Electroacupuncture alleviates neuropathic pain by regulating hippocampal SP/NK1R/ARRB1 pathway. / 电针调控海马SP/NK1R/ARRB1é€šè·¯ç¼“è§£å¤§é¼ ç¥žç»ç— ç†æ€§ç–¼ç—›çš„ç ”ç©¶.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on pain, anxiety like behavior, and substance P(SP) /neurokinin-1 receptor (NK1R) /ß -arrestin 1(ARRB1) pathway related protein expression in hippocampus of chronic constriction injury (CCI) rats, so as to explore its mechanisms underlying improvement of neuropathic pain. METHODS: Twenty-seven male SD rats were randomly divided into sham operation, model and EA groups, with 9 rats in each group. The CCI model was established by ligature of the left sciatic nerve. On the 8th day following modeling, EA (2 Hz, 0.5-1.5 mA) was applied to the left "Huantiao" (GB34) and "Yanglingquan" (GB34) for 30 min, once every other day for 13 times. Mechanical paw withdrawal threshold (MWT), thermal paw withdrawal threshold (TWL) and difference of the weight distribution of the hind limbs were detected before operation and at the 5th, 9th, 17th, 25th and 33rd days after operation. Open field test was used to evaluate the anxiety-like behavior of rats. The content of SP in hippocampus was determined by ELISA. The protein expression of NK1R and ARRB1 in hippocampus was detected by Western blot. RESULTS: Compared with the sham operation group, the MWT and TWL of the left hind limb at the 5th, 9th, 17th, 25th and 33rd days after operation, the time of entering the central area and the total distance of movement, and the content of SP in the hippocampus were significantly decreased (P<0.001, P<0.01), while the difference of the weight distribution of the hind limbs at the 5th, 9th, 17th, 25th and 33rd days after operation and the protein expression of NK1R and ARRB1 were significantly increased (P<0.001, P<0.05) in the model group. After EA intervention, the MWT and TWL of the left hind limb, the time of entering the central area and the total moving distance, and the expression of SP in the hippocampus were significantly increased (P<0.01, P<0.001, P<0.05), while the difference in the weight distribution of the hind limbs was significantly reduced, and the expression of NK1R and ARRB1 protein in the hippocampus were significantly decreased (P<0.001, P<0.05) in the EA group. CONCLUSIONS: EA can effectively improve the pain and anxiety behaviors in CCI rats, and reverse the abnormal expression of SP, NK1R and ARRB1 proteins in the hippocampus, which may be related to its effects in regulating the SP/NK1R/ARRB1 pathway in the hippocampus.

Safety and Effectiveness of Brachial Artery Preclosure by Purse-String Suture Technique for Left Subclavian Artery Revascularization in Stanford B Aortic Dissection.

OBJECTIVES: To assess the safety and efficacy of the combination of brachial artery (BA) cutdown with purse-string suture (PSS) for BA preclosure during fenestrated thoracic endovascular aortic repair (f-TEVAR). METHODS: We reviewed the consecutive data in our center from January 2022 to May 2023. Clinical data were analyzed retrospectively, including the baseline characteristics, procedural details, complications, and outcomes. Dichotomous data were summarized as absolute values and percentages. Continuous variables were presented as median values and interquartile ranges (IQRs). All patients underwent arterial cutdown with the PSS technique for BA preclosure. The technique was considered successful when complete hemostasis was achieved and confirmed by ultrasonography 24 h postoperatively. The patients were followed up 30 days postoperatively for access-related complications. RESULTS: Forty-eight patients who underwent f-TEVAR with 48 BA access sites were included [36 males and 12 females; median age: 62 (IQR: 30-78) years]. The median body mass index was 27.3 (IQR: 21.2-32.7) kg/m2. The median access establishing and closing times were 7.8 (IQR: 6-9.3) min and 3.7 (IQR: 2.5-5) min, respectively. The median operative time and length of stay were 75 (IQR: 63-87) min and 7 (IQR: 5-9) days, respectively. Although the success rate was 100%, partial numbness in the median nerve distribution was noted in 1 patient in the forearm. This resolved spontaneously and no permanent neurological problem was seen. No other access-related complications were noted, and the total complication rate was 2.1% (1/48). CONCLUSIONS: BA preclosure with the PSS technique is safe and effective for left subclavian artery revascularization in Stanford B aortic dissection and can be another option for access closure during f-TEVAR.

Serotonergic modulation of vigilance states in zebrafish and mice.

Vigilance refers to being alertly watchful or paying sustained attention to avoid potential threats. Animals in vigilance states reduce locomotion and have an enhanced sensitivity to aversive stimuli so as to react quickly to dangers. Here we report that an unconventional 5-HT driven mechanism operating at neural circuit level which shapes the internal state underlying vigilance behavior in zebrafish and male mice. The neural signature of internal vigilance state was characterized by persistent low-frequency high-amplitude neuronal synchrony in zebrafish dorsal pallium and mice prefrontal cortex. The neuronal synchronization underlying vigilance was dependent on intense release of 5-HT induced by persistent activation of either DRN 5-HT neuron or local 5-HT axon terminals in related brain regions via activation of 5-HTR7. Thus, we identify a mechanism of vigilance behavior across species that illustrates the interplay between neuromodulators and neural circuits necessary to shape behavior states.

Dual Suture Versus Suture and Plug Closure Devices for Large Bore Access Haemostasis During Percutaneous Access Endovascular Aneurysm Repair.

PURPOSE: This study aimed to compare a dual Proglide strategy versus a combination of one Proglide and dual Exoseal for large-bore access closure during percutaneous access endovascular aneurysm repair (pEVAR). MATERIALS AND METHODS: We retrospectively analyzed 97 patients who underwent pEVAR at our center between January 2021 and February 2023. The patients were divided into two groups: dual Proglide (P + P) and one Proglide with dual Exoseal (P + E). The primary outcome measures were technical success and access-related vascular complications. Technical success was defined as achieving complete hemostasis without a bailout strategy. Postprocedural follow-up for access-related vascular complications was evaluated at 30 and 60 days using computed tomography angiography and ultrasonography. Severity was graded according to the Cardiovascular Interventional Radiological Society of Europe (CIRSE) Classification. RESULTS: Overall, a dual Proglide strategy was used in 46 patients (47.4%) with 65 groins (46.4%), and a combination of one Proglide and dual Exoseal was used in 51 patients (52.6%) with 75 groins (53.6%). The baseline characteristics were similar between the groups. The total technical success rate was 96.4%, and no significant differences were observed (95.4% vs. 97.3%; p = 0.870). Minor bleeding treatable through compression occurred significantly more often in the P group (CIRSE 1, 10.8% vs. 1.3%, p = 0.042). Hemostasis time, procedural time, length of stay in the hospital, closure device failure, and incidence of unplanned intervention did not differ significantly between the groups. CONCLUSIONS: A combined Proglide and Exoseal strategy is safe and effective for large-bore access closure during pEVAR and can be considered an alternative. However, it should be supported by larger prospective studies.

[One-pot synthesis of a poly(styrene-acrylic acid) copolymer-modified silica stationary phase and its applications in mixed-mode liquid chromatography].

As modified ligands with a wide range of sources, abundant functional groups, and good biocompatibility, polymers have been widely used in the development of silica-based chromatographic stationary phases. In this study, a poly(styrene-acrylic acid) copolymer-modified silica stationary phase (SiO2@P(St-b-AA)) was prepared via one-pot free-radical polymerization. In this stationary phase, styrene and acrylic acid were used as functional repeating units for polymerization and vinyltrimethoxylsilane (VTMS) was used as a silane coupling agent to link the copolymer and silica. Various characterization methods, such as Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), scanning electron microscopy (SEM), N2 adsorption-desorption analysis, and Zeta potential analysis, confirmed the successful preparation of the SiO2@P(St-b-AA) stationary phase, which had a well-maintained uniform spherical and mesoporous structure. The retention mechanisms and separation performance of the SiO2@P(St-b-AA) stationary phase in multiple separation modes were then evaluated. Hydrophobic and hydrophilic analytes as well as ionic compounds were selected as probes for different separation modes, and changes in the retention of the analytes under various chromatographic conditions, including different methanol or acetonitrile contents and buffer pH values, were investigated. In reversed-phase liquid chromatography (RPLC) mode, the retention factors of alkyl benzenes and polycyclic aromatic hydrocarbons (PAHs) on the stationary phase decreased with increasing methanol content in the mobile phase. This finding could be attributed to the hydrophobic and π-π interactions between the benzene ring and analytes. The retention changes of alkyl benzenes and PAHs revealed that the SiO2@P(St-b-AA) stationary phase, similar to the C18 stationary phase, exhibited a typical reversed-phase retention behavior. In hydrophilic interaction liquid chromatography (HILIC) mode, as the acetonitrile content increased, the retention factors of hydrophilic analytes gradually increased, and a typical hydrophilic interaction retention mechanism was inferred. In addition to hydrophilic interaction, the stationary phase also demonstrated hydrogen-bonding and electrostatic interactions with the analytes. Compared with the C18 and Amide stationary phases prepared by our groups, the SiO2@P(St-b-AA) stationary phase exhibited excellent separation performance for the model analytes in the RPLC and HILIC modes. Owing to the presence of charged carboxylic acid groups in the SiO2@P(St-b-AA) stationary phase, exploring its retention mechanism in ionic exchange chromatography (IEC) mode is of great importance. The effect of the mobile phase pH on the retention time of organic bases and acids was further studied to explore the electrostatic interaction between the stationary phase and charged analytes. The results revealed that the stationary phase has weak cation exchange ability toward organic bases and electrostatically repels organic acids. Moreover, the retention of organic bases and acids on the stationary phase was influenced by the analyte structure and mobile phase. Thus, the SiO2@P(St-b-AA) stationary phase could provide multiple interactions, as demonstrated by the separation modes described above. The SiO2@P(St-b-AA) stationary phase showed excellent performance and reproducibility in the separation of mixed samples with different polar components, indicating that it has promising application potential in mixed-mode liquid chromatography. Further investigation of the proposed method confirmed its repeatability and stability. In summary, this study not only described a novel stationary phase that could be used in RPLC, HILIC, and IEC modes but also presented a facile "one-pot" preparation approach that could provide a new route for the development of novel polymer-modified silica stationary phases.

From bench to bedside: targeting lymphocyte activation gene 3 as a therapeutic strategy for autoimmune diseases.

BACKGROUND: Immune checkpoints negatively regulate immune response, thereby playing an important role in maintaining immune homeostasis. Substantial studies have confirmed that blockade or deficiency of immune checkpoint pathways contributes to the deterioration of autoimmune diseases. In this context, focusing on immune checkpoints might provide alternative strategies for the treatment of autoimmunity. Lymphocyte activation gene 3 (LAG3), as a member of immune checkpoint, is critical in regulating immune responses as manifested in multiple preclinical studies and clinical trials. Recent success of dual-blockade of LAG3 and programmed death-1 in melanoma also supports the notion that LAG3 is a crucial regulator in immune tolerance. METHODS: We wrote this review article by searching the PubMed, Web of Science and Google Scholar databases. CONCLUSION: In this review, we summarize the molecular structure and the action mechanisms of LAG3. Additionally, we highlight its roles in diverse autoimmune diseases and discuss how the manipulation of the LAG3 pathway can serve as a promising therapeutic strategy as well as its specific mechanism with the aim of filling the gaps from bench to bedside.

Preparation of polyacrylamide hydrophilic stationary phases with adjustable performance.

Polymer modified silica materials are widely used as stationary phases in hydrophilic interaction liquid chromatography (HILIC), whereas a stationary phase with excellent performance is highly desired. In this study, vinyl modified silica was first synthesized through a silane coupling reaction, and then a polyacrylamide modified silica (PAM-SIL) stationary phase was successfully prepared using acrylamide as a copolymer monomer via free radical polymerization. The retention behaviors of polar analytes on the stationary phase under various chromatographic conditions, including acetonitrile content, buffer concentration and pH values were investigated, and a typical hydrophilic interaction retention mechanism was inferred. Exceptionally, the separation performance of the stationary phases could be regulated by controlling the polymer structure. Model analytes separated rapidly on the stationary phase which has an optimal grafting amount of vinyl, with the highest number of theoretical plates of orotic acid reaching 119,966/m. While the stationary phases with high acrylamide concentrations exhibited enhanced retention behavior and higher resolution for analytes. The adjustable separation performance will have huge potential in future separation and analysis applications.

Corrigendum: Smaller baseline subcortical infarct volume predicts good outcomes in patients with a large core in early acute ischemic stroke after endovascular treatment.

[This corrects the article DOI: 10.3389/fnins.2023.1063478.].

Fluorido-bridged robust metal-organic frameworks for efficient C2H2/CO2 separation under moist conditions.

The modern technology for acetylene production is inevitably accompanied by the contamination of carbon dioxide and moisture impurities. Metal-organic frameworks (MOFs), with rational configurations of fluorine as the hydrogen-bonding acceptor (HBA), exhibit excellent affinities to capture acetylene from the gas mixtures. Currently, most research studies feature anionic fluorine groups as structural pillars (e.g., SiF6 2-, TiF6 2-, NbOF5 2-), whereas in situ insertion of fluorine into metal clusters is rather challenging. Herein, we report a unique fluorine-bridged Fe-MOF, i.e., DNL-9(Fe), which is assembled by mixed-valence FeIIFeIII clusters and renewable organic ligands. The fluorine species in the coordination-saturated structure offer superior C2H2-favored adsorption sites facilitated by hydrogen bonding, with a lower C2H2 adsorption enthalpy than other reported HBA-MOFs, demonstrated by static/dynamic adsorption tests and theoretical calculations. Importantly, DNL-9(Fe) shows exceptional hydrochemical stability under aqueous, acidic, and basic conditions, and its intriguing performance for C2H2/CO2 separation was even maintained at a high relative humidity of 90%.

Smaller baseline subcortical infarct volume predicts good outcomes in patients with a large core in early acute ischemic stroke after endovascular treatment.

Background: Patients with acute ischemic stroke (AIS) and a large core may benefit from endovascular treatment (EVT) in the early time window. Purpose: To examine the prognostic factors for good outcomes in patients with a large core (70-130 ml) after EVT. Materials and methods: We retrospectively reviewed 40 patients who met the criteria from October 2019 to April 2021. Based on the modified Rankin Score (mRS) at 90 days, the patients were divided into a good outcome group (mRS 0-2) and a poor outcome group (mRS 3-6). Baseline and procedural characteristics were collected for unilateral and multivariate regression analyses to explore the factors that influence good outcomes. In particular, the infarct territories were quantified as subcortical infarct volume (SIV) and cortical infarct volume (CIV). Results: Of the 40 patients included, good outcomes were observed in 11 (27.5%) patients. Younger age, smaller SIV and larger mismatch volume were noted in the good outcome group than in the poor outcome group (all P < 0.05). Multivariate logistic regression analysis showed that only a smaller SIV [odds ratio (OR) 0.801; 95% CI 0.644-0.996; P = 0.046] was an independent predictor for good outcomes. The receiver operating characteristic curve indicated a moderate value of SIV for predicting good outcomes, with an area under the receiver operating characteristic curve of 0.735 (95% CI 0.572-0.862; P = 0.007). Conclusion: Subcortical infarct volume was a potential useful predictor of good outcomes in patients with a large core after EVT in the early time window.

Correction: Fluorido-bridged robust metal-organic frameworks for efficient C2H2/CO2 separation under moist conditions.

[This corrects the article DOI: 10.1039/D2SC06699H.].

Predictive value of computed tomography perfusion for acute ischemic stroke patients with ASPECTS < 6 in an early time window.

OBJECTIVE: The standard for computed tomography perfusion (CTP) assessment has not been well established in early acute ischemic stroke (AIS). We aimed to examine the prognostic factors for good outcomes in patients who received CTP, with an Alberta Stroke Program Early CT Score (ASPECTS) < 6 after endovascular thrombectomy (EVT) in the early time window (0-6 h). METHODS: We retrospectively reviewed 59 patients who met the criteria from October 2019 to April 2021. Based on the modified Rankin Score (mRS) at 90 days, the patients were divided into a good outcome group (mRS 0-2) and a poor outcome group (mRS 3-6). Baseline and procedural characteristics were collected for unilateral and multivariate regression analyses to explore the influencing factors for good outcomes. RESULTS: Of the 59 patients included, good outcomes were observed in 21 (35.6%). Multivariate logistic regression analysis showed that smaller ischemic core volume (odds ratio [OR]: 0.950; 95% CI: 0.908-0.994; P = 0.026), lower National Institutes of Health Stroke Scale (NIHSS) score (OR: 0.750; 95% CI: 0.593-0.949; P = 0.017) and shorter stroke onset to reperfusion time (ORT) (OR: 0.981; 95% CI: 0.966-0.996; P = 0.016) were independent predictors for good outcomes at 90 days. CONCLUSION: Smaller ischemic core volume based on CTP, lower NIHSS score and shorter ORT were significant independent predictors of good outcomes in patients with ASPECTS < 6 in the early time window after EVT.

Circuit reconstruction of newborn neurons after spinal cord injury in adult rats via an NT3-chitosan scaffold.

An implanted neurotrophin-3 (NT3)-chitosan scaffold can recruit endogenous neural stem cells to migrate to a lesion region and differentiate into mature neurons after adult spinal cord injury (SCI). However, the identities of these newborn neurons and whether they can form functional synapses and circuits to promote recovery after paraplegia remain unknown. By using combined advanced technologies, we revealed here that the newborn neurons of several subtypes received synaptic input from the corticospinal tract (CST), rubrospinal tract (RST), and supraspinal tracts. They formed a functional neural circuit at the injured spinal region, further driving the local circuits beneath the lesion. Our results showed that the NT3-chitosan scaffold facilitated the maturation of spinal neurons and the reestablishment of the spinal neural circuit in the lesion region 12 weeks after SCI. Transsynaptic virus experiments revealed that these newborn spinal neurons received synaptic connections from the CST and RST and drove the neural circuit beneath the lesion via newly formed synapses. These re-established circuits successfully recovered the formation and function of the neuromuscular junction (NMJ) beneath the lesion spinal segments. These findings suggest that the NT3-chitosan scaffold promotes the formation of relay neural circuits to accommodate various types of brain descending inputs and facilitate functional recovery after paraplegia.

Prognostic nomogram for acute pancreatitis after percutaneous biliary stent insertion in patients with malignant obstruction.

OBJECTIVE: This study aimed to develop and validate a nomogram to predict the risk of pancreatitis after percutaneous transhepatic biliary stent insertion (PTBS) in patients with malignant biliary obstruction (MBO). MATERIALS AND METHODS: We enrolled 314 patients who underwent PTBS for MBO from March 2016 to July 2021 in this retrospective study. We used univariate analysis to identify potential risk factors, while a multivariate logistic regression model was employed to establish a nomogram for predicting the risk of pancreatitis. The discrimination and calibration of the nomogram were evaluated by estimating the area under the receiver operator characteristic curve (AUC) and by bootstrap resampling and visual inspection of the calibration curve. The clinical utility of the nomogram was assessed using decision curve analysis (DCA). RESULTS: After the procedure, 41 (13.1%) patients developed pancreatitis. Based on multivariate logistic regression analysis, young age (OR = 2.57, 95% CI 1.16 to 5.69), stent insertion across the papilla (OR = 6.47, 95% CI 2.66 to 15.70), and visualization of the pancreatic duct (OR = 15.40, 95% CI 6.07 to 39.03) were associated with an elevated risk of pancreatitis. Importantly, the performance of the nomogram was satisfactory, with an identical AUC (0.807, 95% CI 0.730 to 0.883) and high-level agreement between predicted and observed probabilities as suggested in calibration curves. The DCA curve subsequently confirmed the clinical utility. CONCLUSION: A predictive nomogram for pancreatitis after PTBS in patients with MBO was successfully established in the present study.

Acupuncture ameliorates breast cancer-related fatigue by regulating the gut microbiota-gut-brain axis.

Cancer-related fatigue (CRF) is the most common side effect of chemotherapy for breast cancer (BC). Acupuncture treatment has an anti-fatigue effect and can regulate gut microbiota disturbance in fatigue patients. Related studies have shown that the gut microbiota-gut-brain axis is closely related to the occurrence of CRF. In this study, we first investigated the alterations of acupuncture on fatigue-like behavior, gut microbiota, gut inflammation and neuroinflammation response, gut barriers, HPA axis, and serum metabolomics in CRF mice after BC chemotherapy. Then, the correlation analysis of gut microbiota and other indicators was discussed. Our results showed that acupuncture treatment could exert an anti-fatigue effect and ameliorate the gut barrier, gut inflammation, neuroinflammation, and dysfunction of the HPA axis in CRF mice after chemotherapy for BC. 16S rRNA sequencing showed that acupuncture treatment could enhance the abundance of Candidatus Arthromitus, Lactobacillus, and Clostridia_UCG-014_unclassified and decrease the abundances of Escherichia-Shigella, Burkholderia-Caballeronia-Paraburkholderia, and Streptococcus. Serum metabolomics analysis showed that acupuncture treatment could regulate the differential metabolites N-methylnicotinamide, beta-glycerophosphoric acid, geranyl acetoacetate, serotonin and phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine, and beta-alanine metabolic pathways. Correlation analysis indicated that there are certain correlations between gut microbiota and gut inflammation, neuroinflammation, gut barrier, HPA axis function and serum metabolites. In conclusion, our findings revealed that the anti-fatigue mechanism of acupuncture treatment may be closely related to the gut microbiota-gut-brain axis. This study also provided a new reference for basic and clinical research on CRF after breast cancer chemotherapy.

Innate immune stimulation prevents chronic stress-induced depressive and anxiogenic-like behaviors in female mice.

It has been reported that pre-stimulation of the innate immune system can prevent depressive and anxiogenic-like behaviors in chronically stressed male mice. However, it is unclear whether similar effects can be observed in female animals. In the present study, we investigated this question in female mice. Our results showed that a single injection of lipopolysaccharide (LPS; 100 µg/kg) one day before stress exposure prevented increased immobility time in the tail suspension test and forced swimming test and decreased sucrose intake in the sucrose preference test in chronic unpredictable stress (CUS)-treated female mice. The single LPS pre-injection (100 µg/kg) prevented the CUS-induced decrease in (i) time spent in open arms and number of entries into open arms in the elevated plus maze test, (ii) time spent in lit side in the light-dark test, and (iii) time spent in the central region of the open field in the open field test, along with no changes in locomotor activity. It was also found that the single LPS pre-injection in female mice prevented the CUS-induced increase in the expression levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6 mRNA in the hippocampus and medial prefrontal cortex. Inhibition of innate immune system stimulation by minocycline pretreatment abrogated the preventive effect of LPS on CUS-induced depressive and anxiogenic-like behaviors and neuroinflammatory responses in the hippocampus and medial prefrontal cortex in female mice. These results suggest that pre-stimulation of the innate immune system by LPS injection may prevent the development of behavioral abnormalities in female mice.

The Clinical Observation and Mechanism of Acupuncture on Cancer-Related Fatigue of Breast Cancer Based on "Gut-Brain Axis": Study Protocol for a Randomized Controlled Trial.

Background. Cancer-related fatigue (CRF) is a painful, persistent feeling of physical and cognitive subjective fatigue related to cancer or cancer remedy. The occurrence of CRF may be related to the hypothalamic-pituitary-adrenaline (HPA) axis, inflammatory mediator theory, and gut microbiota. Moreover, acupuncture could play a vital part in the therapy of CRF. The study will evaluate whether acupuncture can improve fatigue symptoms of CRF patients after breast cancer chemotherapy by regulating the gut-brain axis. Methods/design. Seventy patients with CRF will be enrolled in this study, with 35 patients randomly assigned to each group. Blood and feces will be collected at the beginning and end of treatment. Piper fatigue scale, KPS score scale, and quality-of-life scale will be used to observe the changes of fatigue symptoms and life quality of CRF patients and to evaluate the effect of acupuncture on CRF. Then, the method of ELISA will be used to explore the regulatory effect of acupuncture on the HPA axis and inflammatory cytokines. Moreover, based on 16SrDNA, the changes of gut microbiota structure and flora of CRF patients will be observed. Ultimately, the correlation analysis of gut microbiota can be related to inflammatory cytokines, HPA axis, and clinical efficacy evaluation. Discussion. This study will identify the effect and the mechanism of acupuncture therapy in CRF. And it will offer an alternative treatment modality for the treatment of CRF after chemotherapy for breast cancer. Furthermore, it will also provide the clinical and theoretical bases for the extensive application of acupuncture therapy in tumor rehabilitation. Trial Status. Protocol version number and date: V2.0, 6 May 2021. The trial is registered with the Chinese Clinical Trial Registry on 20 June 2021 (trial identifier: ChiCTR2100047510).

Innate immune stimulation prevents the development of anxiety-like behaviors in chronically stressed mice.

Anxiety is a common psychological disease which can induce severe social burdens. Searching methods that prevent the onset of anxiety is of great significance for ameliorating the social and individual problems induced by this type of disease. In this study, we investigated how innate immune pre-stimulation influences the anxiety-like behaviors in chronically stressed mice. Our results showed that a single injection of an innate immune stimulant lipopolysaccharide (LPS) at the dose of 50, 100, and 500 µg/kg 1 day before stress exposure prevented chronic social defeat stress (CSDS)-induced anxiety-like behaviors in mice. A single injection of LPS (100 µg/kg) 5 days before stress exposure produced similar preventive effects on CSDS-induced anxiety-like behaviors, while similar effects were not observed at the condition of 10-days interval between LPS injection and stress exposure. A second LPS injection 10 days after the first LPS injection or a 4 × LPS injection 10 days before stress exposure also prevented CSDS-induced anxiety-like behaviors. Moreover, a single injection of LPS (100 µg/kg) 1 day before stress exposure prevented the production of pro-inflammatory cytokines in the hippocampus and prefrontal cortex of CSDS mice. Suppression of innate immune stimulation by minocycline pretreatment simultaneously abrogated the preventive effect of LPS pre-injection (100 µg/kg) on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine production in the brain. Our results demonstrated that the pre-stimulation of the innate immune system can prevent the development of anxiety-like behaviors and the progression of the neuroinflammatory responses in the brain in chronically stressed mice.

A comprehensive understanding about the pharmacological effect of diallyl disulfide other than its anti-carcinogenic activities.

Diallyl disulfide (DADS), an oil-soluble sulfur compound that is responsible for the biological effects of garlic, displays numerous biological activities, among which its anti-cancer activities are the most famous ones. In recent years, the pharmacological effects of DADS other than its anti-carcinogenic activities have attracted numerous attentions. For example, it has been reported that DADS can prevent the microglia-mediated neuroinflammatory response and depression-like behaviors in mice. In the cardiovascular system, DADS administration was found to ameliorate the isoproterenol- or streptozotocin-induced cardiac dysfunction via the activation of the nuclear factor E2-related factor 2 (Nrf2) and insulin-like growth factor (IGF)-phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signaling. DADS administration can also produce neuroprotective effects in animal models of Alzheimer's disease and protect the heart, endothelium, liver, lung, and kidney against cellular or tissue damages induced by various toxic factors, such as the oxidized-low density lipoprotein (ox-LDL), carbon tetrachloride (CCl4), ethanol, acetaminophen, Cis-Diammine Dichloroplatinum (CisPt), and gentamicin. The major mechanisms of action of DADS in disease prevention and/or treatment include inhibition of inflammation, oxidative stress, and cellular apoptosis. Mechanisms, including the activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase A (PKA), and cyclic adenosine monophosphate-response element binding protein (CREB) and the inhibition of histone deacetylases (HDACs), can also mediate the cellular protective effects of DADS in different tissues and organs. In this review, we summarize and discuss the pharmacological effects of DADS other than its anti-carcinogenic activities, aiming to reveal more possibilities for DADS in disease prevention and/or treatment.

Tolerance-inducing effect and properties of innate immune stimulation on chronic stress-induced behavioral abnormalities in mice.

Over-activation of the innate immune system constitutes a risk factor for the development of nervous system disorders but may reduce the severity of these disorders by inducing tolerance effect. Here, we studied the tolerance-inducing effect and properties of innate immune stimulation on chronic social defeat stress (CSDS)-induced behavioral abnormalities in mice. A single injection of the innate immune enhancer lipopolysaccharide (LPS) one day before stress exposure prevented CSDS-induced impairment in social interaction and increased immobility time in the tail suspension test and forced swimming test. This effect was observed at varying doses (100, 500, and 1000 µg/kg) and peaked at 100 µg/kg. A single LPS injection (100 µg/kg) either one or five but not ten days before stress exposure prevented CSDS-induced behavioral abnormalities. A second LPS injection ten days after the first LPS injection, or a 2 × or 4 × LPS injections ten days before stress exposure also induced tolerance against stress-induced behavioral abnormalities. Our results furthermore showed that a single LPS injection one day before stress exposure skewed the neuroinflammatory response in the hippocampus and prefrontal cortex of CSDS-exposed mice toward an anti-inflammatory phenotype. Inhibiting the central innate immune response by pretreatment with minocycline or PLX3397 abrogated the tolerance-inducing effect of LPS preconditioning on CSDS-induced behavioral abnormalities and neuroinflammatory responses in the brain. These results provide evidence for a prophylactic effect of innate immune stimulation on stress-induced behavioral abnormalities via changes in microglial activation, which may help develop novel strategies for the prevention of stress-induced psychological disorders.