NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models.

Parkinson's disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1ß, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT-GSK-3ß and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.

[Development of Surgical Robots in Recent Years].

OBJECTIVE: To study the development of surgical robots at home and abroad in recent years. METHODS: Through a large number of literature review and analysis, the qualification approval and technical function characteristics of domestic and foreign surgical robots from January 2019 to July 2022 were analyzed. RESULTS: The related situations of 39 surgical robots were analyzed and reported, and the shortcomings and future development direction of the current surgical robots were summarized. CONCLUSIONS: The development of surgical robots in China is now in a rapid development stage. At present, surgical robots generally have the disadvantages of high cost, lack of tactile feedback (force feedback), large size, large space occupation and difficult to move. In the future, it will develop towards intelligent, miniaturized, remote, open and low-cost.

The pretreatment of chronic restraint stress exerts little impact on the progression of heart failure in mice.

Stress is a potent risk factor for depression. Chronic stress can exacerbate and induce symptoms of depression. Clinical studies suggested that depressive patients are more likely to develop coronary artery diseases. However, the causal relationship between depression and heart failure progression remains unclear. In this study, we aimed to explore the relevance between stress and heart failure (HF) in a mouse model subjected to chronic restraint stress and left anterior descending coronary artery (LAD) ligation. Mice were restrained for 3 h daily for 21 days and the processes were repeated once 3 months later. After the repeated chronic restraint stress, mice showed dramatically increased immobility time in the forced swim test, indicating a state of despair. Restrained and control mice were further subjected to LAD ligation surgery. Echocardiography was conducted 1 week, 2 weeks, and 1 month afterward. LAD-operated mice showed a significant decrease in the values of left ventricular ejection fraction (LVEF), and there was no difference in the LVEF values between the restrained and control mice. Relevant gene expression, neurotransmitter system, glial activation, and morphology of the heart-brain axis were comprehensively evaluated. We found no overall differences between the restrained and control mice with HF. Our results revealed that the repeated chronic restraint stress may have little effects on the progression of heart failure.

Risk Stratifying and Prognostic Analysis of Subclinical Cardiac Implantable Electronic Devices Infection: Insight From Traditional Bacterial Culture.

Background Subclinical infection of cardiac implantable electronic devices (CIEDs) is a common condition and increases the risk of clinical infection. However, there are limited studies focused on risk stratifying and prognostic analysis of subclinical CIED infection. Methods and Results Data from 418 consecutive patients undergoing CIED replacement or upgrade between January 2011 and December 2019 were used in the analysis. Among the patients included, 50 (12.0%) were detected as positive by bacterial culture of pocket tissues. The most frequently isolated bacteria were coagulase-negative staphylococci (76.9%). Compared with the noninfection group, more patients in the subclinical infection group were taking immunosuppressive agents, received electrode replacement, or received CIED upgrade and temporary pacing. Patients in the subclinical infection group had a higher PADIT (Prevention of Arrhythmia Device Infection Trial) score. Univariable and multivariable logistic regression analysis found that use of immunosuppressive agents (odds ratio [OR], 6.95 [95% CI, 1.44-33.51]; P=0.02) and electrode replacement or CIED upgrade (OR, 6.73 [95% CI, 2.23-20.38]; P=0.001) were significantly associated with subclinical CIED infection. Meanwhile, compared with the low-risk group, patients in the intermediate/high-risk group had a higher risk of subclinical CIED infection (OR, 3.43 [95% CI, 1.58-7.41]; P=0.002). After a median follow-up time of 36.5 months, the end points between the subclinical infection group and noninfection group were as follows: composite events (58.0% versus 41.8%, P=0.03), rehospitalization (54.0% versus 32.1%, P=0.002), cardiovascular rehospitalization (32.0% versus 13.9%, P=0.001), CIED infection (2.0% versus 0.5%, P=0.32), all-cause mortality (28.0% versus 21.5%, P=0.30), and cardiovascular mortality (10.0% versus 7.6%, P=0.57). Conclusions Subclinical CIED infection was a common phenomenon. The PADIT score had significant value for stratifying patients at high risk of subclinical CIED infection. Subclinical CIED infection was associated with increased risks of composite events, rehospitalization, and cardiovascular rehospitalization.

Paeonol loaded cyclodextrin metal-organic framework particles for treatment of acute lung injury via inhalation.

Administration of drugs via inhalation can overcome issues related to poor water solubility, low absorption or bioavailability associated with oral administration. In the current study we used γ-cyclodextrin metal organic frameworks (CD-MOFs) - of inhalable particle sizes, with cubic morphologies and favorable aerodynamic properties to achieve targeted pulmonary drug delivery via dry powder inhalers. The active natural compound, paeonol (PAE), was chosen as a model drug for treatment of acute lung injury (ALI). After loading of PAE into CD-MOF particles of inhalable sizes, PAE was rapidly released in phosphate buffer (pH = 7.4; 90% within 30 min) and in vivo experiments. After mixing with coarse and fine lactose (Inhalac®230: Inhalac®400: PAE-CD-MOF = 40:10:50, w/w/w), paeonol had a high fine particle fraction (FPF) (28.59%). Atom force microscopy was used to assess surface roughness and adhesive force. In vivo inhalation of PAE-CD-MOF dry powder inhaler by rat demonstrated rapid absorption (tmax of 4.0 min) and high absolute bioavailability (71%) of PAE, highlighting significant improvements in absorption and bioavailability of PAE when compared with oral administration (Cmax and absolute bioavailability increased 6.5 and 9.3 folds, respectively). Results of in vivo experiments were consistent with cellular permeability studies (after loading into CD-MOF, the permeability of PAE improved about 5 folds in comparison to the pure PAE). Finally, the efficacy of inhaled PAE for ALI was validated by histopathological examination and via reduced levels of inflammatory factors observed in rat plasma. Overall, targeted pulmonary delivery of paeonol by inhaled PAE-CD-MOF particles appears to be promising method of delivery for treatment of ALI.

Pro-survival and anti-inflammatory roles of NF-κB c-Rel in the Parkinson's disease models.

The pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of overactivated glial cells and neuroinflammation. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) c-Rel subunit is closely related in the pathological progress of PD, however the roles and mechanisms of c-Rel in PD development remain unclear. Here, in neurotoxins-induced PD models, the dynamic changes of NF-κB c-Rel and its functions were evaluated. We found that c-Rel was rapidly activated in the nigrostriatal pathway, which mainly occurred in dopaminergic neurons and microglia. c-Rel could maintain neuronal survival by initiating the anti-apoptotic gene expression in MPP+-treated SH-SY5Y cells and it could inhibit microglial overactivation by suppressing the inflammatory gene expression in LPS-challenged BV2 cells. c-Rel inhibitor IT901 aggravated the damage of MPTP on dopaminergic neurons and promoted the activation of microglia in the nigrostriatal pathway of mice. Moreover, the expression of c-Rel in blood samples of PD patients decreased dramatically. Our results indicate that the NF-κB/c-Rel subunit plays an important role in neuroprotection and neuroinflammation inhibition during PD progression.

Inflammation associated with chronic heart failure leads to enhanced susceptibility to depression.

Epidemiological and clinicopathological studies indicate that there is a high risk for chronic heart failure (CHF) in patients suffering from neuropsychiatric disorders, such as depression. However, it is unclear whether CHF causes depression, and the underlying mechanisms of this association remain largely unknown. In this study, mice with myocardial infarction and CHF were used to investigate behavioral alterations as well as changes in the brain-heart axis. During the first 6 months, abnormalities in neuropsychiatric behaviors were detected in mice with CHF. Using the sucrose preference test, a 9 months course of CHF resulted in two subgroups: mice with a significant decrease in sucrose preference, defined herein as "susceptible" (Sus), and mice with a normal sucrose preference, defined herein as "resilient." Compared to the resilient and sham-operated animals, the Sus mice displayed imbalances in glutamate transmission and hypothalamic-pituitary-adrenal axis activation, abnormal synaptic plasticity, and increased inflammatory responses. Furthermore, abnormal kynurenine metabolism was detected in Sus mice. Our results suggest that long-term CHF increases inflammatory responses in the central nervous system and leads to depression in Sus mice.

Long-term Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a common and progressive neurodegenerative disorder. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD is widely used to study the progression of this disease. Behavior impairment is closely related to the damage of the dopaminergic system in the basal ganglia. Here, MPTP-induced changes in mouse behavior and glial activation were evaluated at different time points after the treatment and the long-term changes in the nigrostriatal pathway were analyzed. We found that mice exposed to MPTP displayed a full recovery in the rotarod test and the pole test but not in the wire hanging test at 65 days post-injection. A biphasic activation of microglial cells was revealed in the nigrostriatal pathway of MPTP-treated mice. However, activation of astrocytes displayed an approximately bell-shaped kinetics and an approximately S-shaped kinetics in the striatum and the substantia nigra, respectively. In addition, the numbers of complement component 3 (C3)-positive neurotoxic astrocytes in the substantia nigra of MPTP-treated mice increased with time and reached a maximum at 42 days, and declined at 74 days, after the treatment. Three months later, the dopaminergic system was partially recovered from the lesion of MPTP. The time course of pathophysiological events has important implications for the interventions or treatment of PD.

Dynamic Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson's Disease.

The characteristic brain pathology and motor and nonmotor symptoms of Parkinson's disease (PD) are well established. However, the details regarding the causes of the disease and its course are much less clear. Animal models have significantly enriched our current understanding of the progression of this disease. Among various neurotoxin-based models of PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model is the most commonly studied model. Here, we provide an overview of the dynamic changes in the nigrostriatal pathway in the MPTP mouse model of PD. Pathophysiological events, such as reductions in the striatal dopamine (DA) concentrations and levels of the tyrosine hydroxylase (TH) protein, depletion of TH-positive nerve fibers, a decrease in the number of TH-positive neurons in the substantia nigra pars compacta (SNpc), and glial activation, are addressed. This article will assist with the development of interventions or therapeutic strategies for PD.

Circulating microRNAs as novel biomarkers for dilated cardiomyopathy.

BACKGROUND: Circulating microRNAs (miRNAs) potentially carry disease-specific information. In the current study, we aim to characterize the miRNA signature in plasma from dilated cardiomyopathy (DCM) patients and assess the possible correlation between expression levels of circulating miRNAs and symptom severity in DCM patients. METHODS: Using microarray-based miRNA expression profiling, we compared the miRNA expression levels in plasma samples from 4 DCM patients and 3 healthy controls. The expression levels of selected differentially expressed, upregulated miRNAs (miR-3135b, miR-3908 and miR-5571-5p) were validated independently in plasma samples from 19 DCM patients and 20 controls. RESULTS: We observed that plasma miR-3135b (p < 0.001), miR-3908 (p < 0.001) and miR-5571-5p (p < 0.001) were significantly upregulated in DCM patients. The area under receiver operating characteristic (ROC) curves for the 3 miRNAs ranged from 0.83 to 1.00. Moreover, miR-5571-5p levels in plasma were significantly upregulated with severe New York Heart Association (NYHA) classification (p < 0.05). CONCLUSIONS: The circulating miRNAs (miR-3135b, miR-3908 and miR-5571-5p) have potential as diagnostic biomarkers for DCM. Additionally, miR-5571-5p correlated with NYHA classification.

[A preliminary study on the role of anti-atrial fibrillation pacemaker in the prevention of atrial tachyarrhythmia].

OBJECTIVE: To investigate the effect of anti-atrial fibrillation of Philos DDDR pacemaker on atrial tachyarrhythmia. METHODS: Thirty-eight patients with sick sinus syndrome and paroxysmal atrial fibrillation (AF) were implanted with Philos DDDR pacemaker. After implantation, auto-Mode-Switch (AMS) function was switched "on" and AF preventive algorithms were "off" in all cases. The number of AMS, atrial premature beats, heart rate and the percentage of atrial and ventricular pacing were recorded by pacemaker diagnostic function for one-month after procedure. AF preventive algorithms function with "middle" (approx 8 bpm) was then switched on and the same parameters as above from the database of pacemaker diagnostic function were collected for additional one month. RESULTS: The symptoms of dizziness, dyspnoea, and palpitation in the majority of patients were dramatically improved regardless of whether the AF preventive algorithms function was switched "on" or "off" after pacemaker implantation. There were no significant clinical changes in most patients when AF preventive algorithms were "on". However, 5 cases (13.2%) had palpitations and short of breath. These symptoms were relieved by changing the algorithms from "middle to slight (approx 4 bpm)". When AF preventive algorithms were switched on, atrial premature beats were reduced significantly (P < 0.05) with a dramatic increase in atrial pacing percentage and heart rate (P < 0.05). However, there was no significant difference in AMS (P > 0.05) between the two groups of AF preventive algorithms function switching "on" and "of", indicating that atrial tachyarrhythmias were not inhibited by anti-atrial fibrillation pacemaker. CONCLUSION: This study suggested that atrial fibrillation and atrial tachycardia were not reduced by implantation of an anti-atrial fibrillation Philos DDDR pacemaker, although atrial premature beats decreased significantly with increasing atrial pacing percentage when AF preventive algorithms were in "middle" and "slight".

Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation.

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson's disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD.

NRSF is an essential mediator for the neuroprotection of trichostatin A in the MPTP mouse model of Parkinson's disease.

Neuron-restrictive silencer factor (NRSF) blocks the expression of many neuronal genes in non-neuronal cells and neural stem cells. There is growing body of evidence that NRSF functions in mature neurons and plays critical roles in various neurological disorders. Our previous study demonstrated that the expression of NRSF target genes brain-derived neurotrophic factor (BDNF), and tyrosine hydroxylase (TH) is transiently decreased in 1-methyl-4-phenyl-pyridinium ion (MPP+)-treated SH-SY5Y cells. NRSF neuronal deficient mice are more vulnerable to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we investigated the effect of epigenetic modulation on the expression of NRSF target genes in in vitro and in vivo models of Parkinson's disease (PD). Trichostatin A (TSA) was further used to study the effects of histone deacetylase inhibition on NRSF-mediated repression. We found that the repression of NRSF target genes was relieved by TSA in vitro. A single dose TSA pretreatment also upregulated the expression of TH and BDNF and protected the nigrostriatal dopaminergic pathway against MPTP-induced degeneration in wild type mice. However, the protective functions of TSA were fully abolished in NRSF neuronal deficient mice. Our results suggest that NRSF serves as an essential mediator for the neuroprotection of TSA in the MPTP model of PD.

Subclinical infections of cardiac implantable electronic devices: insights into the host-bacteria dialog from blood and pocket tissue with pyrosequencing.

While bacteria exist in CIED patients without clinical signs of infection, the underlying bacterial community structure and diversity in the bloodstream and pocket tissue of asymptomatic CIED patients remain unknown. In this study, we performed high-throughput 454 pyrosequencing of bacterial 16S rDNA of blood and pocket tissue from 54 asymptomatic CIED patients as well as blood from 30 normal individuals (normal controls). Firstly, we observed a significant increase of blood bacterial diversity in patients as compared with blood of normal subjects or patient tissues. We also found significant differences in 13 blood-associated bacterial genera between patients and normal subjects, and 14 bacteria genera between blood and tissues within patients. Secondly, we found that the serum levels of four inflammatory markers (CRP, IL-1ß, IL-6, and MCP-1) in CIED patients were significantly higher than those in normal subjects. Thirdly, we found that there were significant correlations between 43 bacterial species and these inflammatory markers. Taken together, our results reveal a high diversity in the microbial community in CIED patients, and suggest the potential roles of multiple bacteria co-occurrence in the CIED subclinical infections.

Fluid flow along venous adventitia in rabbits: is it a potential drainage system complementary to vascular circulations?

BACKGROUND: Our previous research and other studies with radiotracers showed evidence of a centripetal drainage pathway, separate from blood or lymphatic vessels, that can be visualized when a small amount of low molecular weight tracer is injected subcutaneously into a given region on skin of humans. In order to further characterize this interesting biological phenomenon, animal experiments are designed to elucidate histological and physiologic characteristics of these visualized pathways. METHODS: Multiple tracers are injected subcutaneously into an acupuncture point of KI3 to visualize centripetal pathways by magnetic resonance imaging or fluorescein photography in 85 healthy rabbits. The pathways are compared with venography and indirect lymphangiography. Fluid flow through the pathways is observed by methods of altering their hydrated state, hydrolyzing by different collagenases, and histology is elucidated by optical, fluorescein and electron microscopy. RESULTS: Histological and magnetic imaging examinations of these visualized pathways show they consist of perivenous loose connective tissues. As evidenced by examinations of tracers' uptake, they appear to function as a draining pathway for free interstitial fluid. Fluorescein sodium from KI3 is found in the pathways of hind limbs and segments of the small intestines, partial pulmonary veins and results in pericardial effusion, suggesting systematical involvement of this perivenous pathway. The hydraulic conductivity of these pathways can be compromised by the collapse of their fiber-rich beds hydrolyzed by either of collagenase type I, III, IV or V. CONCLUSIONS: The identification of pathways comprising perivenous loose connective tissues with a high hydraulic conductivity draining interstitial fluid in hind limbs of a mammal suggests a potential drainage system complementary to vascular circulations. These findings may provide new insights into a systematically distributed collagenous connective tissue with a circulatory function and their potential relevance to the nature of acupuncture meridians.

Fibroblast growth factor receptor 4 polymorphisms are associated with coronary artery disease.

Fibroblast growth factor receptor 4 (FGFR4) plays crucial roles in vascular smooth muscle cell proliferation and atherosclerosis and, therefore, may potentially affect the development of coronary artery disease (CAD). The aim of this study was to investigate the association between FGFR4 polymorphisms and the susceptibility to CAD in the Chinese population. Two polymorphisms, rs192201146G/A (Asp756Asn) and rs188755817C/G (Ser778Arg), were detected by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing in 722 CAD cases and 802 age-matched controls. Data were analyzed using the chi-square test. Results showed that frequencies of rs192201146GA genotype and rs188755817CG genotype were significantly higher in CAD patients than in controls (odds ratio [OR]=1.92, 95% confidence interval [CI] 1.11-3.28, p=0.016, and OR=1.87, 95% CI 1.06-3.30, p=0.027). Similarly, numbers of the rs192201146A allele and the rs188755817G allele were significantly increased in CAD cases (OR=1.89, 95% CI 1.11-3.22, p=0.017, and OR=1.85, 95% CI 1.06-3.24, p=0.029). Haplotype analysis revealed that GG and AC (rs192201146 rs188755817) haplotypes had higher frequencies in CAD patients (OR=2.75, p=0.002 and OR=2.69, p=0.001). Our data suggested that the FGFR4 rs192201146 (Asp756Asn) and rs188755817 (Ser778Arg) polymorphisms could act as risk factors for CAD in the Chinese population.

Visualized regional hypodermic migration channels of interstitial fluid in human beings: are these ancient meridians?

BACKGROUND: Since the 1980s, many studies have indicated there are hypodermic migration channels of radiotracer along meridians independent of lymphatic and blood vessels in vivo. However, the radioactive trajectories were not clear enough to identify the anatomic structures in the living body. OBJECTIVES: To establish an alternative method to image the specific fluid pathways, we hypothesized that a minimal amount of low molecular weight tracer could enter the specific channels and by magnetic resonance imaging technique, we could image the regional channels originating from the acupoints on 6 yin meridians of forearm and lower leg. DESIGN AND RESULTS: Seven (7) healthy volunteers were injected hypodermically with a minimal amount of tracer into 6 acupoints on 6 yin meridians of the hand and foot. We found a total of 6 regional specific channels in one forearm and one lower leg of each subject, respectively, but no specific channels were visualized following injection of the tracer into the sites of nonacupoints. Magnetic resonance angiography confirmed the specific channels were not the superficial veins in the subcutis. Subsequent acupuncture needling studies revealed that migration of tracer along each of the specific channels could not be interrupted by acupuncture needling and remained intact, which was different from the nature of either lymphatics or blood vessels. CONCLUSIONS: We imaged 6 regional migration channels originating from 6 acupoints on 6 yin meridians of hand and foot by injecting a minimal amount of tracer into acupoints directly in humans. The responses of the subcutaneous specific channels to acupuncture needling are different from those of lymphatic or blood vessels and coincide partially with the characteristics of acupuncture therapeutics, suggesting the existence of meridian-like channels in humans. These findings may contribute to further research on the specific interstitial fluid drainage.