Periodontal disease increases the severity of chronic obstructive pulmonary disease: a Mendelian randomization study.

BACKGROUND: Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. METHODS: Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium's genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. RESULTS: We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005-1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy's effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973-1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658-1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941-1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). CONCLUSION: In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Rosmarinic acid suppresses the progression of COPD via Syk by modulating airway inflammation and epithelial apoptosis in vivo and in vitro.

Rosmarinic acid (RosA), a hydrophilic phenolic compound found in various plants, has several biological effects such as anti-inflammatory and anti-apoptosis activities. However, its potential impact on chronic obstructive pulmonary disease (COPD) and its underlying mechanism has not been investigated. In this study, we explored the potential therapeutic effects and mechanism of RosA on COPD airway inflammation and alveolar epithelial apoptosis in vivo and in vitro. Our data suggested that RosA may be a therapeutic candidate for COPD with low toxicity. The corresponding mechanism lies in its anti-inflammatory effect on macrophage and bronchial epithelial cells, as well as protective effect on lung epithelial apoptosis via the jointly cross-target spleen tyrosine kinase (Syk).

Norepinephrine promotes glioma cell migration through up-regulating the expression of Twist1.

BACKGROUND: Glioma cells are characterized by high migration ability, resulting in aggressive growth of the tumors and poor prognosis of patients. It has been reported that the stress-induced hormone norepinephrine (NE) contributes to tumor progression through mediating a number of important biological processes in various cancers. However, the role of NE in the regulation of glioma migration is still unclear. Epithelial-to-mesenchymal transition (EMT) is one of the most important steps for tumor migration and metastasis. Twist1, as a key regulator of EMT, has been found to be elevated during glioma migration. But it is still unknown whether Twist1 is involved in the effect of NE on the migration of glioma cells. METHODS: Wound healing assay and transwell assay were conducted to evaluate the migration of glioma cells upon different treatments. The mesenchymal-like phenotype and the expression of Twist1 after NE treatment were assessed by cell diameters, real-time PCR, western blot and immunofluorescence staining. The gain-and loss-of-function experiments were carried out to investigate the biological function of Twist1 in the migration induced by NE. Finally, the clinical significance of Twist1 was explored among three public glioma datasets. RESULTS: In this study, our finding revealed a facilitative effect of NE on glioma cell migration in a ß-adrenergic receptor (ADRB)-dependent way. Mechanistically, NE induced mesenchymal-like phenotype and the expression of Twist1. Twist1 overexpression promoted glioma cells migration, while knockdown of Twist1 abolished the discrepancy in the migration ability between NE treated glioma cells and control cells. In addition, the clinical analysis demonstrated that Twist1 was up-regulated in malignant gliomas and recurrent gliomas, and predicted a poor prognosis of glioma patients. CONCLUSIONS: NE enhanced the migration ability of glioma cells through elevating the expression of Twist1. Our finding may provide potential therapeutic target for protecting patients with glioma from the detrimental effects of stress biology on the tumor progression.

Repair of ATAAD with a 3D-printing assisted pre-windowed coated stent: A case report.

Acute type A aortic dissection (ATAAD) is a life-threatening vascular disease. We report a case of ATAAD treated with interventional therapy using 3D-printing assisted pre-windowing coated stent combined with in situ window-opening technology. There were few complications and the patient experienced an uneventful recovery.

Perilla Leaf Extract Attenuates Asthma Airway Inflammation by Blocking the Syk Pathway.

Perilla frutescens (L.) Britton is a classic herbal plant used widely against asthma in China. But its mechanism of beneficial effect remains undermined. In the study, the antiallergic asthma effects of Perilla leaf extract (PLE) were investigated, and the underlying mechanism was also explored. Results showed that PLE treatment significantly attenuated airway inflammation in OVA-induced asthma mice, by ameliorating lung pathological changes, inhibiting recruitment of inflammatory cells in lung tissues and bronchoalveolar lavage fluid (BALF), decreasing the production of inflammatory cytokines in the BALF, and reducing the level of immunoglobulin in serum. PLE treatment suppressed inflammatory response in antigen-induced rat basophilic leukemia 2H3 (RBL-2H3) cells as well as in OVA-induced human peripheral blood mononuclear cells (PBMCs). Furthermore, PLE markedly inhibited the expression and phosphorylation of Syk, NF-κB, PKC, and cPLA2 both in vivo and in vitro. By cotreating with inhibitors (BAY61-3606, Rottlerin, BAY11-7082, and arachidonyl trifluoromethyl ketone) in vitro, results revealed that PLE's antiallergic inflammatory effects were associated with the inhibition of Syk and its downstream signals NF-κB, PKC, and cPLA2. Collectively, the present results suggested that PLE could attenuate allergic inflammation, and its mechanism might be partly mediated through inhibiting the Syk pathway.

[Drug glucuronidation and disposition in brain].

UDP-glucuronosyltransferase (UGT), a kind of phase II drug-metabolizing enzyme, catalyzes the conjugation of glucuronic acid and drugs. UGTs are widely expressed in brain, but at a relatively low level compared to that in liver. Brain UGTs are inducible or inhibitable, which influences the drug distribution in the central nervous system. UGTs, cytochrome P450 (CYPs) and transporters act together to effect pharmacokinetics of drugs in brain. Several drugs have the capacity to cross the blood brain barrier after glucuronidation and certain drugs may be subject to direct glucuronidate in brain by the function of UGTs. The brain UGTs' isoforms, localization, induction, inhibition, and interaction with CYP and transporters are introduced in this review. The process of drug glucuronidation and distribution in brain is summarized for five drugs. A deep insight into the process of drug metabolism and distribution in brain may provide a valuable reference for drug design for the central nervous system.

Novel glucomannan-like polysaccharide from Lycium barbarum L. ameliorates renal fibrosis via blocking macrophage-to-myofibroblasts transition.

The macrophage to myofibroblasts transition (MMT) has been reported as a newly key target in renal fibrosis. Lycium barbarum L. is a traditional Chinese medicine for improving renal function, in which its polysaccharides (LBPs) are the mainly active components. However, whether the role of LBPs in treating renal fibrosis is related to MMT process remain unclear. The purpose of this study was to explore the relationship between the regulating effect on MMT process and the anti-fibrotic effect of LBPs. Initially, small molecular weight LBPs fractions (LBP-S) were firstly isolated via Sephadex G-100 column. Then, the potent inhibitory effect of LBP-S on MMT process was revealed on bone marrow-derived macrophages (BMDM) model induced by TGF-ß. Subsequently, the chemical structure of LBP-S was elucidated through monosaccharide, methylation and NMR spectrum analysis. In vivo biodistribution characteristics studies demonstrated that LBP-S exhibited effectively accumulation in kidney via intraperitoneal administration. Finally, LBP-S showed a satisfactory anti-renal fibrotic effect on unilateral ureteral obstruction operation (UUO) mice, which was significantly reduced following macrophage depletion. Overall, our findings indicated that LPB-S could alleviate renal fibrosis through regulating MMT process and providing new candidate agents for chronic kidney disease (CKD) related fibrosis treatment.

Genetic Predisposition to Periodontitis and Risk of Migraine: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Previous observational studies have associated periodontitis (PD) with migraine; however, the results are inconclusive and the causality of the association between PD and migraine remains unclear. This two-sample Mendelian randomization (MR) study was performed to explore the bi-directional causal relationship between PD and migraine. METHODS: To investigate the relationship between PD (17,353 cases; 28,210 controls) and migraine (1072 cases; 360,122 controls), we used genetic tools from the largest available genome-wide association study of European descent. Inverse variance-weighted (IVW) and a series of sensitivity analyses were used to explore the association between migraine and PD. We performed an MR study using seven SNPs (single nucleotide polymorphisms) as instrumental variables for PD to investigate the causal relationship between migraine and PD. RESULTS: We found no significant causal relationship between PD and migraine (odds ratio, OR = 1.000; 95% confidence interval, CI = 0.99-1.00; p = 0.65). Similarly, no evidence supported a causal relationship between migraine and PD (OR = 0.07; CI = 2.04 × 10-9-2.65 × 106; p = 0.77). A sensitivity analysis revealed that no potential polymorphic effect (p = 0.356) and heterogeneity (p = 0.652) exists for the variants used in constructing the genetic instrument. CONCLUSIONS: Based on the results of our MR study, there is no causal relationship between PD and migraines or migraines and PD.

Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats.

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.

Chronic stress promotes glioma cell proliferation via the PI3K/Akt signaling pathway.

High malignancy and high mortality of glioma render it urgent to elucidate the underlying mechanisms of glioma carcinogenesis and explore novel targets for therapy. Epidemiologic and clinical studies have revealed that chronic stress promotes the progression of various solid tumors and is correlated with poor prognosis; however, findings reporting the involvement of chronic stress in glioma are rare. In the present study, a chronic restraint animal model and a chronic stress cell model were established to explore the effects of chronic stress on glioma and its molecular mechanisms. The results revealed that chronic stress promoted glioma growth in vivo, and the serum levels of the stress hormones glucocorticoid (GC) and noradrenaline (NE) were significantly increased. In addition, GC and NE were verified to accelerate the proliferation of glioma cells in vitro. Mechanistically, the phosphatidylinositol 3­kinase (PI3K)/Akt signaling pathway was revealed to be activated under stress conditions, and inhibition of the expression of p­Akt could restrain the stress hormone­induced glioma cell proliferation. In addition, our data indicated that the GC receptor (GR) and ß­adrenergic receptors (ADRBs) were both required for the biological functions of GC and NE in glioma cells. In conclusion, these results indicated that chronic stress and the stress hormones GC and NE activated PI3K/Akt signaling through binding to GR and ADRBs, thereby promoting glioma cell growth. Our findings may provide potential therapeutic targets and pave the way for the development of new strategies to protect patients with glioma from the detrimental effects of stress on tumor progression.

Mallotus oblongifolius extracts ameliorate ischemic nerve damage by increasing endogenous neural stem cell proliferation through the Wnt/ß-catenin signaling pathway.

Mallotus oblongifolius (MO), an edible medicinal plant from Hainan in China, shows a wide range of bioactivities. The daily consumption of MO or its extracts has been observed to ameliorate ischemic nerve injury. However the mechanisms remain unclear. In this study, the effects of MO both in vitro and in vivo were investigated. The results indicated that MO improved the motor ability, neurosensory ability, balance and grasping ability of mice with ischemic injuries, induced by bilateral common carotid artery ligation (BCCAL). In addition, MO improved the morphology of neurons, resisted the loss of neurons, and enhanced the content of the nestin protein in the cerebral cortex and subgranular zone (SGZ) area. Furthermore, in the oxygen-glucose deprivation and reperfusion (OGD/R) treated cell model, MO could effectively activate the Wnt/ß-catenin signaling pathway and promote the proliferation of neural stem cells (NSCs) and increase the protein expression levels of ß-catenin and CyclinD1. Our results suggest that Mallotus oblongifolius may be used as nutraceuticals or functional foods to alleviate ischemic nerve damage and promote recovery from ischemic stroke.

Isolation and Characterization of Fengycins Produced by Bacillus amyloliquefaciens JFL21 and Its Broad-Spectrum Antimicrobial Potential Against Multidrug-Resistant Foodborne Pathogens.

The continuing emergence and development of pathogenic microorganisms that are resistant to antibiotics constitute an increasing global concern, and the effort in new antimicrobials discovery will remain relevant until a lasting solution is found. A new bacterial strain, designated JFL21, was isolated from seafood and identified as B. amyloliquefaciens. The antimicrobial substance produced by B. amyloliquefaciens JFL21 showed low toxicity to most probiotics but exhibited strong antimicrobial activities against multidrug-resistant foodborne pathogens. The partially purified antimicrobial substance, Anti-JFL21, was characterized to be a multiple lipopeptides mixture comprising the families of surfactin, fengycin, and iturin. Compared with commercially available polymyxin B and Nisin, Anti-JFL21 not only could exhibit a wider and stronger antibacterial activity toward Gram-positive pathogens but also inhibit the growth of a majority of fungal pathogens. After further separation through gel filtration chromatography (GFC), the family of surfactin, fengycin, and iturin were obtained, respectively. The results of the antimicrobial test pointed out that only fengycin family presented marked antimicrobial properties against the indicators of L. monocytogenes, A. hydrophila, and C. gloeosporioides, which demonstrated that fengycins might play a major role in the antibacterial and antifungal activity of Anti-JFL21. Additionally, the current study also showed that the fengycins produced by B. amyloliquefaciens JFL21 not only maintained stable anti-Listeria activity over a broad pH and temperature range, but also remained active after treatment with ultraviolet sterilization, chemical reagents, and proteolytic enzymes. Therefore, the results of this study suggest the new strain and its antimicrobials are potentially useful in food preservation for the biological control of the multidrug-resistant foodborne pathogens.

[The effect of baicalin on human brain microvascular endothelial cell under the glucose deprivation combined with hypoxia condition].

OBJECTIVE: To investigate the mechanisms of baicalin on anti-cerebral ischemic through observing the effect of baicalin on human brain microvascular endothelial cell under the glucose deprivation combined with hypoxia condition. METHODS: Human brain microvascular endothelial cells (HBMVECs) cultured in vitro were divided into the following groups: normal group, model group, baicalin high dose group, baicalin middle dose group, baicalin low dose group, nimodipine group. The kits were used to detect the cell viability, leakage rate of lactate dehydrogenase (LDH), Na(+)-K(+)-ATPase, Ca(2+)-ATPase, the concentration of Ca2+ in each group, and apoptosis rates of each group were analyzed by flow cytometry (FCM). RESULTS: Compared with the normal group, the cell viability, Na(+)-K(+)-ATPase and Ca(2+)-ATPase in model group decreased significantly (P < 0.01, P < 0.05). But the leakage rate of LDH, Ca2+ in cells and apoptosis rates increased remarkably (P < 0.01). Compared with the model group, the cell viability, Na(+)-K(+)-ATPase and Ca(2+)-ATPase increased obviously (P < 0.01, P < 0.05) in baicalin high dose group. But the leakage rate of LDH and Ca2+ in cells in baicalin high dose group decreased significantly comparing with that of model group (P < 0.05, P < 0.01). And the reduction of intracellular Ca2+ was superior to that of nimodipine group. Meanwhile, the apoptosis rates decreased significantly in both baicalin high and middle dose groups (P < 0.01). CONCLUSION: Baicalin could improve the cell viability of HBMVECs under the glucose deprivation combined with hypoxia condition. And the mechanisms were related with improving the energy metabolism, inhibiting intracellular calcium overload and decreasing the apoptosis rate of cells further.

[Effect of acupuncture therapy on appetite of obesity patients].

OBJECTIVE: To observe the effect of acupuncture intervention on the appetite of obesity patients. METHODS: A total of 118 obesity patients were randomized into acupuncture group (76 cases, treated by true acupuncture needles) and placebo group (42 cases, treated by placebo acupuncture needles) using single-blind method. All the patients of the two groups were ordered to control their diet during the treatment. The acupoints around the umbilicus [Zhongwan (CV 12), Zhongji (CV 3), Daheng (SP 15), Xiawan (CV 10), Shimen (CV 5) and Tianshu (ST 25), etc.] and Liangqiu (ST 34), Zusanli (ST 36), and Yin-lingquan (SP 9) were punctured with filiform needles which were manipulated with uniform reducing and reinforcing method for a while tijl "Deqi" and retained for 30 min. The treatment was conducted once every other day, 12 times altogether. Body mass index (BMI), and visual analogue scale (VAS) scores of eating-desire and hunger feeling and prospective food consumption were measured before and after the treatment. The gastric fluid survival rate (GFSR) was evaluated by using ultrasound scanning. RESULTS: The BMI in the acupuncture group was obviously declined after the treatment in comparison with the placebo group (P < 0.01). Compared to the placebo group, the VAS scores of eating-desire, hunger feeling and prospective food consumption were significantly decreased in the acupuncture group ( P < 0.05), but there are no significant difference between two groups in the VAS score of gastric fullness feeling (P > 0.05). The GFSR was obviously increased in the acupuncture group compared to the placebo group (P < 0.05). CONCLUSION: Acupuncture therapy can significantly decrease BMI and delay the digesting time and control the appetite in obesity patients, which may contribute to its effect in body weight reduction.

[Clinical observation on simple obesity treated by acupuncture].

OBJECTIVE: To evaluate the effectiveness and safety of simple obesity treated by acupuncture. METHODS: By randomized single-blind clinical trial, one hundred and eighteen cases of simple obesity were divided into an acupuncture group (76 cases) and a placebo-acupuncture control group (42 cases), additionally, health control group (30 cases) was included. In acupuncture group and placebo-acupuncture control group, all the patients received a restricted diet; Zhongwan (CV 12) and Zhongji (CV 3) etc. at abdomen and Liangqiu (ST 34) and Zusanli (ST 36) etc. at limbs were selected; body mass index (BMI), Serum Total Cholesterol, triglyceride (TG), Glucose, Creatinine, urea nitrogen (BUN), Uric Acid and adverse reactions scores were observed. RESULTS: After treatment the BMI in acupuncture grown was lower than that in placebo-acupuncture control group (P < 0.01). In metabolism indices, the serum Total Cholesterol and Glucose after treatment were reduced obviously than those before treatment in acupuncture group (all P < 0.01), and there was no significant differences in other metabolism indices (all P > 0.05) in two groups. After treatment, in adverse reactions scores, the hunger sensation scores in acupuncture group was reduced than that in placebo-acupuncture control group (P < 0.05), and there was no significant differences in other indices (all P > 0.05). CONCLUSION: BMI of simple obesity was reduced by acupuncture, and the Serum Total Cholesterol and Glucose were reduced accordingly. The adverse reac tions such as weakness, nervosa and diarrhea, etc. doesn't appear after acupuncture treatment. Acupuncture therapy is one of the safe and effective methods for simple obesity.

[Effect of acupoint application therapy on expression of IL-4 and IFN-gamma in lung tissue of asthma rats].

OBJECTIVE: To observe the effect of acupoint application of Chinese herbal medicines on pathological changes of pulmonary tissue in asthma rats so as to explore its underlying mechanism. METHODS: A total of 33 Wistar rats were randomized into normal control (n=6), model (n=9), dexamethasone (DX, n=9) and acupoint-application (A-A, n=9) groups. Asthma model was established by intraperitoneal injection of 10% ovalbumin(OVA, 1 mL)and forced inhalation of atomized 2% OVA (25 mL) for 40 min, once daily for 2 weeks. "Dazhui" (GV 14). "Pishu" (BL 20), "Feishu" (BL 13) and "Shenshu" (BL 23) were selected for external application of Chinese medicinal herbs (pricklyash peel, white mustard seeds, asarum herb, etc.) for rats of A-A group, and that of control drugs (ang-kak, black rice, ginger juice, etc) for rats of DX group. Infiltration degrees of eosinophils (Eos), lymphocytes (L) and macrophages (MO) in the pulmonary tissue were observed under microscope. IL-4 and IFN-gamma expression was displayed by using immunohistochemical method. RESULTS: In comparison with control group, the infiltration degrees of E(OS). L and Mphi increased significantly in model, DX and acupoint-application groups (P < 0.05, 0.01); while compared with model group, the infiltration of E(OS), L and Mphi in DX group, E(OS) in A-A group decreased significantly (P < 0.05, 0.01). No significant differences were found between DX and A-A groups in these 3 indexes (P > 0.05). Results of immunohisto chemical staining in the lung tissue indicated that compared with control group, IL-4 expression in model increased significantly (P < 0.01), IFN-gamma expression decreased considerably in model and DX group (P < 0.01); when compared with model group, IL-4 in both A-A group and DX group decreased significantly, and IFN-gamma expression in A-A group increased considerably (P < 0.05, 0.01). No significant differences were found between DX and A-A groups in IL-4 expression (P > 0.05). CONCLUSION: Acupoint application of Chinese herbal medicines can balance Thl/Th2 and effectively reduce the infiltration of eosinophils, which may contribute to its therapeutic effect in relieving asthma.