Gastrodin regulates the expression of renin-angiotensin system-SIRT3 and proinflammatory mediators in reactive astrocytes via activated microglia.

Gastrodin, an anti-inflammatory herbal agent, is known to suppress microglia activation. Here, we investigated whether it would exert a similar effect in reactive astrocytes and whether it might act through the renin-angiotensin system (RAS) and sirtuin 3 (SIRT3). Angiotensinogen (ATO), angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) and type 2 (AT2) receptor and SIRT3 expression was detected in TNC-1 astrocytes treated with BV-2 microglia conditioned medium (CM) with or without gastrodin and lipopolysaccharide (LPS) pre-treatment by RT-PCR, immunofluorescence and western blotting analysis. Expression of C3 (A1 astrocyte marker), S100A10 (A2 astrocyte marker), proinflammatory cytokines and neurotrophic factors was then evaluated. The results showed a significant increase of ATO, ACE, AT1, SIRT3, C3, proinflammatory cytokines and neurotrophic factors expression in TNC-1 astrocytes incubated in CM + LPS when compared with cells incubated in the CM, but AT2 and S100A10 expression was reduced. TNC-1 astrocytes responded vigorously to BV-2 CM treated with gastrodin + LPS as compared with the control. This was evident by the decreased expression of the abovementioned protein markers, except for AT2 and S100A10. Interestingly, SIRT3, IGF-1 and BDNF expression was enhanced, suggesting that gastrodin inhibited the expression of RAS and proinflammatory mediators but promoted the expression of neurotrophic factors. And gastrodin regulated the phenotypic changes of astrocytes through AT1. Additionally, azilsartan (a specific inhibitor of AT1) inhibited the expression of C3 and S100A10, which remained unaffected in gastrodin and azilsartan combination treatment. These findings provide evidence that gastrodin may have a therapeutic effect via regulating RAS-SIRT3.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants.

BACKGROUND: Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. METHODS: The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. RESULTS: Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. CONCLUSIONS: This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines.

Differences in glucose homeostasis and islet injury among diverse mice strains post acute pancreatitis.

Diverse animal models have been used to study postpancreatitis diabetes mellitus (PPDM) development; however, no study has yet conducted a comparative analysis of the specific differences in glucose homeostasis and islet injury between these models. Therefore, we investigated the differences in pancreatic islet injury and glucose homeostasis among diverse strains in a cerulein-induced acute pancreatitis (AP) model to determine the appropriate animal model for PPDM. BALB/cJ, C57BL/6J, C57BL/6 N, and FVB/NJ mice were administered cerulein to induce AP. Serum amylase levels, pancreatic acinar injury, blood glucose homeostasis, islet function, and islet injury were measured and analyzed. All strains exhibited elevated amylase secretion post pancreatitis, and BALB/cJ, C57BL/6J, and C57BL/6 N mice exhibited sex-related differences. All strains exhibited pancreatic acinar injury post pancreatitis but mostly recovered within 15 days. Overall, glucose homeostasis remained balanced post pancreatitis in all strains compared to that in the control groups, except in FVB/NJ male and female mice, which exhibited an imbalance in glucose homeostasis on day 7 post pancreatitis. All the strains, except BALB/cJ mice, exhibited a decline in Homeostasis model assessment-ß(HOMA-ß) values post pancreatitis, with significant decrease in C57BL/6J females and FVB/NJ males. Islet size decreased post pancreatitis in all strains, except BALB/cJ mice. Pancreatic islet insulin secretion levels significantly decreased in male FVB/NJ mice post pancreatitis onset and did not recover within 15 days. Therefore, FVB/NJ male mice are a useful model for studying PPDM.

NIEND: neuronal image enhancement through noise disentanglement.

MOTIVATION: The full automation of digital neuronal reconstruction from light microscopic images has long been impeded by noisy neuronal images. Previous endeavors to improve image quality can hardly get a good compromise between robustness and computational efficiency. RESULTS: We present the image enhancement pipeline named Neuronal Image Enhancement through Noise Disentanglement (NIEND). Through extensive benchmarking on 863 mouse neuronal images with manually annotated gold standards, NIEND achieves remarkable improvements in image quality such as signal-background contrast (40-fold) and background uniformity (10-fold), compared to raw images. Furthermore, automatic reconstructions on NIEND-enhanced images have shown significant improvements compared to both raw images and images enhanced using other methods. Specifically, the average F1 score of NIEND-enhanced reconstructions is 0.88, surpassing the original 0.78 and the second-ranking method, which achieved 0.84. Up to 52% of reconstructions from NIEND-enhanced images outperform all other four methods in F1 scores. In addition, NIEND requires only 1.6 s on average for processing 256 × 256 × 256-sized images, and images after NIEND attain a substantial average compression rate of 1% by LZMA. NIEND improves image quality and neuron reconstruction, providing potential for significant advancements in automated neuron morphology reconstruction of petascale. AVAILABILITY AND IMPLEMENTATION: The study is conducted based on Vaa3D and Python 3.10. Vaa3D is available on GitHub (https://github.com/Vaa3D). The proposed NIEND method is implemented in Python, and hosted on GitHub along with the testing code and data (https://github.com/zzhmark/NIEND). The raw neuronal images of mouse brains can be found at the BICCN's Brain Image Library (BIL) (https://www.brainimagelibrary.org). The detailed list and associated meta information are summarized in Supplementary Table S3.

Gastrodin Regulates PI3K/AKT-Sirt3 Signaling Pathway and Proinflammatory Mediators in Activated Microglia.

Activated microglia and their mediated inflammatory responses play an important role in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Therefore, regulating microglia activation is considered a potential therapeutic strategy. The neuroprotective effects of gastrodin were evaluated in HIBD model mice, and in oxygen glucose deprivation (OGD)-treated and lipopolysaccharide (LPS)activated BV-2 microglia cells. The potential molecular mechanism was investigated using western blotting, immunofluorescence labeling, quantitative realtime reverse transcriptase polymerase chain reaction, and flow cytometry. Herein, we found that PI3K/AKT signaling can regulate Sirt3 in activated microglia, but not reciprocally. And gastrodin exerts anti-inflammatory and antiapoptotic effects through the PI3K/AKT-Sirt3 signaling pathway. In addition, gastrodin could promote FOXO3a phosphorylation, and inhibit ROS production in LPSactivated BV-2 microglia. Moreover, the level P-FOXO3a decreased significantly in Sirt3-siRNA group. However, there was no significant change after gastrodin and siRNA combination treatment. Notably, gastrodin might also affect the production of ROS in activated microglia by regulating the level of P-FOXO3a via Sirt3. Together, this study highlighted the neuroprotective role of PI3K/AKT-Sirt3 axis in HIBD, and the anti-inflammatory, anti-apoptotic, and anti-oxidative stress effects of gastrodin on HIBD.

Full-Spectrum Neuronal Diversity and Stereotypy through Whole Brain Morphometry.

We conducted a large-scale study of whole-brain morphometry, analyzing 3.7 peta-voxels of mouse brain images at the single-cell resolution, producing one of the largest multi-morphometry databases of mammalian brains to date. We spatially registered 205 mouse brains and associated data from six Brain Initiative Cell Census Network (BICCN) data sources covering three major imaging modalities from five collaborative projects to the Allen Common Coordinate Framework (CCF) atlas, annotated 3D locations of cell bodies of 227,581 neurons, modeled 15,441 dendritic microenvironments, characterized the full morphology of 1,891 neurons along with their axonal motifs, and detected 2.58 million putative synaptic boutons. Our analysis covers six levels of information related to neuronal populations, dendritic microenvironments, single-cell full morphology, sub-neuronal dendritic and axonal arborization, axonal boutons, and structural motifs, along with a quantitative characterization of the diversity and stereotypy of patterns at each level. We identified 16 modules consisting of highly intercorrelated brain regions in 13 functional brain areas corresponding to 314 anatomical regions in CCF. Our analysis revealed the dendritic microenvironment as a powerful method for delineating brain regions of cell types and potential subtypes. We also found that full neuronal morphologies can be categorized into four distinct classes based on spatially tuned morphological features, with substantial cross-areal diversity in apical dendrites, basal dendrites, and axonal arbors, along with quantified stereotypy within cortical, thalamic and striatal regions. The lamination of somas was found to be more effective in differentiating neuron arbors within the cortex. Further analysis of diverging and converging projections of individual neurons in 25 regions throughout the brain reveals branching preferences in the brain-wide and local distributions of axonal boutons. Overall, our study provides a comprehensive description of key anatomical structures of neurons and their types, covering a wide range of scales and features, and contributes to our understanding of neuronal diversity and its function in the mammalian brain.

Electroacupuncture at Neiguan (PC6) attenuates cardiac dysfunction caused by cecal ligation and puncture via the vagus nerve.

PURPOSE: Previous studies proved the benefits of electroacupuncture (EA) on heart in ischemia reperfusion injury and chronic heart failure. However, the role of EA on sepsis-induced cardiac dysfunction has rarely been elucidated before. In this study, we aimed to investigate the effects of EA on cardiac dysfunction in a rat model of sepsis and to speculate the underlying mechanisms. METHODS: Sepsis was induced by cecum ligation and puncture in anesthetized rats. EA at the acupoint "Neiguan (PC6)" was applied 0.5 h after the induction of sepsis for 20 min. Heart rate variability was obtained immediately after EA to evaluate autonomic balance. Echocardiography was performed at 6 h and 24 h after sepsis induction in vivo. Measurements of hemodynamics, blood gases, cytokines and biochemistry were collected at 24 h. Cardiac tissue underwent immunofluorescence staining to determine the expression of α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages. RESULTS: EA increased vagus nerve activity, prevented the development of hyperlactatemia, attenuated the decline of left ventricle ejection fraction, suppressed systemic and cardiac inflammation and alleviated the histopathological manifestations of heart in sepsis rats. Furthermore, the cardiac tissue from EA treated rats showed increased expressions of α7nAChR on macrophages. The cardio-protective and anti-inflammatory effects of EA were partly or completely prevented in rats with vagotomy. CONCLUSION: EA at PC6 attenuates left ventricle dysfunction and decreases inflammation in sepsis-induced cardiac dysfunction. The cardio-protective effects of EA are mediated through vagus nerve mediated cholinergic pathway.

Gastrodin Regulates the Notch-1 Signal Pathway via Renin-Angiotensin System in Activated Microglia.

Notch-1 and renin angiotensin system (RAS) are involved in microglia activation. It has been reported that gastrodin inhibited inflammatory responses mediated by activated microglia. This study explored the possible interaction between this two pathways, and to determine whether gastrodin would exert its effects on both of them. Expression of RAS, Notch-1 signaling and proinflammatory mediators in lipopolysaccharide (LPS) activated BV-2 microglia subjected to various treatments was determined by Western blot and immunofluorescence. The protein expression of RAS, Notch-1 pathway and TNF-α and IL-1ß was significantly increased in activated microglia. Exogenous Ang II markedly enhanced the expression of these biomarkers. Meanwhile, Azilsartan [a specific inhibitor of AT1 (AT1I)] inhibited the expression of Notch-1 pathway and proinflammatory cytokines. When Notch-1 signaling was inhibited with DAPT, ACE and AT1 expression remained unaffected, indicating that RAS can regulate the Notch-1 pathway in activated microglia but not reciprocally. Additionally, we showed here that gastrodin inhibited the RAS, Notch-1 pathway and inflammatory response. Remarkably, gastrodin did not exert any effect on expression of Notch-1 signaling when RAS was blocked by AT1I, suggesting that gastrodin acts on the RAS directly, not through the Notch-1 pathway. Furthermore, TNF-α and IL-1ß expression was significantly increased in activated microglia treated with exogenous Ang II; the expression, however, was suppressed by gastrodin. Of note, expression of proinflammatory cytokines was further decreased in gastrodin and AT1I combination treatment. The results suggest that gastrodin acts via the RAS which regulates the Notch-1 signaling and inflammation in LPS-induced microglia.

Light-Controlled Triple-Shape-Memory, High-Permittivity Dynamic Elastomer for Wearable Multifunctional Information Encoding Devices.

Self-powered information encoding devices (IEDs) have drawn considerable interest owing to their capability to process information without batteries. Next-generation IEDs should be reprogrammable, self-healing, and wearable to satisfy the emerging requirements for multifunctional IEDs; however, such devices have not been demonstrated. Herein, an integrated triboelectric nanogenerator-based IED with the aforementioned features was developed based on the designed light-responsive high-permittivity poly(sebacoyl diglyceride-co-4,4'-azodibenzoyl diglyceride) elastomer (PSeDAE) with a triple-shape-memory effect. The electrical memory feature was achieved through a microscale shape-memory property, enabling spatiotemporal information reprogramming for the IED. Macroscale shape-memory behavior afforded the IED shape-reprogramming ability, yielding wearable and detachable features. The dynamic transesterifications and light-heating groups in the PSeDAE afforded a remotely controlled rearrangement of its cross-linking network, producing the self-healing IED.

Dual-functional biocatalytic membrane containing laccase-embedded metal-organic frameworks for detection and degradation of phenolic pollutant.

In this work, a metal-organic framework material, zeolitic imidazolate framework-90 (ZIF-90), was firstly used to encapsulate laccase (LAC) and to prepare ZIF-90/LAC biocomposites. Afterward, the composites were combined with bacterial cellulose (BC) and carboxylated multi-walled carbon nanotubes (c-MWCNTs) by a facile method to achieve a novel cellulose membrane with biocatalytic function, displaying excellent detection and degradation properties towards phenolic pollutant. Notably, the membrane was directly employed as a biosensor electrode, and it exhibited a linear response to catechol from 20 to 400 µM with a detection limit of 1.86 µM (S/N = 3), as well as satisfactory selectivity, reproducibility, and stability. In addition, the biocatalytic membrane showed higher degradation efficiency towards catechol than pure LAC, and the catechol degradation efficiency of the membrane generally ranged from 93.4% to 82.1% for five cycles. Moreover, the membrane was successfully applied in enzyme membrane reactor (EMR), achieving satisfactory results. The novel membrane harbors a broad application prospect in the fields of real-time monitor and treatment of phenolic wastewater.

Increased Expressions of Plasma Galectin-3 in Patients with Amyotrophic Lateral Sclerosis.

BACKGROUND: High expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics. METHODS: A total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed. RESULTS: As compared with the NCs (201.64 [22.35-401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12-859.22] ng/ml, P< 0.05), and the patients with limb onset of disease (254.14 [69.12-859.22] ng/ml, P< 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77-334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20-404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32-859.22] ng/ml, P< 0.05) while no difference was found in the male patients (220.39 [69.12-748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037). CONCLUSIONS: Plasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS.

Android based self-diagnostic electrocardiogram system for mobile healthcare.

BACKGROUND: Cardiovascular diseases are the most common cause of death worldwide and are characterized by arrhythmia (i.e. irregular rhythm of heartbeat). Arrhythmia occasionally happens under certain conditions, such as stress. Therefore, it is difficult to be diagnosed using electrocardiogram (ECG) devices available in hospitals for just a few minutes. Constant diagnosis and monitoring of heartbeat is required to reduce death caused by cardiovascular diseases. OBJECTIVE: Mobile healthcare system has emerged as a potential solution to assist patients in monitoring their own heart condition, especially those who are isolated from the reference hospital. This paper proposes a self-diagnostic electrocardiogram system for mobile healthcare that has the capability to perform a real-time ECG diagnostic. METHODS: The self-diagnostic capability of a real-time ECG signal is achieved by implementing a detrended fluctuation analysis (DFA) method. The result obtained from DFA is used to display the patient's health condition on a smartphone anytime and anywhere. If the health condition is critical, the system will alert the patient and his medical practitioner for further diagnosis. RESULTS: Experimental results verified the validity of the developed ECG diagnostic application on a smartphone. CONCLUSION: The proposed system can potentially reduce death caused by cardiovascular diseases by alerting the patient possibly undergoing a heart attack.

[Analysis of the transfer of the world medical scientific center until modern times].

Since the 16th century, the world medical scientific center has transferred from Italy, Netherlands, the United Kingdom, France and Germany to the United States. The standards by which the above-mentioned countries became the medical scientific center during a certain historical period were not only the number of achievements of the scientific research and the talents, what was more important was their position and function in the leading disciplines. The background of the transfer of the medical scientific center was the economic, cultural and political rise of these countries, and the most important foundation was the innovation of personnel training systems.

[Evaluation of myelin basic protein levels with receiver operating characteristic curves for diagnosis of multiple sclerosis].

OBJECTIVE: To assess the value of cerebral spinal fluid (CSF) and serum myelin basic protein (MBP) levels in the diagnosis of multiple sclerosis (MS). METHODS: Enzyme-linked immunosorbent assay was used to detect the CSF and serum levels of MBP in patients with MS (n=45), patients with Guillain-Barre syndrome (GBS) (n=36) and control subjects (control) (n=33). The sensitivity and specificity of MBP in CSF and serum in the diagnosis of MS were evaluated using the receiver-operating characteristic (ROC) curves. RESULTS: The MBP levels in CSF and serum both increased significantly in MS group as compared with those in GBS (P<0.01) and control groups (P<0.01). The area under the curve (AUC) of the ROC curve of MBP in CSF was 0.853-/+0.037 for MS diagnosis, and with the optimal cut-off value of 0.87 pg/ml, CSF MBP showed a diagnostic sensitivity of 83.7% and specificity of 78.3%. The AUC of the ROC curve of serum MBP was 0.761-/+0.046, and the optimal cut-off value of 0.25 pg/ml resulted in a diagnostic sensitivity of 62.8% and specificity of 73.9%. No statistically significant difference was found between the two AUCs (P>0.05). CONCLUSION: Evaluation of CSF and serum MBP levels allows accurate diagnosis of MS, and MBP level in the CSF has greater diagnostic sensitivity than serum MBP. The combination of both CSF and serum MBP levels may serve as a sensitive index for the diagnosis of MS.