Vanadium pentoxide interfacial layer enables high performance all-solid-state thin film batteries.

Lithium cobalt oxide (LiCoO2) is considered as one of the promising building blocks that can be used to fabricate all-solid-state thin film batteries (TFBs) because of its easy accessibility, high working voltage, and high energy density. However, the slow interfacial dynamics between LiCoO2 and LiPON in these TFBs results in undesirable side reactions and severe degradation of cycling and rate performance. Herein, amorphous vanadium pentoxide (V2O5) film was employed as the interfacial layer of a cathode-electrolyte solid-solid interface to fabricate all-solid-state TFBs using a magnetron sputtering method. The V2O5 thin film layer assisted in the construction of an ion transport network at the cathode/electrolyte interface, thus reducing the electrochemical redox polarization potential. The V2O5 interfacial layer also effectively suppressed the side reactions between LiCoO2 and LiPON. In addition, the interfacial resistance of TFBs was significantly decreased by optimizing the thickness of the interfacial modification layer. Compared to TFBs without the V2O5 layer, TFBs based on LiCoO2/V2O5/LiPON/Li with a 5 nm thin V2O5 interface modification layer exhibited a much smaller charge transfer impedance (Rct) value, significantly improved discharge specific capacity, and superior cycling and rate performance. The discharge capacity remained at 75.6% of its initial value after 1000 cycles at a current density of 100 µA cm-2. This was mainly attributed to the enhanced lithium ion transport kinetics and the suppression of severe side reactions at the cathode-electrolyte interface in TFBs based on LiCoO2/V2O5/LiPON/Li with a 5 nm V2O5 thin layer.

Saikosaponin B2 ameliorates depression-induced microglia activation by inhibiting ferroptosis-mediated neuroinflammation and ER stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Saikosaponins B2 (SSB2) is one of the main active components isolated from Radix Bupleuri (Bupleurum chinense DC.), a herb widely used of traditional Chinese medicine. It has been used for the treatment of depression for more than two thousand years. However, the molecular mechanisms remain to be determined. AIM OF THE STUDY: In this study, we evaluated the anti-inflammatory effect and elucidated underlying molecular mechanisms of SSB2 in LPS-induced primary microglia and CUMS-induced mice model of depression. METHOD: The effects of SSB2 treatment were investigated both in vitro and in vivo. The chronic unpredictable mild stimulation (CUMS) procedure was applied to establish the animal model of depression. Behavioural tests were used to evaluate the depressive-like behaviors in CUMS-exposed mice, including sucrose preference test, open field test, tail suspension test, and forced swimming test. The GPX4 gene of microglia was silenced using shRNA, and inflammatory cytokines were determined by Western Blot and immunofluorescence analysis. Endoplasmic reticulum stress and ferroptosis-related markers were detected by qPCR, flow cytometry and confocal microscopy. RESULT: SSB2 reversed depressive-like behaviours in CUMS-exposed mice and relieved central neuroinflammation and ameliorated hippocampal neural damage. SSB2 alleviated LPS-induced activation of microglia through the TLR4/NF-κB pathway. LPS-induced ferroptosis, with increased levels of ROS, intracellular Fe2+, mitochondrial membrane potential, lipid peroxidation, GSH, SLC7A11, FTH, GPX4 and Nrf2, and decreased transcription levels of ACSL4 and TFR1, was attenuated with SSB2 treatment in primary microglia cells. GPX4 knockdown activated ferroptosis, induced endoplasmic reticulum (ER) stress, and abrogated the protective effects of SSB2. Further, SSB2 attenuated ER stress, balanced calcium homeostasis, reduced lipid peroxidation and intracellular Fe2+ content by regulating the level of intracellular Ca2+. CONCLUSIONS: Our study suggested that SSB2 treatment can inhibit ferroptosis, maintain calcium homeostasis, relieve endoplasmic reticulum stress and attenuate central neuroinflammation. SSB2 exhibited anti-ferroptosis and anti-neuroinflammatory effects through the TLR4/NF-κB pathway in a GPX4-dependent manner.

Safety, pharmacokinetics and pharmacodynamics of a novel γ-aminobutyric acid (GABA) receptor potentiator, HSK3486, in Chinese patients with hepatic impairment.

BACKGROUND: The primary objective of this study was to investigate if hepatic impairment alters the safety, pharmacokinetics, and pharmacodynamics of HSK3486. RESEARCH DESIGN AND METHODS: This was a clinical trial of HSK3486 in subjects with normal hepatic function (n = 8), and mild (Child-Pugh A; n = 8), or moderate (Child-Pugh B; n = 8) hepatic impairment. Each subject received an IV bolus dose of 0.4 mg/kg HSK3486 for 1 min, immediately followed by a maintenance infusion of 0.4 mg/kg/h HSK3486 for 30 min. RESULTS: In total, 24 subjects were enrolled and completed the study. HSK3486 was generally well tolerated by all subjects. There were no serious AEs and no deaths reported during the study. The incidence of AEs was numerically highest in subjects with moderate hepatic impairment. The exposure (AUC) of HSK3486 increased gradually with the decrease in hepatic function; however, degree of hepatic impairment had little effect on HSK3486 PD (MOAA/S and BIS). CONCLUSIONS: Overall, there were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to normal control. These data imply that HSK3486 dose adjustment is not warranted in subjects with mild or moderate hepatic impairment. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04145596).Key MessageHSK3486 at an IV bolus dose of 0.4 mg/kg and a maintenance infusion of 0.4 mg/kg/h was safe and well tolerated by all mild or moderate hepatic impairment subjects and normal hepatic function subjects.There were no clinically relevant differences in HSK3486 exposure or PD in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function.HSK3486 dose adjustment is not required in subjects with mild or moderate hepatic impairment.

Examining the Effects of Installed Capacity Mix and Capacity Factor on Aggregate Carbon Intensity for Electricity Generation in China.

Promoting technological advancements and energy transitions in electricity generation are crucial for achieving carbon reduction goals. Some studies have examined the effectiveness of these measures by analysing the driving forces of "aggregate carbon intensity" (ACI) change. However, only a few studies have considered the effect of the installed capacity mix and capacity factor. Moreover, such analysis has never been applied at China's provincial level after 2015. To alleviate this gap, our study applied a temporal and multi-regional spatial IDA-LMDI model to analyse the driving factors of ACI changes and disparities among the provinces of China from 2005 to 2019. The model notably includes the effects of the installed capacity mix, thermal capacity factor, and overall capacity factor. The analysis revealed that the decline in China's ACI was diminished after 2015, while an ACI rebound was identified in five provinces. The changes in the ACI from 2015 to 2019 were mainly driven by the effect of the installed capacity mix rather than by the thermal efficiency and thermal capacity factor. The overall capacity factor was the only factor with a negative impact on the ACI change. We also found that its combined effect with the thermal capacity factor on increasing ACI can offset the effect of the installed capacity mix by reducing the ACI in provinces with significant additions of renewable energy installed capacity. The analysis of the influencing factors on the provincial ACI differences revealed that the share of hydropower installed capacity was significant. Moreover, the thermal efficiency and thermal capacity factor both played key roles in the ACI disparities in northeast, northwest, and central China. Overall, this study paves the way for data-driven measures of China's carbon peak and carbon neutrality goals by improving the capacity factor of wind and solar power, leveraging the critical impact of hydropower, and narrowing the differences in the thermal power sector among provinces.

Retraction notice to "Neuroprotective effect of Liuwei Dihuang decoction on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat" [J. Ethnopharmacol. 150 (2013) 371-381].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The authors have plagiarized/duplicated part of a paper that appeared in Neurosci Lett, 549 (2013) 63-68, (https://doi.org/10.1016/j.neulet.2013.06.002). Several images in the Journal of Ethnopharmacology paper; 3A, 3B, 4A, 4B correspond to figures; 2A, 2B, 3A and 3B respectively as published in Neuroscience Letters. One of the conditions of submission of a paper for publication is that authors declare explicitly that their work is original and has not appeared in a publication elsewhere. Re-use of any data should be appropriately cited. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

Safety, Pharmacokinetics, and Pharmacodynamics of a Single Bolus of the γ-aminobutyric Acid (GABA) Receptor Potentiator HSK3486 in Healthy Chinese Elderly and Non-elderly.

Background: The present clinical trial investigated the potential influences of dosage and age on the pharmacokinetic properties and safety profile of HSK3486, and whether any adjustment in dosing regimen is necessary in elderly patients. Methods: Twenty-four elderly participants (65-73 years) were apportioned to three equal cohorts to receive a single IV bolus of 0.2, 0.3, and 0.4 mg/kg HSK3486, respectively. An additional control group comprised eight non-elderly participants (21-44 years), who each received a single IV bolus dose of 0.4 mg/kg. Safety was assessed throughout the study, and the clinical effects were assessed based on modified observer's assessment of alertness/sedation and bispectral index (BIS) monitor. Pharmacokinetic parameters were calculated. Results: The rates of drug-related adverse reactions among the elderly groups were a little higher than that of the non-elderly, and were slightly higher in the elderly receiving 0.4 mg/kg compared with the elderly given lower doses. The pharmacokinetic characteristics of 0.4 mg/kg HSK3486 in the elderly and non-elderly were comparable. The time to recovery was similar in elderly 0.3 mg/kg, elderly 0.4 mg/kg and non-elderly 0.4 mg/kg groups. In the elderly 0.2 mg/kg group, the time to loss of consciousness was a little longer, and the time to recovery was shorter, relative to the other three groups. Conclusions: Administration of 0.3 mg/kg to the elderly and 0.4 mg/kg to the non-elderly were similarly efficacious. A dose of HSK3486 of 0.3 mg/kg may be chosen for clinical use in elderly patients.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects.

AIMS: This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. METHODS: A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. RESULTS: The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. CONCLUSION: HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.

A New Perspective on Ameliorating Depression-Like Behaviors: Suppressing Neuroinflammation by Upregulating PGC-1α.

Inflammation plays an important role in depression pathology, making it a promising target for ameliorating depression-like behaviors. The peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional coactivator being able to constrain inflammatory events through NF-κB signaling. However, the role of PGC-1α in depression is not yet clear. This study was designed to investigate the role of PGC-1α in depression and explore the underlying mechanisms. Mice modeled with chronic unpredictable mild stimulation (CUMS) were explored for the relationship between depression-like behaviors and PGC-1α. Baicalin was used to evaluate the effect regulating PGC-1α. Furthermore, the anti-neuroinflammatory effect of baicalin was investigated both in BV2-SH-SY5Y co-culture system and in mice by LPS challenge. The role of PGC-1α in neuroinflammation was explored in cell co-culture systems under gene silencing conditions targeting NF-κB signaling. We found that the expression of PGC-1α was inhibited in the hippocampus of mice exposed to CUMS or LPS, while baicalin could increase the expression of PGC-1α and alleviate the depression-like behaviors. Furthermore, baicalin attenuated neuroinflammation in the hippocampus of mice and BV2-SH-SY5Y co-culture system by LPS challenge via regulating NF-κB signaling; however, knockdown of the PGC-1α could reverse the effect of baicalin on neuroinflammation and NF-κB signaling. Our results revealed a vital role for PGC-1α in attenuating neuroinflammation in depression, indicating that PGC-1α might be a therapeutic target for depression.

Saikosaponin-d impedes hippocampal neurogenesis and causes cognitive deficits by inhibiting the survival of neural stem/progenitor cells via neurotrophin receptor signaling in mice.

Neural stem/progenitor cells (NPCs) are multipotent stem cells in the central nervous system. Damage to NPCs has been demonstrated to cause adverse effects on neurogenesis and to contribute to neurological diseases. Our previous research suggested that saikosaponin-d (SSd), a cytostatic drug belonging to the bioactive triterpenoid saponins, exhibited neurotoxicity by inhibiting hippocampal neurogenesis, but the underlying mechanism remained elusive. This study was performed to clarify the role of SSd in cognitive function and the mechanism by which SSd induced damage to hippocampal neurogenesis and NPCs. Our results indicated that SSd caused hippocampus-dependent cognitive deficits and inhibited hippocampal neurogenesis by reducing the numbers of newborn neurons in mice. RNA sequencing analysis revealed that SSd-induced neurotoxicity in the hippocampus involved neurotrophin receptor-interacting MAGE (NRAGE)/neurotrophin receptor interacting factor (NRIF)/p75NTR -associated cell death executor (NADE) cell signaling activated by the p75 neurotrophin receptor (p75NTR ). Mechanistic studies showed that a short hairpin RNA targeting p75NTR intracellular domain reversed SSd-increased NRAGE/NRIF/NADE signaling and the c-Jun N-terminal kinase/caspase apoptotic pathway, subsequently contributing to the survival of NPCs, as well as cell proliferation and differentiation. The addition of recombinant brain-derived neurotrophic factor (BDNF) ameliorated the SSd-induced inhibition of BDNF/Tyrosine kinase receptor B (TrkB) neurotrophic signaling, but did not affect SSd-activated pro-BDNF/p75NTR signaling. Moreover, the SSd-induced elevation of cytosolic Ca2+ concentration was responsible for damage to NPCs. The extracellular Ca2+ chelator ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), rather than the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM), attenuated SSd-induced cytosolic Ca2+ dysfunction and SSd-disordered TrkB/p75NTR signaling. Overall, this study demonstrated a new mechanism for the neurotoxic effect of SSd, which has emerging implications for pharmacological research of SSd and provides a better understanding of neurotoxicity induced by cytostatic drugs.

The Association Between Obesity and Risk of Acute Kidney Injury After Cardiac Surgery.

Objective: To determine the relationship between obesity and the risk of AKI after cardiac surgery (CS-AKI) in a cohort study. Methods: A total of 1,601 patients undergoing cardiac surgery were collected and their incidence of CS-AKI was recorded. They were divided into underweight, normal weight, overweight, and obese groups. Logistic regression was used to estimate the association between BMI (body mass index) and CS-AKI risk. Then, a meta-analysis of published cohort studies was conducted to confirm this result using PubMed and Embase databases. Results: A significant association was observed in this independent cohort after adjusting age, gender, hypertension and New York Heart Association classification (NYHA) class. Compared with normal BMI group (18.5 ≤ BMI < 24.0), the individuals with aberrant BMI level had an increased AKI risk (OR: 1.68, 95% CI: 1.01-2.78) for BMI < 18.5 group and (OR: 1.43, 95% CI: 0.96-2.15) for BMI ≥ 28.0. Interestingly, the U-shape curve showed the CS-AKI risk reduced with the increasing of BMI when BMI ≤ 24.0. As BMI increases with BMI > 24.0, the risk of developing CS-AKI increased significantly. In the confirmed meta-analysis, compared with normal weight, overweight group with cardiac surgery had higher AKI risk (OR: 1.28, 95% CI: 1.16-1.41, Pheterogeneity = 0.49). The similar association was found in obesity subgroup (OR: 1.79, 95% CI: 1.57-2.03, Pheterogeneity = 0.42). Conclusion: In conclusion, the results suggested that abnormal BMI was a risk factor for CS-AKI independently.

Saikosaponin-d attenuated lipopolysaccharide-induced depressive-like behaviors via inhibiting microglia activation and neuroinflammation.

Saikosaponin-d (SSd), a triterpenoid saponins compound extracted from Radix Bupleuri, has been demonstrated to effectively alleviate chronic mild stress-induced depressive behaviors in rats, but the underlying molecular mechanisms are still uncertain. Increasing evidence indicated that microglia activation and inflammatory responses were involved in the pathogenesis of depression. Thus, we desired to induce inflammation-related depressive-like behaviors in mice by injecting lipopolysaccharide (LPS) to investigate whether the antidepressant effect of SSd is related to inhibiting inflammation. The results of behavioral tests showed that SSd administration ameliorated LPS-induced depressive-like behaviors, as shown by increased sucrose consumption in the sucrose preference test and decreased immobility time in the tail suspension test and forced swimming test. Furthermore, immunostaining results showed that SSd pretreatment inhibited LPS-induced microglia activation in the hippocampus of mice and primary microglia cells. Enzyme-linked immunosorbent assay (ELISA) results showed that SSd pretreatment suppressed LPS-induced overexpression of inflammatory factors such as interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α both in vivo and in vitro. Immunostaining and western blot analysis results demonstrated that SSd pretreatment also inhibited LPS-induced HMGB1 translocation from nuclear to extracellular and decreased the protein levels of TLR4, p-IκB-α, NF-κBp65. These results suggested that SSd effectively improved LPS-induced inflammation-related depressive-like behaviors by inhibiting LPS-induced microglia activation and neuroinflammation, and the possible mechanism might associate with the regulation of the HMGB1/TLR4/NF-κB signaling pathway.

The synergistic effect of the PEO-PVA-PESf composite polymer electrolyte for all-solid-state lithium-ion batteries.

Blending with poly(vinyl alcohol) (PVA) and poly(oxyphenylene sulfone) (PESf) has been investigated to improve the properties of a polymer electrolyte based on a poly(ethylene oxide) (PEO) matrix. The composite electrolyte shows a high ionic conductivity of 0.83 × 10-3 S cm-1 at 60 °C due to the significant inhibition of crystallization caused by the synergistic effects of PVA and PESf. The symmetrical cell Li/CPE/Li is continuously operated for at least 200 hours at a current density of 0.1 mA cm-2 without the enhancement in the polarization potential. In addition, the all-solid-state LiFePO4/CPE/Li cells exhibit small hysteresis potential (about 0.10 V), good cycle stability and excellent reversible capacity (126 mA h g-1 after 100 cycles).

Formononetin Ameliorates Cognitive Disorder via PGC-1α Pathway in Neuroinflammation Conditions in High-Fat Diet-Induced Mice.

BACKGROUND: Alzheimer's disease is one of the most common neurodegenerative diseases in many modern societies. The core pathogenesis of Alzheimer's disease includes the aggregation of hyperphosphorylated Tau and abnormal Amyloid-ß generation. In addition, previous studies have shown that neuroinflammation is one of the pathogenesis of Alzheimer's disease. Formononetin, an isoflavone compound extracted from Trifolium pratense L., has been found to have various properties including anti-obesity, anti-inflammation, and neuroprotective effects. But there are very few studies on the treatment of Alzheimer's disease with Formononetin. OBJECTIVE: The present study focused on the protective activities of Formononetin on a high-fat dietinduced cognitive decline and explored the underlying mechanisms. METHODS: Mice were fed with HFD for 10 weeks and intragastric administrated daily with metformin (300 mg/kg) and Formononetin (20 and 40 mg/kg). RESULTS: We found that Formononetin (20, 40 mg/kg) significantly attenuated the learning and memory deficits companied by weight improvement and decreased the levels of blood glucose, total cholesterol and triglyceride in high-fat diet-induced mice. Meanwhile, we observed high-fat diet significantly caused the Tau hyperphosphorylation in the hippocampus of mice, whereas Formononetin reversed this effect. Additionally, Formononetin markedly reduced the levels of inflammation cytokines IL-1ß and TNF-α in high-fat diet-induced mice. The mechanism study showed that Formononetin suppressed the pro-inflammatory NF-κB signaling and enhanced the anti-inflammatory Nrf-2/HO-1 signaling, which might be related to the regulation of PGC-1α in the hippocampus of high-fat diet -induced mice. CONCLUSION: Taken together, our results showed that Formononetin could improve the cognitive function by inhibiting neuroinflammation, which is attributed to the regulation of PGC-1α pathway in HFD-induced mice.

Cyclocarya paliurus Triterpenoids Improve Diabetes-Induced Hepatic Inflammation via the Rho-Kinase-Dependent Pathway.

This study aimed to assess the effects of triterpene extract of Cyclocarya paliurus (Batal.) Iljinskaja (CPT) on diabetes-induced hepatic inflammation and to unveil the underlying mechanisms. Diabetes in db/db mice was alleviated after CPT administration, as assessed by the oral glucose tolerance test. In addition, treatment with CPT dramatically reduced serum insulin, aspartate amino-transaminase, alanine aminotransferase, triglyceride, and total cholesterol amounts. Besides, serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were also reduced after CPT administration. Western blot analysis revealed that CPT treatment significantly reversed the protein expression levels of Rho, ROCK1, ROCK2, p-P65, p-IκBα, p-IKKα, and p-IKKß in liver samples obtained from db/db mice. Upon palmitic acid stimulation, the protective effects of CPT on the liver were further assessed in HepG2 and LO2 cells, and no appreciable cytotoxic effects were found. Therefore, these findings indicate that CPT alleviates liver inflammation via Rho-kinase signaling. Chemical compounds evaluated in this report: Metformin (PubChem CID: 4091); Fasudil (PubChem CID: 3547); Palmitic acid (PubChem CID: 985).

Esculetin improves cognitive impairments induced by transient cerebral ischaemia and reperfusion in mice via regulation of mitochondrial fragmentation and mitophagy.

Mitochondrial dynamics regulate mitochondrial autophagy (mitophagy) and apoptosis, which are important events for the quality control of mitochondria and mitochondrial-associated diseases. Esculetin (ESC) is a natural coumarin that exhibits inspiring biological activities in a variety of animal models, but its neuroprotective effects on cerebral ischaemia have not been clearly elucidated. In this paper, we demonstrated the effects of ESC on transient cerebral ischaemia and reperfusion injury induced in a mouse model and examined the possible underlying mechanisms by investigating mitochondrial fragmentation-regulated mitochondrial autophagy and apoptosis. The experimental results showed that ESC treatment alleviated neurological defects and improved cognitive impairments in transient bilateral common carotid artery occlusion (tBCCAO)-treated mice. Further mechanism studies showed that tBCCAO induced mitochondrial oxidative stress injuries and triggered mitochondrial fragmentation, which were evident by the elevated levels of malondialdehyde and mitochondrial dynamin-related protein 1 (Drp1) and the downregulated activities of superoxide dismutase and nuclear transcription factor E2-related factor 2 (Nrf2). ESC treatment significantly alleviated tBCCAO-induced mitochondrial stress and mitochondrial fragmentation. Moreover, mitophagy and mitochondrial apoptosis were stimulated in response to the mitochondrial oxidative stress in the hippocampus of tBCCAO-treated mice, and ESC treatment regulated the expression of mitophagy-related factors, including Bnip3, Beclin1, Pink1, and parkin, the LC-3 II/I ratio, and apoptosis-related factors, including p53, Bax, and caspase 3. Taken together, our results suggest that ESC treatment regulated hippocampal mitophagy and mitochondrial apoptosis triggered by mitochondrial stress via the mediation of mitochondrial fragmentation during transient cerebral ischaemia and reperfusion injury, which provides insight into the potential of ESC for further therapeutic implications.

Modification of GSK3ß/ß-catenin signaling on saikosaponins-d-induced inhibition of neural progenitor cell proliferation and adult neurogenesis.

Saikosaponins-d (SSd) is a major bioactive compound isolated from Radix Bupleuri, an herb widely used in traditional Chinese medicine. Emerging studies demonstrate that SSd adversely affects adult neurogenesis and impairs learning and memory. However, the molecular mechanisms remain to be determined. The current study investigated the potential regulatory of GSK3ß/ß-catenin signaling on SSd-induced neurotoxicity. We demonstrated that SSd exposure inhibited the cell viability and proliferation of primary neuronal stem/progenitor cells (NPCs) from hippocampus in a concentration-dependent manner. Significantly, SSd exposure induced activation of GSK3ß and reduced the cellular ß-catenin in NPCs. Treatment with SB216763, a specific inhibitor for GSK3ß activation, we showed that inactivation GSK3ß improved the ß-catenin signaling by inhibiting degradation complex comprising Axin and APC and attenuated SSd-induced toxicity in NPCs. In addition, administration of SB216763 ameliorated SSd-induced inhibition of NPCs proliferation and enhanced radial glial cells in the hippocampus of mice. Moreover, inactivation GSK3ß promoted dendritic arborization and the survival of newborn neurons together with alleviated the impairment of SSd-induced cognitive function in mice. Overall, these data demonstrated that the significant inhibitory effects of SSd on NPCs proliferation and adult neurogenesis via GSK3ß/ß-catenin signaling pathway. Our results contribute to a better understanding of the molecular mechanisms of SSd-induced neurotoxicity.

Suppressing the Na+/H+ exchanger 1: a new sight to treat depression.

Na+/H+ exchanger 1 (NHE1), an important regulator of intracellular pH (pHi) and extracellular pH (pHe), plays a crucial role in various physiological and pathological processes. However, the role of NHE1 in depression has not yet been reported. This study was designed to investigate the role of NHE1 in the animal model of depression and explore the underlying mechanisms. Our results showed that inhibition of rho-associated kinase 2 (ROCK2) by fasudil (Fas) or baicalin (BA) significantly alleviated chronic unpredictable mild stress (CUMS) paradigm-induced depression-related behaviours in mice, as shown by decreased sucrose consumption in sucrose preference test (SPT), reduced locomotor activity in the open field test (OFT), and increased immobility time in the tail suspension test (TST) and forced swimming test (FST). Furthermore, ROCK2 inhibition inhibited the activation of NHE1, calpain1, and reduced neuronal apoptosis in the CUMS animal model of depression. Next, we used the lipopolysaccharide (LPS)-challenged animal model of depression to induce NHE1 activation. Our results revealed that mice subjected to 1 µl LPS (10 mg/ml) injection intracerebroventricularly (i.c.v.) showed depressive-like behaviours and NHE1 activation. Amiloride (Ami), an NHE1 inhibitor, significantly reversed the decrease in sucrose consumption and reduction in immobility time in the TST and FST induced by LPS challenge. Furthermore, Ami decreased the expression of ROCK2, NHE1, calpain1, and caspase-3 and increased the Bcl-1/Bax ratio in the hippocampus of LPS-challenged mice. Ami treatment also led to antidepressive effects in the CUMS-induced animal model of depression. Thus ROCK2 inhibition could be proposed as a neuroprotective strategy against neuronal apoptosis, and NHE1 might be a potential therapeutic target in depression.

Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway.

BACKGROUND: Baicalin, which is isolated from Radix Scutellariae, possesses strong biological activities including an anti-inflammation property. Recent studies have shown that the anti-inflammatory effect of baicalin is linked to toll-like receptor 4 (TLR4), which participates in pathological changes of central nervous system diseases such as depression. In this study, we explored whether baicalin could produce antidepressant effects via regulation of TLR4 signaling in mice and attempted to elucidate the underlying mechanisms. METHODS: A chronic unpredictable mild stress (CUMS) mice model was performed to explore whether baicalin could produce antidepressant effects via the inhibition of neuroinflammation. To clarify the role of TLR4 in the anti-neuroinflammatory efficacy of baicalin, a lipopolysaccharide (LPS) was employed in mice to specially activate TLR4 and the behavioral changes were determined. Furthermore, we used LY294002 to examine the molecular mechanisms of baicalin in regulating the expression of TLR4 in vivo and in vitro using western blot, ELISA kits, and immunostaining. In the in vitro tests, the BV2 microglia cell lines and primary microglia cultures were pretreated with baicalin and LY292002 for 1 h and then stimulated 24 h with LPS. The primary microglial cells were transfected with the forkhead transcription factor forkhead box protein O 1 (FoxO1)-specific siRNA for 5 h and then co-stimulated with baicalin and LPS to investigate whether FoxO1 participated in the effect of baicalin on TLR4 expression. RESULTS: The administration of baicalin (especially 60 mg/kg) dramatically ameliorated CUMS-induced depressive-like symptoms; substantially decreased the levels of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the hippocampus; and significantly decreased the expression of TLR4. The activation of TLR4 by the LPS triggered neuroinflammation and evoked depressive-like behaviors in mice, which were also alleviated by the treatment with baicalin (60 mg/kg). Furthermore, the application of baicalin significantly increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and FoxO1. The application of baicalin also promoted FoxO1 nuclear exclusion and contributed to the inhibition of the FoxO1 transactivation potential, which led to the downregulation of the expression of TLR4 in CUMS mice or LPS-treated BV2 cells and primary microglia cells. However, prophylactic treatment of LY294002 abolished the above effects of baicalin. In addition, we found that FoxO1 played a vital role in baicalin by regulating the TLR4 and TLR4-mediating neuroinflammation triggered by the LPS via knocking down the expression of FoxO1 in the primary microglia. CONCLUSION: Collectively, these results demonstrate that baicalin ameliorated neuroinflammation-induced depressive-like behaviors through the inhibition of TLR4 expression via the PI3K/AKT/FoxO1 pathway.

Modulation of LPA1 receptor-mediated neuronal apoptosis by Saikosaponin-d: A target involved in depression.

Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation that binds to its specific cell surface G protein coupled receptors (LPA1-6). It is reported that LPA induced cell apoptosis by targeting LPA1, while LPA1 blockade eliminated LPS-induced production of peritoneal neutrophil chemokines and cytokines. Previous studies have shown that Saikosaponin-d (SSd) mitigated depressive-like behaviors in rats exposed to chronic unpredictable mild stress (CUMS), as well as corticosterone-induced apoptosis in PC12 cells. The present study explored the role of SSd during modulating LPA1 mediated neuronal apoptosis in LPS-stimulated mice. The phenomenon that SSd alleviated LPS-induced depressive-like behaviors were observed by open field test (OPT), forced swim test (FST) and tail suspension test (TST). SSd inhibited the protein expression of LPA1 both in the CA1 and CA3 region of the hippocampus. Moreover, SSd significantly decreased the levels of RhoA, ROCK2, p-p38, p-ERK, p-p65, p-IκBα in LPS-stimulated mice as well as in LPA-stimulated SH-SY5Y cells. Additionally, SSd significantly decreased the expression of LPA1 and the degree of neuronal apoptosis in SH-SY5Y cells which were co-cultured with LPS-stimulated BV2 microglia. These results suggested that SSd improved LPS-induced depressive-like behaviors in mice and suppressed neuronal apoptosis by regulating LPA1/RhoA/ROCK2 signaling pathway.

Reduning injection ameliorates paraquat-induced acute lung injury by regulating AMPK/MAPK/NF-κB signaling.

Reduning injection (RDN), a patented Chinese medicine, is broadly used for common cold and lung infection in clinic, but the mechanism underlying its effects on inflammation-related pulmonary injury remains unclear. Paraquat (PQ, bolus 15 mg/kg dose, ip) was administered for acute lung injury induction in mice, which were orally administered dexamethasone (2 mg/kg) or RDN (50 and 100 mg/kg/day) for 5 days. After treatment, plasma and lung tissue samples from the euthanized animals were obtained and analyzed by histological, biochemical and immunoblot assays. Histological observation demonstrated RDN alleviated PQ-induced lung damage. Meanwhile, RDN suppressed myeloperoxidase (MPO) activity, reduced the wet/dry (W/D) ratio and decreased the amounts of total leukocytes and neutrophils. Treatment also markedly decreased the amounts of malondialdehyde, MPO, and inflammatory cytokines while increasing superoxide dismutase activity in comparison with the PQ group. In immunoblot, RDN blocked the phosphorylation levels of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), JNK, ERK, p38, inhibitor of nuclear factor κB kinase and nuclear factor-κB (NF-κB) in lung tissue specimens in PQ-challenged animals, which was further verified in vitro. The above data indicated protective effects for RDN in PQ-induced lung damage, possibly through inhibition of the AMPK/MAPK/NF-κB pathway.