Applicability of the low-grade inflammation score in predicting 90-day functional outcomes after acute ischemic stroke.

BACKGROUND AND PURPOSE: The low-grade inflammation (LGI) score, a novel indicator of chronic LGI, combines C-reactive protein (CRP), leukocyte counts, the neutrophil/lymphocyte ratio (NLR), and the platelet (PLT) count to predict outcomes of patients with various conditions, such as cardiovascular diseases, cancers, and neurodegenerative diseases. However, few studies have examined the role of the LGI score in predicting functional outcomes of patients with ischemic stroke. The present study aimed to evaluate the association between the LGI score and functional outcomes of patients with ischemic stroke. METHODS: A total of 1,215 patients were screened in the present study, and 876 patients were finally included in this retrospective observational study based on the inclusion and exclusion criteria. Blood tests were conducted within 24 h of admission. Severity of ischemic stroke was assessed using the NIHSS score with severe stroke denoted by NIHSS > 5. Early neurological deterioration (END) was defined as an increment in the total NIHSS score of ≥ 2 points within 7 days after admission. Patient outcomes were assessed on day 90 after stroke onset using the modified Rankin Scale (mRS). RESULTS: The LGI score was positively correlated with baseline and the day 7 NIHSS scores (R2 = 0.119, p < 0.001;R2 = 0.123, p < 0.001). Multivariate regression analysis showed that the LGI score was an independent predictor of stroke severity and END. In the crude model, the LGI score in the fourth quartile was associated with a higher risk of poor outcomes on day 90 compared with the LGI score in the first quartile (OR = 5.02, 95% CI: 3.09-8.14, p for trend < 0.001). After adjusting for potential confounders, the LGI score in the fourth quartile was independently associated with poor outcomes on day 90 (OR = 2.65, 95% CI: 1.47-4.76, p for trend = 0.001). Finally, the ROC curve analysis showed an AUC of 0.682 for poor outcomes on day 90 after stroke onset. CONCLUSION: The LGI score is strongly correlated with the severity of acute ischemic stroke and that the LGI score might be a good predictor for poor outcomes on day 90 in patients with acute ischemic stroke.

Microglial glutaminase 1 deficiency mitigates neuroinflammation associated depression.

Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease.

Proteomics analyses of Xiaopi granules in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric epithelial dysplasia rat model using LC-MS.

Xiaopi granules have been shown to ameliorate gastric epithelial dysplasia in patients. However, the therapeutic mechanism is unclear. Herein, the proteomics method was applied to identify the differentially expressed proteins and related pathways. Sixty male Sprague-Dawley rats were randomly divided into four groups: control (C group, n = 10), model (M group), Xiaopi granules (X group), and vitacoenzyme (V group). The rat gastric epithelial dysplasia model was established by intragastrically administering N-methyl-N'-nitro-N-nitrosoguanidine and ranitidine and by orally administering 0.05% ammonia solution. After 12 weeks, the stomach tissue was analyzed by hematoxylin and eosin staining and proteomics analyses. Western-blot analysis was applied to further validate the proteomics results. Compared to the M group, levels of 326 and 350 proteins were altered significantly in the X and V groups (1.5-fold, p < 0.05), which were significantly enriched in digestion, metabolism, coagulation, and cell apoptosis. CELA2A, GHRL, NDUFB9, and PGC were significantly upregulated (p < 0.0001), whereas CLCA1, PLG, and DAC2 were downregulated (p < 0.001 or 0.0001) in the M group vs. the C group. The change in these proteins could be reversed after the treatment of Xiaopi granules or vitacoenzyme tablets. Xiaopi granules ameliorated gastric epithelial dysplasia by intervening in digestion, metabolism, blood coagulation, cell apoptosis, and other related pathways.

The Frequency and Associated Factors of Asymmetrical Prominent Veins: A Predictor of Unfavorable Outcomes in Patients with Acute Ischemic Stroke.

Objectives: The present study is aimed at investigating the frequency and associated factors of asymmetrical prominent veins (APV) in patients with acute ischemic stroke (AIS). Methods: Consecutive patients with AIS admitted to the Comprehensive Stroke Center of Shanghai Fourth People's Hospital between January 2013 and December 2017 were enrolled. MRI including diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and susceptibility-weighted imaging (SWI) was performed within 12 hours of symptom onset. The volume of asymmetrical prominent veins (APV) was evaluated using the Signal Processing In nuclear magnetic resonance software (SPIN, Detroit, Michigan, USA). Multivariate analysis was used to assess relationships between APV findings and medical history, clinical variables as well as cardio-metabolic indices. Results: Seventy-six patients met the inclusion criteria. The frequency of APV ≥ 10 mL was 46.05% (35/76). Multivariate analyses showed that proximal artery stenosis or occlusion (≥50%) (P < 0.001, adjusted odds ratio (OR) = 660.0, 95%CI = 57.28-7604.88) and history of atrial fibrillation (P < 0.001, adjusted OR = 10.48, 95%CI = 1.78-61.68) were independent factors associated with high APV (≥10 mL). Conclusion: Our findings suggest that the frequency of APV ≥ 10 mL is high in patients with AIS within 12 hours of symptom onset. History of atrial fibrillation and severe proximal artery stenosis or occlusion are strong predictors of high APV as calculated by SPIN on the SWI map.

Assessment of diets containing curcumin, epigallocatechin-3-gallate, docosahexaenoic acid and α-lipoic acid on amyloid load and inflammation in a male transgenic mouse model of Alzheimer's disease: Are combinations more effective?

Increasingly, evidence is accumulating pointing at a protective role of a healthy diet at decreasing the risk of Alzheimer's disease. To test the effectiveness of nutritional components, the following food-derived compounds: curcumin alone (curcumin), curcumin combined with (-)epigallocatechin-3-gallate (EGCG), docosahexaenoic acid (DHA) and α-lipoic acid (ALA) (curcumin + EDA), or a combination of EGCG, DHA and ALA (EDA) were assessed in male Tg2576 transgenic mice on amyloid plaque load, amyloid levels (Aß40/Aß42, but not oligomers due to tissue limitations), microglial activation and memory using the contextual and cued fear conditioning test. The combination diet EDA, resulted in the strongest reduction of amyloid plaque load in both the cortical (p < .0001) and hippocampal (p < .0001) areas of the Tg2576 mouse brain, along with lower Aß40/Aß42 levels in the frontal cortex (p = .000129 and p = .000039, respectively) and Aß42 levels in the temporal lobe (p = .000082). A curcumin only diet was shown to lower amyloid plaque load (p = .028), but when combined with EGCG, DHA and ALA did not result in further decreases in amyloid plaque load. The EDA combination group showed the most prominent decrease in microglial activation (number of microglia around plaques: p < .05 and p < .0001, respectively, for the cortex and hippocampus). Analysing the hippocampal associated contextual fear conditioning revealed that both the curcumin+EDA (p < .0001) and EDA groups (p = .001) spent increased time on freezing compared to the control group. In addition, the curcumin+EDA group showed a significant increase in time spent freezing compared with the curcumin only group. In the amygdala associated cued test, all mice demonstrated the ability to associate the conditioned stimulus with the unconditioned stimulus as evidenced by a significant increase in freezing behaviour in response to the presentation of the cue (p < .0001). Post-hoc analysis showed that only curcumin+EDA (p < .0001) and EDA groups (p < .0001) developed a significant increase in freezing during the cue presentation. The results from this study show that the combination of EGCG, DHA and ALA (EDA) appeared to have the most potent anti-inflammatory and neuroprotective effect. Our results also demonstrate that interactions between nutraceutical products might result in counterproductive outcomes, highlighting the fact that manufacturers of nutraceuticals containing multiple compounds should be careful not to claim additive or synergistic effects of their combination products in vivo without having tested it in animal models and/or human clinical trials.

Ligustilide Ameliorates the Permeability of the Blood-Brain Barrier Model In Vitro During Oxygen-Glucose Deprivation Injury Through HIF/VEGF Pathway.

Chuanxiong rhizome has been widely used for the treatment of cerebral vascular disease in traditional Chinese medicine. The integrity of blood-brain barrier (BBB) is closely linked to the cerebral vascular disease. The protective effects of ligustilide, the major bioactive component in Chuanxiong rhizome, on cerebral blood vessels have been reported previously, but its effects and potential mechanism on BBB have not been entirely clarified. In the current work, the effects of ligustilide on BBB permeability and the underlying molecular mechanisms had been investigated using the model of BBB established by coculturing astrocytes and brain microvascular endothelial cells isolated from the rat brain. The ischemia-damaged model of BBB has been established with oxygen and glucose deprivation (OGD). Our results indicated that OGD significantly increased the permeability in the coculture BBB model. This OGD-induced increase in permeability could suppress by ligustilide in a concentration-dependent manner. Also, ligustilide promoted both gene and protein expression of tight junction proteins. Ligustilide suppressed the upregulation of HIF-1α, vascular endothelial growth factor, and AQP-4 in the BBB model induced by OGD. Collectively, all results have demonstrated that ligustilide is capable of reducing the permeability of BBB in vitro model induced by OGD through HIF-1α/vascular endothelial growth factor pathway and AQP-4, which provide a new target for the clinical application of ligustilide on BBB after stroke in future.

Low-Frequency Fluctuations Amplitude Signals Exhibit Abnormalities of Intrinsic Brain Activities and Reflect Cognitive Impairment in Leukoaraiosis Patients.

BACKGROUND This study aimed to explore the amplitude of low-frequency fluctuations (ALFF) for whole-brain in leukoaraiosis (LA) patients suffering from cognitive decline or impairment. MATERIAL AND METHODS Patients were selected by employing magnetic resonance imaging (MRI) technique. According to results of the clinical dementia rating and Montreal cognitive assessment (MoCA), patients were divided into 3 groups: LA patients diagnosed as vascular mild-cognitive impairment (LA-VaMCI, n=28), LA patients diagnosed as vascular-dementia (LA-VaD, n=18), and normal individuals (NC, n=28). Executive functions were evaluated by using the Stroop test and Trail Making Test (TMT). The higher scores in TMT test mean greater impairments. Changes for the ALFF were measured by using resting-state functional MRI (rs-fMRI) technique. Correlations between ALFF and cognition scores were analyzed. RESULTS It was found that widespread differences in ALFF were present predominantly in the posterior cingulate cortex/precuneus (PCC/PCu) and in the right inferior temporal gyrus (ITG). Compared with the NC group, ALFF values in PCC/PCu were significantly decreased (F=3.273, P=0.022) and ALFF values were significantly increased (F=2.864, P=0.033) in temporal regions of the LA-VaD patients. ALFF values in LA-VaMCI patients were significantly increased in ITG compared to that in the NC group (F=1.064, P=0.042) and the LA-VaD group (F=2.725, P=0.037). Impairment in executive functions were positively correlated with average ALFF of the left PCu. CONCLUSIONS This research showed that LA patients exhibited abnormal intrinsic-brain activities. Furthermore, altered ALFF was positively correlated with executive function scores.

The Role of Disturbed Small-World Networks in Patients with White Matter Lesions and Cognitive Impairment Revealed by Resting State Function Magnetic Resonance Images (rs-fMRI).

BACKGROUND Leukoaraiosis is characterized by white matter lesions (WMLs) on magnetic resonance imaging (MRI) and is associated with cognitive impairment. The small-world network is viewed as the optimal brain network with maximal efficiency in information processing. Patients with cognitive impairment are thought to have disrupted small-world networks. In this study, we compared the small-world network attributes between controls (study participants without memory complaints) and patients with WMLs with cognitive impairment. MATERIAL AND METHODS All study participants were prescreened using MRI and neuropsychological tests. Patients with WMLs were further divided into 2 groups according to the result of Montreal Cognitive Assessment (MoCA), i.e., WMLs with non-dementia vascular cognitive impairment (WMLs-VCIND) and WMLs with vascular dementia (WMLs-VaD). Resting-state functional MRI data were collected and applied with graph theoretical analysis to compare small-world properties between the 3 groups. RESULTS We found that the overall functional connectivity strength was lowest in the WMLs-VaD patients but highest in the normal control study participants. Patients in both the WMLs-VCIND and the WMLs-VaD groups had decreased small-world properties compared with the group of normal control study participants. Moreover, the small-world properties significantly correlated with MoCA scores. CONCLUSIONS These findings suggest potential constructive reorganization of brain networks secondary to WMLs, and provides novel insights into the role of small-world properties in cognitive dysfunction in WMLs.

Investigation Into the Effects of Tenilsetam on Markers of Neuroinflammation in GFAP-IL6 Mice.

PURPOSE: To test the short- and long-term effects of Tenilsetam on chronic neuroinflammation in the GFAP-IL6 mouse. METHODS: From 3 months of age, GFAP-IL6 mice were divided into 2 groups and fed with Tenilsetam enriched food pellets or control food pellets, respectively, for either 5 or 15 months. Total numbers of Iba-1+ microglia, TSPO+ cells were determined using an unbiased stereological method. Levels of methylglyoxal and TNF-α in the cerebellar homogenate were tested using HPLC and ELISA, respectively. RESULTS: Tenilsetam decreased the total number of Iba-1+ microglia in both the cerebellum and the hippocampus of GFAP-IL6 mice at 8 months and in the cerebellum at 18 months. In the cerebellum, it decreased the density of microglia in GFAP-IL6 mice to a similar level after 5 and 15 months' feeding. Tenilsetam prevented the volume loss of the cerebellum at 8 months. It also significantly decreased TNF-α in the cerebellum of GFAP-IL6 mice to a similar level of WT mice after 15 months of feeding. CONCLUSION: Tenilsetam has anti-inflammatory effects evidenced by the decreased number of microglia in both the cerebellum and hippocampus, and decreased TNF-α levels in the GFAP-IL6 Tenilsetam fed animals.

Genetic polymorphisms in MMP 2, 3, 7, and 9 genes and the susceptibility and clinical outcome of cervical cancer in a Chinese Han population.

Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of tumor progression, including the invasion and metastasis. However, there are no data about the role of MMP polymorphism in the development of cervical cancer. A hospital-based case-control study was conducted in 230 patients with cervical cancer and 230 healthy controls to investigate the possible association between the MMP2 rs243865, MMP3 rs3025058, MMP7 rs11568818, and MMP9 rs3918242 polymorphisms, respectively, and the risk of cervical cancer. Our results suggested that the MMP2 rs243865-1306 C/T was significantly associated with an increased risk of cervical cancer (CT vs. CC, OR = 1.46; 95 % CI 1.18-3.55; P = 0.032; TT vs. CC, OR = 1.72; 95 % CI 1.28-4.02; P = 0.031; CT + TT vs. CC, OR = 1.43; 95 % CI 1.21-3.44; P = 0.029). Similarly, the MMP7 rs11568818-181A/G genotypes can also elevate the risk of cervical cancer in all genetic models. However, the genotype and allele frequencies of MMP3 rs3025058 and MMP9 rs3918242 polymorphisms in cervical cancer patients were not significantly different from controls. Further analysis showed MMP2 rs243865 and MMP7 rs11568818 genotypes were associated with advanced tumor stages of cervical cancer patients. More interestingly, the MMP2 rs243865 and MMP7 rs11568818 genotype was statistically significantly associated with a poor survival in cervical cancer patients. Our results showed that the MMP2 rs243865 and MMP7 rs11568818 genotypes e were associated with increased susceptibility and development of cervical cancer in Chinese Han population.

Distribution of raphespinal fibers in the mouse spinal cord.

BACKGROUND: Serotonergic raphespinal neurons and their fibers have been mapped in large mammals, but the non-serotonergic ones have not been studied, especially in the mouse. The present study aimed to investigate the termination pattern of fibers arising from the hindbrain raphe and reticular nuclei which also have serotonergic neurons by injecting the anterograde tracer BDA into them. RESULTS: We found that raphespinal fibers terminate in both the dorsal and ventral horns in addition to lamina 10. There is a shift of the fibers in the ventral horn towards the dorsal and lateral part of the gray matter. Considerable variation in the termination pattern also exists between raphe nuclei with raphe magnus having more fibers terminating in the dorsal horn. Fibers from the adjacent gigantocellular reticular nucleus show similar termination pattern as those from the raphe nuclei with slight difference. Immunofluorescence staining showed that raphespinal fibers were heterogeneous and serotoninergic fibers were present in all laminae but mainly in laminae 1, 2, medial lamina 8, laminae 9 and 10. Surprisingly, immunofluorescence staining on clarified spinal cord tissue revealed that serotoninergic fibers formed bundles regularly in a short distance along the rostrocaudal axis in the medial part of the ventral horn and they extended towards the lateral motor neuron column area. CONCLUSION: Serotonergic and non-serotonergic fibers arising from the hindbrain raphe and reticular nuclei had similar termination pattern in the mouse spinal cord with subtle difference. The present study provides anatomical foundation for the multiple roles raphe and adjacent reticular nuclei play.

Middle aged CAMKII-Cre:Cbsfl/fl mice: a new model for studying perioperative neurocognitive disorders.

Postoperative complications, such as perioperative neurocognitive disorders (PND), have become a major issue affecting surgical outcomes. However, the mechanism of PND remains unclear, and stable animal models of middle-aged PND are lacking. S-adenosylmethionine (SAM), a cystathionine beta-synthase (CBS) allosteric activator, can reduce the level of plasma homocysteine and prevent the occurrence of PND. However, the time and resource-intensive process of constructing models of PND in elderly animals have limited progress in PND research and innovative therapy development. The present study aimed to construct a stable PND model in middle-aged CAMKII-Cre:Cbsfl/fl mice whose Cbs was specifically knocked out in CAMKII positive neurons. Behavioral tests showed that these middle-aged mice displayed cognitive deficits which were aggravated by exploratory laparotomy under isoflurane anesthesia. Compared with typical PND mice which were 18-month-old, these middle-aged mice showed similar cognitive deficits after undergoing exploratory laparotomy under isoflurane anesthesia. Though there was no significant difference in the number of neurons in either the hippocampus or the cortex, a significant increase in numbers of microglia and astrocytes in the hippocampus was observed. These indicate that middle-aged CAMKII-Cre:Cbsfl/fl mice can be used as a new PND model for mechanistic studies and therapy development for PND.

Extrasynaptic distribution of NMDA receptors in cochlear inner hair cell afferent signaling complex.

OBJECTIVE: The distribution and role of NMDA receptors is unclear in the afferent signaling complex of the cochlea. The present study aimed to examine the distribution of NMDA receptors in cochlear afferent signaling complex of the adult mouse, and their relationship with ribbon synapses of inner hair cells (IHCs) and GABAergic efferent terminals of the lateral olivocochlear (LOC). METHODS: Immunofluorescence staining in combination with confocal microscopy was used to investigate the distribution of glutamatergic NMDA and AMPA receptors in afferent terminals of SGNs, and their relationship with ribbon synapses of IHCs and GABAergic efferent terminals of LOC. RESULTS: Terminals with AMPA receptors along with Ribbons of IHC formed afferent synapses in the basal pole of IHCs, and those with NMDA receptors were mainly distributed longitudinally in the IHCs nuclei region. Significant difference was found in the distribution of NMDA and AMPA receptors in IHC afferent signaling complex (P<0.05). Some GABAergic terminals colocalized with NMDA receptors at the IHC nucleus region (P>0.05). CONCLUSION: There is significant difference in the distribution of NMDA and AMPA receptors in cochlear afferent signaling complex. NMDA receptors are present in the extra-synaptic region of ribbon synapses of IHCs, and they are related to GABA efferent terminals of the afferent signaling complex.

The value of lipid accumulation products in predicting type 2 diabetes mellitus: a cross-sectional study on elderlies over 65 in Shanghai.

Purpose: As lifestyle changes, there is an increasing number of type 2 diabetes mellitus (T2DM) patients in China. The present study aimed to investigate the predictive value of the lipid accumulation product (LAP) for T2DM in Chinese elderlies over 65 years. Methods: The present cross-sectional study recruited 2,092 adults from communities of Pudong New Area of Shanghai. Questionnaires were filled and anthropometric and laboratory examinations were completed by all participants. The predictive value of different risk factors for T2DM was analyzed using the receiver operating characteristics curve (ROC). Results: LAP was found to be closely related to T2DM (adjusted OR: 0.613, 95% CI: 0.581-0.645). Fasting plasma glucose (FPG), LAP, and urea nigrogen (UN) were associated with T2DM in females, whereas FPG, LAP, neck circumference (NC) were associated with T2DM in males. When the cut-off value was 33.8, LAP displayed the optimal predictive performance. A gender difference was observed with an LAP of 37.95 demonstrating the best predictive value in males (AUC = 0.604, 95% CI: 0.577-0.652) and 60.2 in females (AUC = 0.617, 95% CI: 0.574-0.660), respectively. Conclusion: LAP is more significantly associated with the risk of T2DM in elderlies than FPG, UN or NC, and it serves as a strong predictor of T2DM. However, this is impacted by FPG and neck circumference to a certain extent. Future large-scale studies are needed to confirm its efficacy in predicting diabetes.

Exercise attenuates the perioperative neurocognitive disorder induced by hyperhomocysteinemia in mice.

The perioperative neurocognitive disorder (PND) is a severe complication that affects millions of surgical patients each year. Homocysteine (Hcy) is known to increase the risk of developing PND in both young and elderly mice. However, whether Hcy alone can induce cognitive deficits in middle-aged mice (12-month-old), whether exercise can attenuate Hcy-induced hippocampus-related cognitive deficits after surgery through suppressing neuroinflammation, synaptic elimination, and the level of Hcy remains unknown. The present study aimed to answer these questions through testing the possibility of establishing a PND model using 12-month-old mice which received homocysteine injections before exploratory laparotomy and the therapeutic mechanism of exercise. In the present study, it was found that levels of serum homocysteine were age-dependently increased in mice with a significant difference between that of 18-month-old mice and 6-week, 6-month, and 12-month-old mice. PND occurred in 18-month but not in 12-month-old mice after exploratory laparotomy under isoflurane anesthesia. Intraperitoneal injection of Hcy for 3 consecutive days before surgery rendered 12-month-old mice to develop PND after abdominal laparotomy under isoflurane anesthesia at a minimal dosage of 20 mg/kg. Neuroinflammation and synaptic elimination was present in 12-month-old preoperative Hcy-injected mice. Preoperative voluntary wheel exercise could prevent PND in 12-month-old mice that have received Hcy injection before surgery, which might be related to the decreased level of serum Hcy. Activation of glial cells, proinflammatory phenotype markers and synaptic elimination were attenuated in the hippocampus of 12-month-old preoperative Hcy-injected mice by this exercise. These results provide direct evidence that hyperhomocysteinemia can induce postoperative cognitive deficits in middle-aged mice. Pre-surgery exercise can effectively prevent Hcy-precipitated postoperative cognitive dysfunction.

Dietary Restriction Improves Perioperative Neurocognitive Disorders by Inhibiting Neuroinflammation and Gut Microbial Dysbiosis.

Anesthesia/surgery have been identified as potential factors contributing to perioperative neurocognitive disorders, with a notably heightened risk observed in aging populations. One of the primary drivers of this impairment is believed to be neuroinflammation, specifically inflammation of hippocampal microglia. Dietary restriction has demonstrated a favorable impact on cognitive impairment across various disorders, primarily by quelling neuroinflammation. However, the precise influence of dietary restriction on perioperative neurocognitive disorders remains to be definitively ascertained. This investigation aims to explore the effects of dietary restriction on perioperative neurocognitive disorders and propose innovative therapeutic strategies for their management. The model of perioperative neurocognitive disorder was induced through exploratory laparotomy under isoflurane anesthesia. Cognitive performance was evaluated using the open field test, Barnes maze test, and fear conditioning test. The enzyme-linked immunosorbent assay (ELISA) was employed to quantify concentrations of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in both serum and hippocampal samples. The Western blot technique was utilized to assess expression levels of hippocampal PSD 95, Synaptophysin, TLR4, MyD88, and NF-kB p65. Microglial polarization was gauged using a combination of reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence labeling techniques. We conducted 16S rRNA sequencing to investigate the impact of dietary restriction on the intestinal flora of aged mice following anesthesia/surgery. Our findings indicate that dietary restrictions have the potential to ameliorate anesthesia/surgery-induced cognitive dysfunction. This effect is achieved through the modulation of gut microbiota, suppression of inflammatory responses in hippocampal microglia, and facilitation of neuronal repair and regeneration.

Sanhua decoction: Current understanding of a traditional herbal recipe for stroke.

Both thrombolytic and endovascular therapies are optimal treatment options for patients with acute ischemic stroke, but only less than half of these patients can benefit from these treatments. Traditional Chinese medicine has a long history of successfully managing ischemic stroke using both herbal and physical therapeutics. Among herbal recipes, Sanhua decoction (SHD) is one of the classical prescriptions for ischemic stroke. The present review aimed to summarize evidence from both clinical and basic research to demonstrate its efficacy in managing ischemic stroke and the potential mechanisms underlying its therapeutic effects, which will provide evidence on the therapeutic effect of this herbal recipe and guide future studies on this recipe. SHD is composed of four herbs, Rheum palmatum L. [Polygonaceae], Magnolia officinalis Rehder & E.H.Wilson [Magnoliaceae], Citrus × aurantium L. [Rutaceae], Hansenia weberbaueriana (Fedde ex H.Wolff) Pimenov & Kljuykov [Apiaceae]. We found that the majority of clinical studies on SHD are case reports and they showed positive therapeutic effect of SHD on both acute and chronic ischemic stroke. There are over 40 bioactive compounds identified in SHD, but few experimental studies have examined their individual molecular mechanisms. As an extract of SHD, it improves neurological functions through suppressing inflammation, protecting the blood brain barrier from degradation, restoring the number of neural stem cells, inhibiting apoptosis and brain edema, scavenging oxygen free radicals, and regulating the brain-gut axis. These will lay the theoretical foundation for future studies on this prescription and its clinical application. Future research may need to confirm its clinical efficacy in large-scale clinical trials and to disentangle its bioactive compounds and their potential mechanisms.

Brain pericyte biology: from physiopathological mechanisms to potential therapeutic applications in ischemic stroke.

Pericytes play an indispensable role in various organs and biological processes, such as promoting angiogenesis, regulating microvascular blood flow, and participating in immune responses. Therefore, in this review, we will first introduce the discovery and development of pericytes, identification methods and functional characteristics, then focus on brain pericytes, on the one hand, to summarize the functions of brain pericytes under physiological conditions, mainly discussing from the aspects of stem cell characteristics, contractile characteristics and paracrine characteristics; on the other hand, to summarize the role of brain pericytes under pathological conditions, mainly taking ischemic stroke as an example. Finally, we will discuss and analyze the application and development of pericytes as therapeutic targets, providing the research basis and direction for future microvascular diseases, especially ischemic stroke treatment.

Construction and validation of a deterioration model for elderly COVID-19 Sub-variant BA.2 patients.

Rationale: COVID-19 pandemic has imposed tremendous stress and burden on the economy and society worldwide. There is an urgent demand to find a new model to estimate the deterioration of patients inflicted by Omicron variants. Objective: This study aims to develop a model to predict the deterioration of elderly patients inflicted by Omicron Sub-variant BA.2. Methods: COVID-19 patients were randomly divided into the training and the validation cohorts. Both Lasso and Logistic regression analyses were performed to identify prediction factors, which were then selected to build a deterioration model in the training cohort. This model was validated in the validation cohort. Measurements and main results: The deterioration model of COVID-19 was constructed with five indices, including C-reactive protein, neutrophil count/lymphocyte count (NLR), albumin/globulin ratio (A/G), international normalized ratio (INR), and blood urea nitrogen (BUN). The area under the ROC curve (AUC) showed that this model displayed a high accuracy in predicting deterioration, which was 0.85 in the training cohort and 0.85 in the validation cohort. The nomogram provided an easy way to calculate the possibility of deterioration, and the decision curve analysis (DCA) and clinical impact curve analysis (CICA)showed good clinical net profit using this model. Conclusion: The model we constructed can identify and predict the risk of deterioration (requirement for ventilatory support or death) in elderly patients and it is clinically practical, which will facilitate medical decision making and allocating medical resources to those with critical conditions.

Immunohistochemical Localization of MD2, a Co-Receptor of TLR4, in the Adult Mouse Brain.

Myeloid differentiation factor 2 (MD2) is a co-receptor of a classical proinflammatory protein TLR4 whose activation leads to neuroinflammation. It is widely accepted that TLR4 is expressed on the cell surface of microglia and astrocytes, and MD2 is expected to be expressed by these cells as well. However, our previous study showed that neurons from certain nuclei also expressed MD2. Whether MD2 is expressed by other brain nuclei is still unknown. It is the aim of the present study to map the distribution of MD2-positive cells in the adult mouse brain. Immunohistochemical staining against MD2 was completed to localize MD2-positive cells in the mouse brain by comparing the location of positive cells with the mouse brain atlas. MD2-positive cells were found in the majority of mouse brain nuclei with clusters of cells in the olfactory bulb, cortices, the red nucleus, and cranial nuclei. Subcortical nuclei had heterogeneous staining of MD2 with more prominent cells in the basolateral and the central amygdaloid nuclei. The ventral pallidum and the diagonal bands had positive cells with similar density and shape. Prominent cells were present in thalamic nuclei which were nearly homogeneous and in reticular formation of the brainstem where cells were dispersed with similar density. The hypothalamus had fewer outstanding cells compared with the thalamus. The red nucleus, the substantia nigra, and the ventral tegmental area in the pretectum had outstanding cells. Motor cranial nuclei also had outstanding MD2-positive cells, whereas raphe, sensory cranial, and deep cerebellar nuclei had MD2-positive cells with moderate density. The presence of MD2 in these nuclei may suggest the involvement of MD2 in their corresponding physiological functions.