involved analyzed. Ten differentially expressed genes involved in glycolipid metabolism with fold change more than 2 were selected for verification by real-time PCR.</p><p><b>RESULTS</b>(1) Compared with the normal group, contents of liver TG and FFA, and serum activities of ALT and AST obviously increased in the model group (P <0. 01). Compared with the model group, contents of liver TG and FFA, and activities of ALT and AST obviously decreased in the QHR group (P <0. 05, P <0. 01). QHR could reduce high fat induced fatty degeneration of liver cells , alleviate inflammation, and improve pathological changes of liver tissue. (2) Compared with the model group, there were 80 differentially expressed genes (with fold change > 2, P < 0.05) with clear functions and appointed gene names, including 44 up-regulated and 36 down-regulated genes. Eighty genes were involved in 27 signal pathways with statistical difference, including glycerolipid metabolism, adipocytokine signaling pathway, insulin signal pathway, drug metabolism signal pathway, etc (P < 0.05). (3) RT-PCR results of 10 glycolipids metabolism regulating genes such as Gk, Scd1, Gpat2, G6pc, Irs1, and so on showed that all RT-PCR genes were completely coincide with up-regulated or down-regulated tendency in results of gene chips. 80% genes had approximate fold change.</p><p><b>CONCLUSION</b>QHR could regulate gene expressions related to fat metabolism, carbohydrate metabolism, anti-lipid peroxidation, and drug metabolism in high fat diet induced fatty liver rats, and its comprehensive pharmacological actions could be manifested.</p>
Subject(s)
Animals , Male , Rats , Alanine Transaminase , Metabolism , Aspartate Aminotransferases , Metabolism , Carbohydrate Metabolism , Diet, High-Fat , Drugs, Chinese Herbal , Pharmacology , Fatty Acids, Nonesterified , Metabolism , Fatty Liver , Metabolism , Lipid Metabolism , Lipid Peroxidation , Random Allocation , Rats, Sprague-Dawley , Transcriptome , Triglycerides , MetabolismABSTRACT
In this paper, the five strains of Polygonatum odoratum were used as the experimental materials to test the supercooling point, freezing point, the degree of supercooling, the transition stage time, cooling time and water composition of the plant tissue. The cold resistance of P. odoratum was analyzed with the Gray Correlation Method. The results showed that the cold resistances of the five strains of P. odoratum were different, and the water content of plant tissue had some relevance with freezing point and supercooling point, whereas, it could not be measured when the moisture content was too low. The order of cold resistance of the five strains of P. odoratum was ZJCY, DYYZ, XYYZ, CYYZ and JZ I.
Subject(s)
Cold Temperature , Plant Roots , Chemistry , Physiology , Polygonatum , Chemistry , Classification , Physiology , WaterABSTRACT
Objective: To investigate the antitumor effect of volatile oil from Sinapis Albae Semen (VOSAS) on H22-bearing mice and to determine the mechanism. Methods: To establish the H22 implanted hepatocellular carcinoma animal model which was used to analyze the effect of VOSAS on the growth of transplanted tumor. Mice were divided into five groups 24 h after modeling: model, cytoxan (CTX, 25 mg/kg) positive control, low-, mid-, and high-dose (20, 40, and 80 mg/kg) VOSAS groups. The mice were ip administered once daily for 10 d. Morphological changes in H22 solid tumor cells were observed by both Hematoxylin-eosin (HE) and acridine orange (AO) staining. The expression of Bax and Bcl-2 in the tumor tissue was determined using immunohistochemistry. Results: VOSAS could inhibit the tumor growth and extend the life span of H22-bearing mice (P < 0.01); and it could also raise the expression of Bax while suppress the expression of Bcl-2; the antitumor effect of VOSAS on H22-bearing mice demonstrated a good dose-effect relationship, but the high-dose group of the volatile oil has obvious toxicity and side effects on the mice. Conclusion: VOSAS could inhibit the growth of H22 tumor cells and the mechanism may be related to up-regulating the expression of Bax and down-regulating the expression of Bcl-2, and the induction of apoptosis.
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<p><b>OBJECTIVE</b>To investigate the correlation between blood flow assessed by CT perfusion imaging and characteristics of microvascular ultrastructure in non-small cell lung cancer (NSCLC).</p><p><b>METHODS</b>twenty-eight patients with non-small cell lung cancer proven surgically and pathologically underwent perfusion CT examination. The patients were divided into a hyper-perfusion group and a hypo-perfusion group by the median value of blood flow, and then the differences of microvascular ultrastructure in the two groups were analyzed.</p><p><b>RESULTS</b>The median BF value of the 28 patients was 36.40 ml×100 g(-1)×min(-1). Take this median value as the boundary, the group with hypo-perfusion showed a significantly lower BF value than the group with hyper-perfusion [(30.84 ± 4.79) ml×100 g(-1)×min(-1) vs. (49.67 ± 10.89) ml×100 g(-1)×min(-1), t = -5.925, P < 0.001]. The group with lymph node metastasis showed a significantly lower BF value than the group without lymph node metastasis [(30.78 ± 5.24) ml×100 g(-1)×min(-1) vs. (50.73 ± 11.16) ml×100 g(-1)×min(-1), t = 3.490, P = 0.015]. The maturity of microvessels of the hyper-perfusion group was higher than that of the hypo-perfusion group. Under the electron microscope, the microvessels in the hypo-perfusion group showed a more narrow lumen, poorer integrity of basement membrane, a more close relationship between cancer cells and microvascular wall, and cancer cells were more easily seen in the microvascular lumen.</p><p><b>CONCLUSION</b>The blood flow value of CT perfusion imaging may be related with the abnormal microvascular ultrastructure, and may be helpful to the prediction of metastasis risk in NSCLC.</p>
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Carcinoma, Non-Small-Cell Lung , Diagnostic Imaging , Metabolism , Pathology , Follow-Up Studies , Lung Neoplasms , Diagnostic Imaging , Metabolism , Pathology , Lymphatic Metastasis , Microvessels , Diagnostic Imaging , Neoplasm Metastasis , Perfusion Imaging , Tomography, Spiral Computed , Vascular Endothelial Growth Factor A , MetabolismABSTRACT
<p><b>BACKGROUND</b>Data on the epidemiology of hypertension in Chinese non-dialysis chronic kidney disease (CKD) patients are limited. The aim of the present study was to investigate the prevalence, awareness, treatment, and control of hypertension in the non-dialysis CKD patients through a nationwide, multicenter study in China.</p><p><b>METHODS</b>The survey was performed in 61 tertiary hospitals in 31 provinces, municipalities, and autonomous regions in China (except Hong Kong, Macao, and Taiwan). Trained physicians collected demographic and clinical data and measured blood pressure (BP) using a standardized protocol. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, and/or use of antihypertensive medications. BP < 140/90 mmHg and < 130/80 mmHg were used as the 2 thresholds of hypertension control. In multivariate logistic regression with adjustment for sex and age, we analyzed the association between CKD stages and uncontrolled hypertension in non-dialysis CKD patients.</p><p><b>RESULTS</b>The analysis included 8927 non-dialysis CKD patients. The prevalence, awareness, and treatment of hypertension in non-dialysis CKD patients were 67.3%, 85.8%, and 81.0%, respectively. Of hypertensive CKD patients, 33.1% and 14.1% had controlled BP to < 140/90 mmHg and < 130/80 mmHg, respectively. With successive CKD stages, the prevalence of hypertension in non-dialysis CKD patients increased, but the control of hypertension decreased (P < 0.001). When the threshold of BP < 130/80 mmHg was considered, the risk of uncontrolled hypertension in CKD 2, 3a, 3b, 4, and 5 stages increased 1.3, 1.4, 1.4, 2.5, and 4.0 times compared with CKD 1 stage, respectively (P < 0.05). Using the threshold of < 140/90 mmHg, the risk of uncontrolled hypertension increased in advanced stages (P < 0.05).</p><p><b>CONCLUSIONS</b>The prevalence of hypertension Chinese non-dialysis CKD patients was high, and the hypertension control was suboptimal. With successive CKD stages, the risk of uncontrolled hypertension increased.</p>
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Adult , Aged , Female , Humans , Male , Middle Aged , Awareness , Hypertension , Epidemiology , Therapeutics , Prevalence , Renal Insufficiency, ChronicABSTRACT
The present study was designed to test the hypothesis that a medium-term simulated microgravity can induce region-specific remodeling in large elastic arteries with their innermost smooth muscle (SM) layers being most profoundly affected. The second purpose was to examine whether these changes can be prevented by a simulated intermittent artificial gravity (IAG). The third purpose was to elucidate whether vascular local renin-angiotensin system (L-RAS) plays an important role in the regional vascular remodeling and its prevention by the gravity-based countermeasure. This study consisted of two interconnected series of in-vivo and ex-vivo experiments. In the in-vivo experiments, the tail-suspended, hindlimb unloaded rat model was used to simulate microgravity-induced cardiovascular deconditioning for 28 days (SUS group); and during the simulation period, another group was subjected to daily 1-hour dorso-ventral (-G(x)) gravitation provided by restoring to normal standing posture (S + D group). The activity of vascular L-RAS was evaluated by examining the gene and protein expression of angiotensinogen (Ao) and angiotensin II receptor type 1 (AT1R) in the arterial wall tissue. The results showed that SUS induced an increase in the media thickness of the common carotid artery due to hypertrophy of the four SM layers and a decrease in the total cross-sectional area of the nine SM layers of the abdominal aorta without significant change in its media thickness. And for both arteries, the most prominent changes were in the innermost SM layers. Immunohistochemistry and in situ hybridization revealed that SUS induced an up- and down-regulation of Ao and AT1R expression in the vessel wall of common carotid artery and abdominal aorta, respectively, which was further confirmed by Western blot analysis and real time PCR analysis. Daily 1-hour restoring to normal standing posture over 28 days fully prevented these remodeling and L-RAS changes in the large elastic arteries that might occur due to SUS alone. In the ex-vivo experiments, to elucidate the important role of transmural pressure in vascular regional remodeling and differential regulation of L-RAS activity, we established an organ culture system in which rat common carotid artery, held at in-vivo length, can be perfused and pressurized at varied flow and pressure for 7 days. In arteries perfused at a flow rate of 7.9 mL/min and pressurized at 150 mmHg, but not at 0 or 80 mmHg, for 3 days led to an augmentation of c-fibronectin (c-FN) expression, which was also more markedly expressed in the innermost SM layers, and an increase in Ang II production detected in the perfusion fluid. However, the enhanced c-FN expression and increased Ang II production that might occur due to a sustained high perfusion pressure alone were fully prevented by daily restoration to 0 or 80 mmHg for a short duration. These findings from in-vivo and ex-vivo experiments have provided evidence supporting our hypothesis that redistribution of transmural pressures might be the primary factor that initiates region-specific remodeling of arteries during microgravity and the mechanism of IAG is associated with an intermittent restoration of the transmural pressures to their normal distribution. And they also provide support to the hypothesis that L-RAS plays an important role in vascular adaptation to microgravity and its prevention by the IAG countermeasure.
Subject(s)
Animals , Male , Rats , Angiotensinogen , Genetics , Metabolism , Aorta, Abdominal , Pathology , Carotid Artery, Common , Pathology , Hindlimb Suspension , Muscle, Smooth, Vascular , Metabolism , Pathology , RNA, Messenger , Genetics , Metabolism , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1 , Genetics , Metabolism , Renin-Angiotensin System , Physiology , Weightlessness SimulationABSTRACT
<p><b>OBJECTIVE</b>To investigate the distribution of GAD67 and the co-localization with bNOS in the main olfactory bulb of GAD67-GFP knock-in mouse.</p><p><b>METHODS</b>Polymerase chain reaction was applied to identify the genotype of GAD67-GFP knock-in mouse, the animals were sacrificed and frozen sections of olfactory bulb were prepared. The Nissl-staining was performed to show an framework of the neuron in the olfactory bulb. The distribution of GAD67 and co-localization with bNOS were detected by immunofluorescence technique.</p><p><b>RESULTS</b>The proportion of GAD67-positive cells among DAPI-positive cells were (42.98 ± 0.92)% in glomerular layer, (23.64 ± 0.84)% in mitral cell layer and (77.75 ± 0.84)% in granule cell layer; the bNOS-positive cells mainly existed in glomerular layer and mitral cell layer, very few in granule cell layer. No co-localization of GAD67 and bNOS in granule cell layer and mitral cell layer was found, but there was dispersed distribution in glomerular layer.</p><p><b>CONCLUSION</b>GAD67-positive neurons mainly appear in glomerular layer and granule cell layer, and the bNOS is mostly expressed in glomerular layer and mitral cell layer; while the co-localization of GAD67 and bNOS only occurs in glomerular layer of olfactory bulb.</p>
Subject(s)
Animals , Mice , Gene Knock-In Techniques , Glutamate Decarboxylase , Genetics , Metabolism , Green Fluorescent Proteins , Genetics , Metabolism , Mice, Transgenic , Neurons , Metabolism , Nitric Oxide Synthase Type I , Metabolism , Olfactory Bulb , Metabolism , Tissue DistributionABSTRACT
<p><b>BACKGROUND</b>It has been long suggested that abnormal clinical factors in the body, such as dyslipidemia and diabetes, can affect the presence of atherosclerosis. However, few studies on the effect of factors within the normal range, such as the loss of renal function with age, on the prevalence of atherosclerosis are few know in healthy individuals. The aim of this study was to investigate risk factors affecting the presence of asymptomatic carotid plaques in a middle-aged and elderly healthy population.</p><p><b>METHODS</b>In this regard, we prospectively evaluated 245 healthy individuals (98 males and 147 females) at baseline and after 5 years. Changes in the presence of carotid plaque between 2003 and 2008 were categorized into four groups, i.e. subjects without plaque at entry (n = 165): Group 1 (without plaque on two occasions, n = 129) and Group 2 (with nascent plaque at follow-up, n = 36); subjects with plaque at entry (n = 80); Group 3 (with plaque regression at follow-up, n = 29) and Group 4 (with plaque on two occasions, n = 51).</p><p><b>RESULTS</b>Univariate analysis showed that the positive rate of carotid plaques in males was higher than that in females at the baseline, and that a significantly inverse correlation existed between the prevalence rate of plaque and aging. Logistic regression analysis of cross-sectional research showed that independent risk factors for the prevalence of atherosclerosis were male gender, lower estimated glomerular filtration rate (eGFR) and higher low-density lipoprotein cholesterol (LDL-C) at the baseline, and older age and lower eGFR were involved in the presence of carotid plaques at follow-up point. However, logistic regression analysis of the longitudinal data showed that older age, decreased eGFR and increased systolic blood pressure (SBP) independently predicted the presence of carotid plaques after 5 years in subjects without plaque at entry. In addition, in subjects with plaque at entry, age, changes in eGFR and the baseline levels of serum albumin (ALB) and serum total bilirubin (BIL) dependently influenced the outcome of carotid plaque.</p><p><b>CONCLUSION</b>Physiological decline of renal function, together with advancing age, was an independent risk factor which consistently affected the presence of carotid atherosclerosis in two categories of healthy individuals.</p>
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Aging , Physiology , Carotid Artery Diseases , Pathology , Glomerular Filtration Rate , Physiology , Kidney , Physiology , Prospective Studies , Risk FactorsABSTRACT
<p><b>OBJECTIVE</b>To investigate the type and frequency of gene conversion from SMN1 to SMN2 in Chinese patients affected with spinal muscular atrophy (SMA), and to explore the relationship between gene conversion and clinical phenotype.</p><p><b>METHODS</b>Non-homozygous deletion of SMN1 gene exon 8 was screened among 417 patients with SMN1 exon 7 homozygous deletions. To analyze and verify the types of gene conversion, genomic DNA sequencing, multiplex ligation-dependent probe amplification (MLPA), and gene subcloning and sequencing were carried out.</p><p><b>RESULTS</b>Thirty-one patients (7.4% of all) with non-homozygous deletions of SMN1 exon 8 were detected. Through series of experiments, the fusion genes SMN1/SMN2 in all cases were delineated. Five types of gene conversions were identified, which included SMN2-I7b/SMN1 E8, SMN2-I7a/SMN1 I7b, SMN2-E7/SMN1 I7a, SMN1 I6/SMN2 E7/SMN1 I7a and SMN2-E7/SMN1 I7a/SMN2 I7b. Such conversions were found in the type I-III patients. For 10 patients with type I-III SMA and 3 copies of SMN2 gene produced by conversion, the average survival age was 5 year and 4 months.</p><p><b>CONCLUSION</b>Partial conversions of SMN1 gene have been found among Chinese SMA patients. The type of conversion and frequency seem to be different from those of other races. Gene conversion to some extent may impact on survival time and rate of SMA patients, especially type I SMA.</p>