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Background: Social isolation not only increases the risk of mortality in later life but also causes depressive symptoms, cognitive and physical disabilities. Although RNA m6A modifications are suggested to play key roles in brain development, neuronal signaling and neurological disorders, both the roles of m6A and the enzymes that regulate RNA m6A modification in social isolation induced abnormal behavior is unknown. The present study aims to explore the possible epitranscriptomic role of RNA m6A modifications and its enzymes in social isolation induced impaired behavior., Methods: 3-4 weeks mice experiencing 8 weeks social isolation stress (SI) were used in the present study. We quantified m6A levels in brain regions related to mood and cognitive behavior. And the expression of hippocampal m6A enzymes was also determined. The role of hippocampal m6A and its enzymes in SI induced abnormal behavior was further verified by the virus tool., Results: SI led to not only depressive and anxiety-like behaviors but also cognitive impairment, with corresponding decreases in hippocampal m6A and METTL14. Hippocampal over-expression METTL14 with lentivirus not only rescued these behaviors but also enhanced the hippocampal m6A level. Hippocampal over-expression METTL14 resulted in increased synaptic related genes., Conclusions: We provide the first evidence that post-weaning social isolation reduces hippocampal m6A level and causes altered expression of m6A enzyme in mice. Importantly, hippocampal METTL14 over-expression alleviated the SI-induced depression/anxiety-like and impaired cognitive behaviors and enhanced m6A level and synaptic related genes expression., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest or any known competing financial interests or personal relationships that may bias the performance or interpretation of the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Physical exercise has beneficial effect on anxiety disorders, but the underlying molecular mechanism remains largely unknown. Here, it is demonstrated that physical exercise can downregulate the S-nitrosylation of gephyrin (SNO-gephyrin) in the basolateral amygdala (BLA) to exert anxiolytic effects. It is found that the level of SNO-gephyrin is significantly increased in the BLA of high-anxiety rats and a downregulation of SNO-gephyrin at cysteines 212 and 284 produced anxiolytic effect. Mechanistically, inhibition of SNO-gephyrin by either Cys212 or Cys284 mutations increased the surface expression of GABA A R γ2 and the subsequent GABAergic neurotransmission, exerting anxiolytic effect in male rats. On the other side, overexpression of neuronal nitric oxide synthase in the BLA abolished the anxiolytic-like effects of physical exercise. This study reveals a key role of downregulating SNO-gephyrin in the anxiolytic effects of physical exercise, providing a new explanation for protein post-translational modifications in the brain after exercise., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Melatonin (N-acetyl-5-methoxytryptamine) is reported to improve mood disorders in perimenopausal women and gut microbiome composition is altered during menopausal period. The possible role of microbiome in the treatment effect of melatonin on menopausal depression remains unknown. Here, it is shown that melatonin treatment reverses the gut microbiota dysbiosis and depressive-like behaviors in ovariectomy (OVX) operated mice. This effect of melatonin is prevented by antibiotic cocktails (ABX) treatment. Transferring microbiota harvested from adolescent female mice to OVX-operated mice is sufficient to ameliorate depressive-like behaviors. Conversely, microbiota transplantation from OVX-operated mice or melatonin-treated OVX-operated mice to naïve recipient mice exhibits similar phenotypes to donors. The colonization of Alistipes Inops, which is abundant in OVX-operated mice, confers the recipient with depressive-like behaviors. Further investigation indicates that the expansion of Alistipes Inops induced by OVX leads to the degradation of intestinal tryptophan, which destroys systemic tryptophan availability. Melatonin supplementation restores systemic tryptophan metabolic disorders by suppressing the growth of Alistipes Inops, which ameliorates depressive-like behaviors. These results highlight the previously unrecognized role of Alistipes Inops in the modulation of OVX-induced behavioral disorders and suggest that the application of melatonin to inhibit Alistipes Inops may serve as a potential strategy for preventing menopausal depressive symptoms., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Hereditary angioedema (HAE) is a rare hereditary disorder characterized by episodic swelling and life-threatening airway obstruction caused by laryngeal angioedema. In most HAE patients, reduced level of serum C1-Inhibitor (type-I-HAE) or presence of aberrant C1-Inhibitor (type-II-HAE) result in the lost of regulation of the complementary system and contact activation system with downstream over-activation of bradykinin - the chief mediator leading to angioedema. Type-III HAE (HAE-nl-C1INH) is rare without deficient or dysfunction of C1-Inhibitor, often with genetic aberrant related to the contact activation system. The prevalence of HAE in the population is estimated at 1 in 50,000 individuals, often with early onset, but due to the heterogeneity of the disease, there is frequently a significant delay in diagnosis. Recently, better awareness by physicians, more access to diagnostic tools, better management and prophylaxis has decreased morbidity and mortality. A focus in HAE patient care shift from management of attacks with on-demand medication, to use of prophylaxis to reduce attacks has improved the overall quality of life of patients with HAE. One area in HAE research that has not been emphasized is the long-term consequence of C1-INH deficiency in HAE patients, other than the typical manifestations of HAE, as evidence have emerged linking this disorder with increased risk of cardiovascular diseases, auto-immune disorders, and malignancy. This review aims to gather the current knowledge and evidence of potential consequence of C1-Inhibitor deficiency in HAE aside from angioedema with emphasis in the improvement of long-term care and overall quality of life for HAE patients.

Sepsis-associated encephalopathy (SAE) refers to diffuse brain dysfunction caused by sepsis, which is characterized by decreased attention, directional impairment, being prone to irritation, and in severe cases the patient will experience drowsiness and coma. The pathogenesis of SAE mainly includes neuroinflammation, damage of blood-brain barrier, cerebral vascular dysfunction, and neurometabolic changes, among which neuroinflammation is the core pathological process. Microglia are considered to be important immune cells of the central nervous system and play an important role in neuroinflammation. This article systematically describes the role of microglia in the development of SAE, and discusses the phenotype and related signaling pathways of microglia, in order to clarify the role of microglia in SAE and provide a theoretical basis for clinical treatment of SAE.

Neurons are particularly susceptible to energy fluctuations in response to stress. Mitochondrial fission is highly regulated to generate ATP via oxidative phosphorylation; however, the role of a regulator of mitochondrial fission in neuronal energy metabolism and synaptic efficacy under chronic stress remains elusive. Here, we show that chronic stress promotes mitochondrial fission in the medial prefrontal cortex via activating dynamin-related protein 1 (Drp1), resulting in mitochondrial dysfunction in male mice. Both pharmacological inhibition and genetic reduction of Drp1 ameliorates the deficit of excitatory synaptic transmission and stress-related depressive-like behavior. In addition, enhancing Drp1 fission promotes stress susceptibility, which is alleviated by coenzyme Q10, which potentiates mitochondrial ATP production. Together, our findings unmask the role of Drp1-dependent mitochondrial fission in the deficits of neuronal metabolic burden and depressive-like behavior and provides medication basis for metabolism-related emotional disorders., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Recent studies based on animal models of various neurological disorders have indicated that mitophagy, a selective autophagy that eliminates damaged and superfluous mitochondria through autophagic degradation, may be involved in various neurological diseases. As an important mechanism of cellular stress response, much less is known about the role of mitophagy in stress-related mood disorders. Here, we found that tumor necrosis factor-α (TNF-α), an inflammation cytokine that plays a particular role in stress responses, impaired the mitophagy in the medial prefrontal cortex (mPFC) via triggering degradation of an outer mitochondrial membrane protein, NIP3-like protein X (NIX). The deficits in the NIX-mediated mitophagy by TNF-α led to the accumulation of damaged mitochondria, which triggered synaptic defects and behavioral abnormalities. Genetic ablation of NIX in the excitatory neurons of mPFC caused passive coping behaviors to stress, and overexpression of NIX in the mPFC improved TNF-α-induced synaptic and behavioral abnormalities. Notably, ketamine, a rapid on-set and long-lasting antidepressant, reversed the TNF-α-induced behavioral abnormalities through activation of NIX-mediated mitophagy. Furthermore, the downregulation of NIX level was also observed in the blood of major depressive disorder patients and the mPFC tissue of animal models. Infliximab, a clinically used TNF-α antagonist, alleviated both chronic stress- and inflammation-induced behavioral abnormalities via restoring NIX level. Taken together, these results suggest that NIX-mediated mitophagy links inflammation signaling to passive coping behaviors to stress, which underlies the pathophysiology of stress-related emotional disorders., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Dysfunctional autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the VPS34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment., (© 2023. Center for Excellence in Molecular Cell Science, CAS.)

Emerging evidence demonstrates the vital role of synaptic transmission and structural remodeling in major depressive disorder. Activation of melanocortin receptors facilitates stress-induced emotional behavior. Prolylcarboxypeptidase (PRCP) is a serine protease, which splits the C-terminal amino acid of α-MSH and inactivates it. In this study, we asked whether PRCP, the endogenous enzyme of melanocortin system, might play a role in stress susceptibility via regulating synaptic adaptations. Mice were subjected to chronic social defeat stress (CSDS) or subthreshold social defeat stress (SSDS). Depressive-like behavior was assessed in SIT, SPT, TST and FST. Based on to behavioral assessments, mice were divided into the susceptible (SUS) and resilient (RES) groups. After social defeat stress, drug infusion or viral expression and behavioral tests, morphological and electrophysiological analysis were conducted in PFX-fixed and fresh brain slices containing the nucleus accumbens shell (NAcsh). We showed that PRCP was downregulated in NAcsh of susceptible mice. Administration of fluoxetine (20 mg·kg -1 ·d -1 , i.p., for 2 weeks) ameliorated the depressive-like behavior, and restored the expression levels of PRCP in NAcsh of susceptible mice. Pharmacological or genetic inhibition of PRCP in NAcsh by microinjection of N-benzyloxycarbonyl-L-prolyl-L-prolinal (ZPP) or LV-shPRCP enhanced the excitatory synaptic transmission in NAcsh, facilitating stress susceptibility via central melanocortin receptors. On the contrary, overexpression of PRCP in NAcsh by microinjection of AAV-PRCP alleviated the depressive-like behavior and reversed the enhanced excitatory synaptic transmission, abnormal dendritogenesis and spinogenesis in NAcsh induced by chronic stress. Furthermore, chronic stress increased the level of CaMKIIα, a kinase closely related to synaptic plasticity, in NAcsh. The elevated level of CaMKIIα was reversed by overexpression of PRCP in NAcsh. Pharmacological inhibition of CaMKIIα in NAcsh alleviated stress susceptibility induced by PRCP knockdown. This study has revealed the essential role of PRCP in relieving stress susceptibility through melanocortin signaling-mediated synaptic plasticity in NAcsh., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress-induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress., Methods: Chronic social defeat stress (CSDS) was used to develop depressive-like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit., Results: CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVT Glu -NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling., Conclusions: Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress-induced depressive-like behavior., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Taking the Xiaojiang and Xiangxi Rivers, two typical tributaries of the Three Gorges Reservoir, as examples, this study analyzed and compared the hydrodynamic, thermal stratification, and temporal and spatial differences in dissolved oxygen (DO) and their responses to the water storage process in the two tributaries through field monitoring at different stages of the 2020 impoundment period. The results showed that:① at the initial stage of water storage, the DO in the surface layer of the Xiaojiang River was higher (7.00-13.00 mg·L -1 ) due to atmospheric reoxygenation and phytoplankton photosynthesis, and the oxycline appeared in the water depth of 3-5 m. A large area of anoxia (DO<2.00 mg·L -1 ) or even an anaerobic sublayer occurred in the water below 5 m. The DO in the Xiangxi River could be divided into three layers vertically:oxygen-rich surface water (8.00-12.00 mg·L -1 ), middle water (6.00-8.00 mg·L -1 ), and low-oxygen bottom water (4.00-6.00 mg·L -1 ). ② Thermal stratification provided a stable physical environment, whereas the upstream inflow and vegetation decomposition in the water-level fluctuation zone increased the content of organic matter, which likely increased the oxygen consumption which was conducive to the formation of an anaerobic bottom layer. In the Xiangxi River, the risk of hypoxia in the bottom water body was low because of the oxygen replenishment from the long-term downslope-bottom density current.③ Continuous monitoring also showed that the storage of the reservoir played a significant role in the replenishment of DO in tributaries, which effectively and rapidly improved the anaerobic phenomenon in the Xiaojiang River. In the Three Gorges Reservoir, it is feasible to ameliorate the water ecological problems such as anoxia and anaerobic conditions in the tributaries via reservoir operation. This study aids understanding of the characteristics and differences of DO stratification in different tributaries of the Three Gorges Reservoir, which can provide theoretical and technical support for reservoir ecological operation.

Repeated vagus nerve stimulation (rVNS) exerts anxiolytic effect by activation of noradrenergic pathway. Centrolateral amygdala (CeL), a lateral subdivision of central amygdala, receives noradrenergic inputs, and its neuronal activity is positively correlated to anxiolytic effect of benzodiazepines. The activation of β-adrenergic receptors (β-ARs) could enhance glutamatergic transmission in CeL. However, it is unclear whether the neurobiological mechanism of noradrenergic system in CeL mediates the anxiolytic effect induced by rVNS. Here, we find that rVNS treatment produces an anxiolytic effect in male rats by increasing the neuronal activity of CeL. Electrophysiology recording reveals that rVNS treatment enhances the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated excitatory neurotransmission in CeL, which is mimicked by β-ARs agonist isoproterenol or blocked by β-ARs antagonist propranolol. Moreover, chemogenetic inhibition of CeL neurons or pharmacological inhibition of β-ARs in CeL intercepts both enhanced glutamatergic neurotransmission and the anxiolytic effects by rVNS treatment. These results suggest that the amplified AMPAR trafficking in CeL via activation of β-ARs is critical for the anxiolytic effects induced by rVNS treatment., Competing Interests: The authors declare no competing interests., (© 2022 Published by Elsevier Inc.)

Robotic surgery offers three-dimensional visualization and precision of movement that could be of great value to gastrointestinal surgeons. There were many previous reports on robotic technology in performing Soave colonic resection and pull-through for Hirschsprung's disease in children. This study described the follow-up of the Robotic-assisted Soave procedure for Hirschsprung's disease in children. Robotic-assisted endorectal pull-through was performed using three robotic arms and an additional 5-mm trocar. The ganglionic and aganglionic segments were initially identified by seromuscular biopsies. The rest of the procedure was carried out according to the Soave procedure. We left a short rectal seromuscular sleeve of 1.5-2 cm above the dentate line. From December 2014 to December 2017, 55 pediatric patients were operated on. Age ranged from 6 months to 10 years old (median = 24.5 months). The aganglionic segment was located in the rectum (n = 38), the sigmoid colon (n = 13), and the left colon (n = 4). The mean total operative time was 93.2 ± 35 min (ranging from 80 to 180 min). Minimal blood was lost during the surgery. During the follow-up period, 41 patients (74.6%) had 1-2 defecations per day, 12 patients (21.8%) had 3-4 defecations per day, and 2 patients (3.6%) had more than 4 defecations per day. Fecal incontinence, enterocolitis, and mild soiling occurred in three (5.4%), four (7.3%), and two pediatric patients, respectively. Robotic-assisted Soave procedure for Hirschsprung's disease in children is a safe and effective technique. However, a skilled robotic surgical team and procedural modifications are needed., (© 2021. The Author(s).)

Stroke, which is the second leading cause of mortality in the world, is urgently needed to explore the medical strategies for ischemic stroke treatment. Both icariin (ICA) and icaritin (ICT) are the major active flavonoids extracted from Herba epimedii that have been regarded as the neuroprotective agents in disease models. In this study, we aimed to investigate and compare the neuroprotective effects of ICA and ICT in a middle cerebral artery occlusion (MCAO) mouse model. Male ICR mice were pretreated with both ICA and ICT, which ameliorated body weight loss, neurological injury, infarct volume, and pathological change in acute ischemic stroke mice. Furthermore, administration of both ICA and ICT could also protect against neuronal cell apoptotic death, oxidative and nitrosative stress, lipid peroxidation, and extracellular matrix (ECM) accumulation in the brains. The neuroprotective effects of ICT are slightly better than that of ICA in acute cerebral ischemic stroke mice. These results suggest that pretreatment with both ICA and ICT improves the neuronal cell apoptosis and responses of oxidative/nitrosative stress and counteracts the ECM accumulation in the brains of acute cerebral ischemic stroke mice. Both ICA and ICT treatment may serve as a useful therapeutic strategy for acute ischemic stroke.

Background: Deficiency in neuronal structural plasticity is involved in the development of major depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential for morphogenesis and organogenesis, is normally expressed at low levels in mature neurons. However, it is poorly understood what role TWIST1 plays in the brain and whether it is involved in the pathophysiology of depression., Methods: Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat stress. Genetic and pharmacological approaches were used to investigate the role of the TWIST1-miR-214-PPAR-δ signaling pathway in depressive-like behaviors. Molecular biological and morphological studies were performed to define the molecular mechanisms downstream of TWIST1., Results: The expression of TWIST1 was positively correlated with depressive behaviors in humans and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1 increased susceptibility to stress, the knockdown of TWIST1 prevented the defective morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant property of TWIST1 was mediated, at least in part, through the repression of miR-214-PPAR-δ signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-δ., Conclusions: These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic stress-induced dendritic remodeling and facilitates the occurrence of depressive-like behavior, providing new information for developing drug targets for depression therapy., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Reservoirs are an important source of atmospheric methane (CH 4 ), a potent greenhouse gas. The Mekong, one of the largest Asian rivers, has been heavily dammed and can be a potential hotspot for CH 4 emissions. While low diffusive CH 4 flux was previously reported from cascading reservoirs in the Upper Mekong, the contribution of ebullition (bubbling) remained unexplored. To better constrain the magnitude and drivers of ebullition from these reservoirs, automated bubble traps were deployed in four reservoirs, allowing for continuous measurement of the ebullitive flux with high temporal resolution for a period of six months. To characterize the spatial variability of CH 4 fluxes mediated by ebullition and diffusion, whole-reservoir surveys were conducted using a scientific echo sounder for bubble observations together with a gas equilibrator for mapping dissolved CH 4 concentration in surface water from which diffusive fluxes were estimated. Potential production and anaerobic oxidation rates of CH 4 were estimated in laboratory incubations of sediment cores collected near the bubble trap deployment sites. The CH 4 production potential in sediments increased strongly along the reservoir cascade, with mostly minor reduction by anaerobic oxidation. Surface CH 4 fluxes, in contrast, showed high spatial variability in both ebullitive and diffusive pathways (ranging 0.05-44 and 1.8-6.4 mg m -2  d -1 , respectively, among all reservoirs). Ebullitive fluxes were about one order of magnitude higher than diffusive fluxes and remained significant at sites as deep as 30-45 m. The repeated spatial pattern of ebullition (higher fluxes at the dam area than in upstream sections) suggests the possible control of emission rates by sediment transport and deposition., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Angiotensin-converting enzyme inhibitors (ACEIs) are widely prescribed antihypertensive agents. Intriguingly, case reports and clinical trials have indicated that ACEIs, including captopril and lisinopril, may have a rapid mood-elevating effect in certain patients, but few experimental studies have investigated their value as fast-onset antidepressants., Methods: The present study consisted of a series of experiments using biochemical assays, immunohistochemistry, and behavioral techniques to examine the effect and mechanism of captopril on depressive-like behavior in 2 animal models, the chronic unpredictable stress model and the chronic social defeat stress model., Results: Captopril (19.5 or 39 mg/kg, intraperitoneal injection) exerted rapid antidepressant activity in mice treated under the chronic unpredictable stress model and mice treated under the chronic social defeat stress model. Pharmacokinetic analysis revealed that captopril crossed the blood-brain barrier and that lisinopril, another ACEI with better blood-brain barrier permeability, exerted a faster and longer-lasting effect at a same molar equivalent dose. This antidepressant effect seemed to be independent of the renin-angiotensin system, but dependent on the bradykinin (BK) system, since the decreased BK detected in the stressed mice could be reversed by captopril. The hypofunction of the downstream effector of BK, Cdc42 (cell division control protein 42) homolog, contributed to the stress-induced loss of dendritic spines, which was rapidly reversed by captopril via activating the mTORC1 (mammalian target of rapamycin complex 1) pathway., Conclusions: Our findings indicate that the BK-dependent activation of mTORC1 may represent a promising mechanism underlying antidepressant pharmacology. Considering their affordability and availability, ACEIs may emerge as a novel fast-onset antidepressant, especially for patients with comorbid depression and hypertension., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: To identify multiparametric magnetic resonance imaging (mp-MRI)-based radiomics features as prognostic factors in patients with localized prostate cancer after radiotherapy. Methods: From 2011 to 2016, a total of 91 consecutive patients with T1-4N0M0 prostate cancer were identified and divided into two cohorts for an adaptive boosting (Adaboost) model (training cohort: n = 73; test cohort: n = 18). All patients were treated with neoadjuvant endocrine therapy followed by radiotherapy. The optimal feature set, identified through an Inception-Resnet v2 network, consisted of a combination of T1, T2, and diffusion-weighted imaging (DWI) MR series. Through a Wilcoxon sign rank test, a total of 45 distinct signatures were extracted from 1,536 radiomics features and used in our Adaboost model. Results: Among 91 patients, 29 (32%) were classified as biochemical recurrence (BCR) and 62 (68%) as non-BCR. Once trained, the model demonstrated a predictive classification accuracy of 50.0 and 86.1% respectively for BCR and non-BCR groups on our test samples. The overall classification accuracy of the test cohort was 74.1%. The highest classification accuracy was 77.8% between three-fold cross-validation. The areas under the curve (AUC) of receiver operating characteristic curve (ROC) indices for the training and test cohorts were 0.99 and 0.73, respectively. Conclusion: The potential of multiparametric MRI-based radiomics to predict the BCR of localized prostate cancer patients was demonstrated in this manuscript. This analysis provided additional prognostic factors based on routine MR images and holds the potential to contribute to precision medicine and inform treatment management., (Copyright © 2020 Zhong, Long, Liu, Li, Xiu, Hou, Wu, Gao, Xu, Zhao, Wang, Lin, Sha, Wang, Chen and Li.)

Background: Recurrence is the major cause of mortality in patients with resected HCC. However, without a standard approach to evaluate prognosis, it is difficult to select candidates for additional therapy., Methods: A total of 201 patients with HCC who were followed up for at least 5 years after curative hepatectomy were enrolled in this retrospective, multicentre study. A total of 3144 radiomics features were extracted from preoperative MRI. The random forest method was used for radiomics signature building, and five-fold cross-validation was applied. A radiomics model incorporating the radiomics signature and clinical risk factors was developed., Results: Patients were divided into survivor (n = 97) and non-survivor (n = 104) groups based on the 5-year survival after surgery. The 30 most survival-related radiomics features were selected for the radiomics signature. Preoperative AFP and AST were integrated into the model as independent clinical risk factors. The model demonstrated good calibration and satisfactory discrimination, with a mean AUC of 0.9804 and 0.7578 in the training and validation sets, respectively., Conclusions: This radiomics model is a valid method to predict 5-year survival in patients with HCC and may be used to identify patients for clinical trials of perioperative therapies and for additional surveillance.

The construction of the Three Gorges Reservoir has had certain effects on the ecological environment of the water and serious phytoplankton blooms have occurred in its tributary embayment. To explore the spatial distribution of nitrogen and phosphorus nutrients and chlorophyll-a in different tributaries of the Three Gorges Reservoir, a water quality study (June 2018) was conducted in the Xiangxi River, Shengnongxi River, and Daning River of the Three Gorges Reservoir. The results showed that the average TN in the three tributaries was 1.86 mg·L -1 , 1.90 mg·L -1 , and 1.43 mg·L -1 , respectively, and average TP was 0.09 mg·L -1 , 0.07 mg·L -1 , and 0.05 mg·L -1 , respectively. Single-factor ANOVA analysis showed that the spatial difference in TN was significant and occurred in the following order:Shennongxi River > Xiangxi River > Daning River. There were significant differences in the spatial distribution of TP, which were in the order off Xiangxi River > Shennongxi River > Daning River. The mean concentrations of chlorophyll-a in the three tributaries was 6.41 μg·L -1 , 21.39 μg·L -1 , and 9.85μg·L -1 , respectively. The results from the Pearson correlation analysis, showed that chlorophyll-a concentrations were closely related to TP distribution in all tributaries, but Z eu / Z mix was also correlated with the distribution of chlorophyll-a in the Shennongxi River and Daning River. The ratio of TN and TP concentrations was 22.36, 26.76, and 28.6, respectively, which revealed that TP is a critical and limiting factor affecting phytoplankton growth in its tributary embayment.

The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this study, we hypothesized that LIPUS treatment possessed therapeutic benefits for the improvement of stroke recurrence. Adult male C57BL/6J mice were subjected to a middle cerebral artery occlusion (MCAO) surgery and then followed to secondary MCAO surgery as a stroke recurrence occurred after nine days from the first MCAO. LIPUS was administered continuously for nine days before secondary MCAO. LIPUS treatment not only decreased the mortality but also significantly moderated neuronal function injury including neurological score, motor activity, and brain pathological score in the recurrent stroke mice. Furthermore, the administration of LIPUS attenuated the apoptotic neuronal cells and increased Bax/Bcl-2 protein expression ratio and accelerated the expression of BDNF in the brain of the recurrent stroke mice. Taken together, these results demonstrate for the first time that LIPUS treatment arouses the expression of BDNF and possesses a therapeutic benefit for the improvement of stroke recurrence in a mouse model. The neuroprotective potential of LIPUS may provide a useful strategy for the prevention of a recurrent stroke.

Background: The basolateral amygdala (BLA) has been widely implicated in the pathophysiology of major depressive disorder. A-kinase anchoring protein 150 (AKAP150) directs kinases and phosphatases to synaptic glutamate receptors, controlling synaptic transmission and plasticity. However, the role of the AKAP150 in the BLA in major depressive disorder remains poorly understood., Methods: Depressive-like behaviors in C57BL/6J mice were developed by chronic restraint stress (CRS). Mice received either intra-BLA injection of lentivirus-expressing Akap5 short hairpin RNA or Ht-31, a peptide to disrupt the interaction of AKAP150 and protein kinase A (PKA), followed by depressive-like behavioral tests. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptor (AMPAR)-mediated miniature excitatory postsynaptic currents were recorded by whole-cell patch-clamp techniques., Results: Chronic stress exposure induced depressive-like behaviors, which were accompanied by an increase in total and synaptic AKAP150 expression in the BLA. Accordingly, CRS facilitated the association of AKAP150 with PKA, but not of calcineurin in the BLA. Intra-BLA infusion of lentivirus-expressing Akap5 short hairpin RNA or Ht-31 prevented depressive-like behaviors and normalized phosphorylation of serine 845 and surface expression of AMPAR subunit 1 (GluA1) in the BLA of CRS mice. Finally, blockage of AKAP150-PKA complex signaling rescued the changes in AMPAR-mediated miniature excitatory postsynaptic currents in depressive-like mice., Conclusions: These results suggest that AKAP150-PKA directly modulates BLA neuronal synaptic strength, and that AKAP150-PKA-GluA1 streamline signaling complex is responsible for CRS-induced disruption of synaptic AMPAR-mediated transmission and depressive-like behaviors in mice., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Benzodiazepines (BZDs) have been used to treat anxiety disorders for more than five decades as the allosteric modulator of the gamma-aminobutyric acid A receptor (GABA A R). Little is known about other mechanisms of BZDs. Here, we describe how the rapid stabilization of postsynaptic GABA A R is essential and sufficient for the anxiolytic effect of BZDs via a palmitoylation-dependent mechanism., Methods: Palmitoylated proteins in the basolateral amygdala (BLA) of rats with different anxious states were assessed by a biotin exchange protocol. Both pharmacological and genetic approaches were used to investigate the role of palmitoylation in anxiety behavior. Electrophysiological recording, reverse transcription polymerase chain reaction, Western blotting, and coimmunoprecipitation were used to investigate the mechanisms., Results: Highly anxious rats were accompanied by the deficiency of gephyrin palmitoylation and decreased the synaptic function of GABA A R in the BLA. We then identified that the dysfunction of DHHC12, a palmitoyl acyltransferase that specifically palmitoylates gephyrin, contributed to the high-anxious state. Furthermore, diazepam, as an anxiolytic drug targeting GABA A Rs, was found to increase gephyrin palmitoylation in the BLA via a GABA A R-dependent manner to activate DHHC12. The anxiolytic effect of diazepam was nearly abolished by the DHHC12 knockdown. Specifically, similar to the effect of BZD, the overexpression of DHHC12 in the BLA exerted a significant anxiolytic action, which was prevented by flumazenil., Conclusions: Our results support the view that the strength of inhibitory synapse was controlled by gephyrin palmitoylation in vivo and proposes a previously unknown palmitoylation-centered mode of BZD's action., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Autophagy has been demonstrated to play an important role in memory deficits as well as the degradation of neurotransmitter receptors. SAR405 is a newly discovered inhibitor that can specifically inhibit vacuolar sorting protein 34 and prevent autophagosome biogenesis. However, the effects of SAR405 on memory processes remain largely unknown., Methods: Western blotting, immunofluorescence, and transmission electron microscopy were used to assess the level of autophagy after fear conditioning and SAR405 treatment. Behavioral tests, biotinylation assay, electrophysiology, and co-immunoprecipitation were used to unravel the mechanisms of SAR405 in memory consolidation., Results: SAR405 infusion into the basolateral amygdala impaired long-term memory through autophagy inhibition. Furthermore, the trafficking of gamma-aminobutyric acid type A receptors (GABA A Rs) following fear conditioning was disrupted by SAR405, and the decreased frequency and amplitude of miniature inhibitory postsynaptic currents induced by fear conditioning were also reversed by SAR405, suggesting that SAR405 disrupted memory consolidation through blockade of the downregulated inhibitory neurotransmission in basolateral amygdala. GABA A R-associated protein (GABARAP) and its interaction with GABA A R γ2 subunit were found to be upregulated after fear conditioning, and SAR405 could suppress this increased interaction. Moreover, disruption of the GABARAP-GABA A R binding by a trans-activating transcriptional activator-GABARAP inhibitory peptide blocked the decrease in surface expression of GABA A Rs and attenuated long-term memory., Conclusions: The present study suggests that SAR405 can prevent the memory consolidation via intervening autophagy and GABA A R trafficking and has a potential therapeutic value for disorders characterized by exaggerated fear memories, such as posttraumatic stress disorder., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Both inflammatory processes and glutamatergic systems have been implicated in the pathophysiology of mood-related disorders. However, the role of caspase-1, a classic inflammatory caspase, in behavioral responses to chronic stress remains largely unknown. To address this issue, we examined the effects and underlying mechanisms of caspase-1 on preclinical murine models of depression. We found that loss of caspase-1 expression in Caspase-1 -/- knockout mice alleviated chronic stress-induced depression-like behaviors, whereas overexpression of caspase-1 in the hippocampus of wild-type (WT) mice was sufficient to induce depression- and anxiety-like behaviors. Furthermore, chronic stress reduced glutamatergic neurotransmission and decreased surface expression of glutamate receptors in hippocampal pyramidal neurons of WT mice, but not Caspase-1 -/- mice. Importantly, pharmacological inhibition of caspase-1-interleukin-1β (IL-1β) signaling pathway prevented the depression-like behaviors and the decrease in surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in stressed WT mice. Finally, the effects of chronic stress on both depression- and anxiety-like behaviors can be mimicked by exogenous intracerebroventricular (i.c.v.) administration of IL-1β in both WT and Caspase-1 -/- mice. Taken together, our findings demonstrate that an increase in the caspase-1/IL-1β axis facilitates AMPAR internalization in the hippocampus, which dysregulates glutamatergic synaptic transmission, eventually resulting in depression-like behaviors. These results may represent an endophenotype for chronic stress-induced depression.

Aims: Reactive sulfur species, including hydrogen sulfide (H 2 S) and its oxydates, have been raised as novel redox signaling molecules. The present study aimed at examining whether endogenous sulfhydration signal is required for long-term potentiation (LTP), a cellular model for memory., Results: In this study, we found that increased synaptic activity triggered sulfide generation and protein sulfhydration. Activity-triggered sulfide production was essential for N-methyl-D-aspartate subtype glutamate receptor (NMDAR)-dependent LTP via maintaining the availability of d-serine, a primary coagonist for synaptic NMDARs. Genetic knockdown of cystathionine β-synthase, not cystathionine γ-lyase, impaired LTP. H 2 S increased NMDAR-dependent LTP via sulfhydration and disinhibition of serine racemase (SR), a main synthetase of d-serine. We found that polysulfides also increased NMDAR-dependent LTP and NMDAR activity. In aged rats, the level of H 2 S and SR sulfhydration decreased significantly. Exogenous supplement of H 2 S restored the sulfhydration of SR, followed by the improvement of age-related deficits in LTP. Furthermore, boost of H 2 S signal in vivo improves hippocampus-dependent memory. Innovation and Conclusion: Our results provide a direct evidence for the biological significance of endogenous sulfhydration signal in synaptic plasticity. Exogenous supplement of H 2 S could be considered as the new therapeutic approach for the treatment of neurocognitive dysfunction after aging. Antioxid. Redox Signal. 27, 398-414.

Methionine (Met) sulfoxide reductase A (MsrA) is a key endogenous antioxidative enzyme with longevity benefits in animals. Only very few approaches have been reported to enhance MsrA function. Recent reports have indicated that the antioxidant capability of MsrA may involve a Met oxidase activity that facilities the reaction of Met with reactive oxygen species (ROS). Herein, we used a homology modeling approach to search the substrates for the oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae, emerged as a good substrate for MsrA-catalytic antioxidation. MsrA bounds to DMS and promoted its antioxidant capacity via facilitating the reaction of DMS with ROS through a sulfonium intermediate at residues Cys72, Tyr103, and Glu115, followed by the release of dimethyl sulfoxide (DMSO). DMS reduced the antimycin A-induced ROS generation in cultured PC12 cells and alleviated oxidative stress. Supplement of DMS exhibited cytoprotection and extended longevity in both Caenorhabditis elegans and Drosophila. MsrA knockdown abolished the cytoprotective effect and the longevity benefits of DMS. Furthermore, we found that the level of physiologic DMS was at the low micromolar range in different tissues of mammals and its level decreased after aging. This study opened a new window to elucidate the biological role of DMS and other low-molecular sulfides in the cytoprotection and aging., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: Peripherally inserted central venous catheters (PICCs) are widely used in patients with cancer. Catheter usage is one of the risk factors for venous thromboembolism. We aimed to scrutinize the incidence and risk factors for PICC-related upper extremity venous thrombosis (UEVT) in patients with lung cancer receiving chemotherapy., Patients and Methods: We performed a retrospective cohort study of patients with lung cancer with PICC insertion undergoing chemotherapy. Symptomatic PICC-UEVT was diagnosed by ultrasound. The relationship between chemotherapeutic agent exposure and PICC-UEVT was evaluated. Patient-, catheter-, and insertion-related factors were analyzed in univariable and multivariable logistic regression to identify significant independent risk factors for PICC-UEVT in patients with lung cancer., Results: A total of 328 patients with lung cancer having PICC undergoing chemotherapy were included, for a total of 34 895 catheter days. Seventeen (5.2%) patients developed PICC-related UEVT, with an incidence of 0.49 per 1000 catheter days. In multivariable logistic analysis, advanced disease was shown to be a significant risk factor for PICC-UEVT (odds ratio [OR]: 4.9; 95% confidence interval [CI]: 1.4-16.7; P = .011). Patients treated with etoposide had a higher risk of PICC-related UEVT (OR: 3.6; 95% CI: 1.1-12.1; P = .042). Patients were followed up after PICC removal for a median duration of 246 days. None of the patients developed pulmonary embolism., Conclusion: Patients with lung cancer harboring an advanced disease or treating with etoposide were at higher risk of PICC-UEVT.

Sulfhydryl compounds such as dithiothreitol (DTT) and β-mercaptoethanol (β-ME) are widely used as redox agents. Previous studies in our group and other laboratory have reported the effect of sulfhydryl compounds on the function of glutamate receptor, including plasticity. Most of these findings have focused on the N-methyl-D-aspartic acid receptor, in contrast, very little is known about the effect of sulfhydryl compounds on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). Here, we observed that DTT (100 μM), β-ME (200 μM) and L-cysteine (200 μM) significantly elevated the surface expression of AMPARs via reducing their palmitoylation in rat hippocampal slices in vitro. Increased surface stability of AMPARs was not be correlated with the altered redox status, because the chemical entities containing mercapto group such as penicillamine (200 μM) and 2-mercapto-1-methylimidazole (200 μM) exhibited little effects on the surface expression of AMPARs. Computing results of Asp-His-His-Cys (DHHC) 3, the main enzyme for palmitoylation of AMPARs, indicated that only the alkyl mercaptans with chain-like configuration, such as DTT and β-ME, can enter the pocket of DHHC3 and disrupt the catalytic activity via inhibiting DHHC3 auto-palmitoylation. Collectively, our findings indicate a novel redox-independent mechanism underlay the multiple effects of thiol reductants on synaptic function.

Sulfite is a compound commonly used as preservative in foods and pharmaceuticals. Many studies have examined the neurotoxicity of sulfite, but its effect on neuronal calcium homeostasis has not yet been reported. Here, we observed the effect of sulfite on the cytosolic free calcium concentration ([Ca(2+)]i) in cultured cortical neurons using Fura-2/AM based calcium imaging technique. Sulfite (250-1000μM) caused a sustained increase in [Ca(2+)]i in the neurons via a dose-dependent manner. In Ca(2+)-free solution, sulfite failed to increase [Ca(2+)]i. After the depletion of the intracellular calcium store, the effect of sulfite on the [Ca(2+)]i was largely abolished. Pharmacological inhibition of phospholipase C (PLC)-inositol 1,4,5-triphosphate (IP3) signaling pathway blocked sulfite-induced increase of [Ca(2+)]i. Interestingly, antioxidants such as trolox and dithiothreitol, abolished the increase of [Ca(2+)]i induced by sulfite. Exposure to sulfite triggered generation of sulfur- and oxygen-centered free radicals in neurons and increased oxidative stress both in the cultured cortical neurons and the prefrontal cortex of rats. Furthemore, sulfite decreased cell viability in cultured cortical neurons via a calcium-dependent manner. Thus, our current study suggests that the redox-dependent calcium overload triggered by sulfite in cortical neuronsmay be involved in its neurotoxicity., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Aims: Hydrogen sulfide (H2 S) has been widely accepted as a gas neuromodulator to regulate synaptic function. Herein, we set out to determine the effect of H2 S on α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and its mechanism., Methods: BS(3) protein cross-linking, Western blot, patch clamp, and biotin-switch assay., Results: Bath application of H2 S donor NaHS (50 and 100 μM) rapidly promoted surface insertion of hippocampal AMPAR GluR1 subunit. This effect can be abolished by dithiothreitol (DTT) and mimicked by Na2 S4 , indicating that a sulfhydration-dependent mechanism may be involved. NaHS increased APMAR-mediated EPSC and led to an elevation of GluR2-lacking AMPAR content. Notably, NaHS did not increase the sulfhydration of AMPAR subunits, but it significantly increased the phosphorylation of GluR1 at serine-831 and serine-845 sites. Postsynaptic signal pathways that control GluR1 phosphorylation, such as protein kinase A (PKA), protein kinase C, and calcium/calmodulin-dependent protein kinases II (CaMKII), were sulfhydrated, activated by NaHS, and these effects can be occluded by DTT. H2 S increased S-sulfhydration of protein phosphatase type 2A (PP2A), which may be partially involved in the activation of signal pathways., Conclusion: Our data suggest that H2 S promotes surface insertion of AMPARs via phosphorylation of GluR1, which depends on a sulfhydration-mediated mechanism., (© 2016 John Wiley & Sons Ltd.)

Objective: To evaluate the efficacy and safety of inhaled antibiotics for the treatment of non-cystic fibrosis bronchiectasis (NCFB)., Methods: Pubmed, Cochrane library, Embase, Elsevier, OVID, Springerlink, Web of knowledge and NEJM were searched for randomized controlled trials (RCTs) on inhaled antibiotics in treatment of NCFB from inception until April 2015. Meta-analysis was conducted to assess the efficacy and safety of inhaled antibiotics in the treatment of NCFB., Results: Twelve RCTs involving 1154 participants were included. They showed that inhaled antibiotics were more effective in reduction of sputum bacterial density, eradication of P. aeruginosa, prolonged time to exacerbation and reduction of new pathogens emergence with no significant difference in adverse events compared with control groups. However, we did not find significant benefits of inhaled antibiotics in reducing the risk of acute exacerbation, improving health-related quality of life and reduction of P. aeruginosa resistance. Moreover, inhaled antibiotics exerted a statistically significant reduction in FEV1%., Conclusions: Inhaled antibiotics may be an alternative pathway to inhibit airway inflammation with no more adverse events in patients with NCFB.

Ethnopharmacological Relevance: Polygonum multiflorum Thunb is a traditional Chinese medicine with anti-aging effect. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is generally considered as the main active component in Polygonum multiflorum Thunb. However, the effect of TSG on memory in adult is unclear till now., Aim of Study: 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a polyphenols compound from Polygonum multiflorum Thunb. The present study aimed to evaluate the effect of chronic administration of TSG on hippocampal memory in normal mice., Materials and Methods: Behavioral test, electrophysiology and golgi staining were used to evaluate the effect of TSG on hippocampus-dependent memory and synaptic plasticity. Western blotting was used to determine the expression of ERK1/2, CaMKII, and SIRT1. Real-time quantitative PCR was explored to measure miR-134., Results: It was found that TSG enhanced hippocampus-dependent contextual fear memory and novel object recognition, facilitated hippocampal LTP and increased dendrite spine density in the CA1 region of hippocampus. TSG obviously promoted the phosphorylations of ERK1/2, CaMKII, CREB and the expression of BDNF in the hippocampus, with upregulation of silent information regulator 1 (SIRT1) and downregulation of miR-134., Conclusions: Chronic administration of TSG promotes hippocampal memory in normal mice, suggesting that supplementary of TSG might serve as an enhancement of memory., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Chronic stress induces altered energy metabolism and plays important roles in the etiology of depression, in which the glucocorticoid negative feedback is disrupted due to imbalanced glucocorticoid receptor (GR) functions. The mechanism underlying the dysregulation of GR by chronic stress remains elusive. In this study, we investigated the role of AMP-activated protein kinase (AMPK), the key enzyme regulating cellular energy metabolism, and related signaling pathways in chronic stress-induced GR dysregulation. In cultured rat cortical astrocytes, glucocorticoid treatment decreased the level, which was accompanied by the decreased expression of liver kinase B1 (LKB1) and reduced phosphorylation of AMPK. Glucocorticoid-induced effects were attenuated by glucocorticoid-inducible kinase 1 (SGK1) inhibitor GSK650394, which also inhibited glucocorticoid induced phosphorylation of Forkhead box O3a (FOXO3a). Furthermore, glucocorticoid-induced down-regulation of GR was mimicked by the inhibition of AMPK and abolished by the AMPK activators or the histone deacetylase 5 (HDAC5) inhibitors. In line with the role of AMPK in GR expression, AMPK activator metformin reversed glucocorticoid-induced reduction of AMPK phosphorylation and GR expression as well as behavioral alteration of rats. Taken together, these results suggest that chronic stress activates SGK1 and suppresses the expression of LKB1 via inhibitory phosphorylation of FOXO3a. Downregulated LKB1 contributes to reduced activation of AMPK, leading to the dephosphorylation of HDAC5 and the suppression of transcription of GR.

Background: The AMP-activated protein kinase (AMPK) is a sensor of cellular energy and nutrient status, with substantial amount of cross talk with other signaling pathways, including its phosphorylation by Akt, PKA, and GSK3β., Aims: Various signaling pathways and energy-consuming transport of glutamate receptors subunits are required in synaptic plasticity. However, it is unknown which energy sensors integrate the signaling pathways in these processes. In this article, we elucidated the role of AMPK activation and GSK3β phosphorylation after HFS during the inducement of early-phase long-term potentiation (E-LTP)., Methods: Synaptic LTP in vivo was induced by high-frequency stimulation (HFS at 200 Hz at a 5-s interval). In addition, phosphorylation of AMPK and glycogen synthase kinase 3β (GSK3β) were measured using Western blotting. The amount of hippocampal AMP, ADP and ATP was measured by HPLC., Results: We showed that the phosphorylation of AMPK and GSK3β was significantly increased by HFS in vivo. HFS-induced AMPK activation occurred via increased (AMP + ADP)/ATP ratio and activation of Ca(2+) /calmodulin-dependent kinase kinase beta (CaMKKβ). Pharmacological inhibition of AMPK by compound C (CC) prevented HFS-induced inhibitory phosphorylation of GSK3β and the induction of LTP in dentate gyrus (DG) area in vivo., Conclusions: Our findings reveal that HFS-triggered AMPK activation phosphorylates GSK3β and induces E-LTP in vivo., (© 2016 John Wiley & Sons Ltd.)

Aims: Chemical entities containing mercapto group have been increasingly attractive in the therapy of central nerve system (CNS) diseases. In the recent study, we screened a series of mercapto-tacrine derivatives with synergistic neuropharmacological profiles in vitro., Methods: We investigated the effect and mechanism of ST09, a thioester derivative of tacrine containing a potential mercapto group, on the vascular dementia (VaD) model of rat induced by bilateral common carotid arteries occlusion (2-VO)., Results: ST09 and its active metabolite ST10 retained excellent inhibition on acetylcholinesterase (AChE) activity. ST09 significantly attenuated the 2-VO-induced impairment in spatial acquisition performance and inhibited the 2-VO-induced rise of AChE activity. In the VaD model, ST09 attenuated the oxidative stress and decreased the apoptosis in the cortex and hippocampus. Compared with donepezil, ST09 exhibited a better effect on the regeneration of free thiols in 2-VO rats. Interestingly, ST09, not donepezil, greatly improved glucose metabolism in various brain regions of 2-VO rats using functional imaging of (18) F-labeled fluoro-deoxyglucose (FDG) positron emission tomography (PET)., Conclusions: ST09 may serve as a more promising agent for the therapy of VaD than tacrine owing to the introduction of a potential mercapto group into the parent skeleton., (© 2016 John Wiley & Sons Ltd.)

Background: Tigecycline is an antibiotic agent with a broad spectrum, which has an antibacterial effect against many multidrug-resistant organisms. However, its clinical efficacy in the treatment of hospital-acquired pneumonia (HAP) is disputed., Materials and Methods: In this report, a systematic review and meta-analysis were conducted to evaluate the efficacy and safety of tigecycline for the treatment of HAP. The primary outcome was the rate of clinical cure, and the secondary outcomes were mortality and adverse events (AEs)., Results: Four trials involving 1,234 patients were included. The standard-dose tigecycline and comparator groups did not differ significantly in their rates of clinical cure. However, high-dose tigecycline was more effective than standard-dose tigecycline or the comparators for the treatment of HAP. There was no significant difference in mortality between the standard-dose or high-dose regimen and the comparators. Although the safety profile of standard-dose tigecycline was similar to the comparators, the high-dose regimen exhibited more AEs compared with the other groups., Conclusion: High-dose tigecycline is efficient for the treatment of HAP but is associated with more AEs., (© 2016 S. Karger AG, Basel.)

Previous studies have demonstrated that AMP-activated protein kinase (AMPK) controls autophagy through the mammalian target of rapamycin (mTOR) and Unc-51 like kinase 1 (ULK1/Atg1) signaling, which augments the quality of cellular housekeeping, and that β-guanidinopropionic acid (β-GPA), a creatine analog, leads to a chronic activation of AMPK. However, the relationship between β-GPA and aging remains elusive. In this study, we hypothesized that feeding β-GPA to adult Drosophila produces the lifespan extension via activation of AMPK-dependent autophagy. It was found that dietary administration of β-GPA at a concentration higher than 900 mm induced a significant extension of the lifespan of Drosophila melanogaster in repeated experiments. Furthermore, we found that Atg8 protein, the homolog of microtubule-associated protein 1A/1B-light chain 3 (LC3) and a biomarker of autophagy in Drosophila, was significantly upregulated by β-GPA treatment, indicating that autophagic activity plays a role in the effect of β-GPA. On the other hand, when the expression of Atg5 protein, an essential protein for autophagy, was reduced by RNA interference (RNAi), the effect of β-GPA on lifespan extension was abolished. Moreover, we found that AMPK was also involved in this process. β-GPA treatment significantly elevated the expression of phospho-T172-AMPK levels, while inhibition of AMPK by either AMPK-RNAi or compound C significantly attenuated the expression of autophagy-related proteins and lifespan extension in Drosophila. Taken together, our results suggest that β-GPA can induce an extension of the lifespan of Drosophila via AMPK-Atg1-autophagy signaling pathway., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Dopamine, a key neurotransmitter mediating the rewarding effects, exerts some of its effects by modulating neuronal excitability of striatal medium spiny neurons. A D1-like dopamine receptor-dependent phosphatidylinositol signal pathway exists in the striatum, however little is known about its role in the dopaminergic modulation of striatal neuronal excitability. 3-Methyl-6-chloro-7, 8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is a selective D1 receptor agonist with high-affinity. Here, we observed its effect on the voltage-gated sodium channels (VGSCs) in primary cultured striatal neurons by whole cell patch-clamp technique. We found that SKF83959 induced an inhibition on VGSCs in a dose-dependent manner in striatal neurons (IC50 value: 3.31 ± 0.39 μM), which could be prevented by antagonist of D1 receptor, but not that of D2, α1 adrenergic, or cholinoceptor. The effect of SKF83959 on VGSCs was also prevented by pretreatment with inhibitors of phospholipase C (PLC) and protein kinases C (PKC), but the inositol-1,4,5-phosphate 3 (IP3) antagonist did not occlude SKF83959 (1μM)-induced reduction of VGSCs. These data indicate that SKF83959 inhibits VGSCs in cultured striatal neurons via D1-like receptor-phosphatidylinositol-PKC pathway, which may underlie the dopaminergic modulation on striatal neuronal excitability., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Context: To systematically evaluate the effects of hepatoprotective agents, when delivered either alone or in combination with other antiviral or non-antiviral drugs in patients with hepatitis B and hepatic fibrosis., Objectives: The current randomized controlled clinical trials aimed to evaluate the efficacy of combinations of antiviral and non-antiviral hepatoprotective agents on indexes of liver function and liver fibrosis in patients with hepatitis B., Data Sources: Published literatures in Chinese and English on hepatoprotective treatment strategies for chronic hepatitis B and liver fibrosis were searched in three databases and randomized controlled clinical trials were selected., Study Selection: Data were extracted according to a variety of inclusion and exclusion criteria. Meta-analysis was employed to analyze the data., Results: A total of 22 randomized controlled trials encompassing 1,714 cases were considered in the meta-analysis. The obtained results indicated that the combination of antiviral drug and hepatoprotective agent was better than antiviral drug alone to improve liver function. Similarly, regarding liver fibrosis, using two different hepatoprotective agents was better than using one agent. The normalization rates of Aminotransferase (ALT) and total Bilirubin (TBil) were improved 25.7% by two hepatoprotective agents compared to the single agent. Acetylcysteine was superior to ursodeoxycholic acid or silibinin to reduce ALT. Ursodeoxycholic acid was superior to acetylcysteine or silibinin to reduce TBIL., Conclusions: Hepatoprotective agents combined with antiviral drugs can significantly improve liver function and liver fibrosis parameters in patients with hepatitis B.

Considerable evidence indicates that methionine sulfoxide (MetO) reductase A (MsrA) plays an important role in cytoprotection against oxidative stress and serves as a potential drug target. To screen for MsrA regulators, a rapid and specific assay to monitor MsrA activity is required. Most of current assays for MsrA activity are based on the reduction of radioactive substrates such as [3H]-N-acetyl-MetO or fluorescent derivatives such as dimethylaminoazo-benzenesulfonyl-MetO. However, these assays require extraction procedures and special instruments. Here, we developed a specific colorimetric microplate assay for testing MsrA activity quickly, which was based on the fact that MsrA can catalyze the reduction of methyl sulfoxides and simultaneously oxidize dithiothreitol (DTT), whose color can be produced by reacting with Ellman's reagent (dithio-bis-nitrobenzoic acid, DTNB). The corresponding absorbance change at 412nm was recorded with a microplate reader as the reaction proceeded. This method to monitor MsrA activity is easy to handle. Our findings may serve as a rapid method for the characterization of recombinant enzyme and for the screening of enzyme inhibitors, pharmacological activators, gene expression regulators and novel substrates., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca²⁺ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor-phospholipase C-protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A's orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A-induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-β-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca²⁺-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.

Purpose: This study examined the influence of body fatness on body core temperature and heat loss responses during moderate-intensity exercise., Methods: Nine men with lower body fat and eight men with higher body fat, matched for aerobic fitness, completed 1 h of recumbent cycling at the same absolute intensity in a warm environment (30 degrees C, 40% RH). Percent body fat was measured by hydrostatic weighing, using oxygen dilution to determine residual volume. Esophageal temperature (T(es)), mean skin temperature (T(sk)), and local sweat rate (m(sw)) were measured at rest and continuously during exercise while forearm blood flow (FBF) was measured at rest and every 10 min during exercise., Results: The lower body fat and higher body fat groups were successfully matched for aerobic fitness, removing the influence of body fatness, given that V/O2(peak) was 50.72 +/- 7.34 and 50.43 +/- 5.01 ml x kg LBM(-1) x min(-1), respectively. When compared to lower body fat individuals, % body fat, body surface area (A(D)), and body mass were higher and A(D)/ mass was lower in higher body fat individuals. T(es), T(sk), FBF, m(sw), and the slope of m(sw):T(es) were not different between groups. Metabolic heat production was similar between the lower body fat (299.7 +/- 40.5 W x m(-2)) and higher body fat (288.1 +/- 30.6 W x m(-2)) subjects, respectively. Dry and evaporative heat loss, as well as heat storage during exercise, were not different between groups., Conclusion: These data suggest that there is no effect of body fatness on body core temperature or heat loss responses during moderate-intensity exercise in a warm environment.

Three new sodium salts of iridoid acids, deacetylasperulosidic acid sodium salt (1), teneoside D (2), and teneoside E (3) were isolated from the leaves of Hedyotis tenelliflora Blume (Rubiaceae), together with seven known iridoids, 6alpha-hydroxygeniposide (4), 6beta-hydroxygeniposide (5), 6-O-methyldeacetylasperulosidic acid methyl ester (6), 6-O-methylscandoside methyl ester (7), 6alpha-methoxygeniposidic acid (8), daphylloside (9), and mollugoside methyl ester (10). Their chemical structures were elucidated by 1D and 2D NMR spectroscopy, as well as HR-ESI-MS analysis.

Purpose: This study is aiming to investigate the feasibility and effect of applying modified Nuss procedure on recurrent pectus excavatum following previous open repair., Methods: By retrospectively reviewing patients of pectus excavatum enrolled in our department from July 2007 to August 2012, we find 27 cases of recurrent PE who received open repair previously. Twenty-six patients received Nuss repair, while one patient refused. Relevant data are collected and processed. A 3-month follow-up after operation is also reviewed. Analysis of data is conducted., Results: Twenty-six recurrent patients underwent modified Nuss procedure safely. Pneumothorax after operation occurred in one case. Pleural effusion occurred for every case, most were mild in quantity except two cases whose pleural effusion were moderate. All patients left hospital within 2 weeks after operation except one patient who died of respiration failure. Mean postoperative Haller Index is significantly different from the preoperative one. Cosmetic effect was excellent for 5 cases, good for 15 cases, moderate for 6 cases. In a 3-month follow-up, no bar displacement or rejection happened and pleural effusion was completely absorbed., Conclusion: Although technically challenging, Nuss procedure is feasible and good for recurrent PE after open repair.

Methionine sulfoxide reductases A (MsrA) has been postulated to act as a catalytic antioxidant system involved in the protection of oxidative stress-induced cell injury. Recently, attention has turned to MsrA in coupling with the pathology of Parkinson's disease, which is closely related to neurotoxins that cause dopaminergic neuron degeneration. Here, we firstly provided evidence that pretreatment with a natural polyphenol resveratrol (RSV) up-regulated the expression of MsrA in human neuroblastoma SH-SY5Y cells. It was also observed that the expression and nuclear translocation of forkhead box group O 3a (FOXO3a), a transcription factor that activates the human MsrA promoter, increased after RSV pretreatment. Nicotinamide , an inhibitor of silent information regulator 1 (SIRT1), prevented RSV-induced elevation of FOXO3a and MsrA expression, indicating that the effect of RSV was mediated by a SIRT1-dependent pathway. RSV preconditioning increased methionine sulfoxide(MetO)-reducing activity in SH-SY5Y cells and enhanced their resistance to neurotoxins, including chloramine-T and 1-methyl-4-phenyl-pyridinium. In addition, the enhancement of cell resistance to neurotoxins caused by RSV preconditioning can be largely prevented by MsrA inhibitor dimethyl sulfoxide. Our findings suggest that treatment with polyphenols such as RSV can be used as a potential regulatory strategy for MsrA expression and function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Purpose: Impairment of glucose utilization contributes to neuronal degeneration of Alzheimer's disease patients. Cellular glucose utilization can be regulated by calcium-dependent signaling pathways. Resveratrol (RSV) is a plant-derived polyphenol with multiple beneficial effects, including neuroprotection and metabolic improvement. Here, we investigated the effect of RSV on neuronal calcium signal and glucose utilization., Experimental Methods: Primary culture of cortical neurons, calcium imaging, 2-NBDG assay and western blotting were employed to investigate RSV-mediated effects on neuronal calcium signal and glucose utilization., Results: RSV elevated intracellular calcium in cortical neurons via modulation of secondary messenger system including nitrous oxide, cGMP and cAMP. Secondarily, a calcium-dependent enhancement of neuronal glucose utilization after RSV treatment was observed. The effects on neuronal glucose utilization are largely dependent on RSV-induced calcium-dependent AMP-activated protein kinase activation., Conclusion: Our findings show that activation of calcium-dependent signaling pathways by RSV may convey improvements of neuronal glucose utilization., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Chemical investigation of the fruits of Alpinia oxyphylla led to an isolation of the two new natural products, 9-hydroxy epinootkatol (1) and (S)-2-pentanol-2-O-β-D-glucopyranoside (2), in addition to the nine known compounds, pinocembrin (3), tectochrysin (4), izalpinin (5), nookatone (6), yakuchinone A (7), protocatechuic acid (8), β-sitosterol (9), daucosterol (10) and β-sitosterol palmitate (11). Their structures were elucidated on the basis of physicochemical constants and NMR spectral data analysis. The effects of the isolated components on nitric oxide production in LPS-induced RAW 264.7 macrophages were examined. The two new natural compounds showed inhibitory activities with IC(50) values of 21.8 and 32.8 μg/mL, respectively.

Reactive oxygen species (ROS) is reported to be a critical pathogenic factor and mitochondria is one of the susceptible subcellular organs for oxidative damage. Methionine sulfoxide reductase A (MsrA) is a key anti-oxidant enzyme associated with cytoprotection and previous reports have revealed its importance in mitochondrial function. The anti-oxidation of MsrA is due to Met-centered redox cycle, suggesting that Met-centered redox cycle may play a critical role in mitochondrial protection. L-Methionine (L-Met), a natural amino acid with anti-oxidation activity, can mimic the effect of Met-centered redox cycle. Here, we investigated the protection of L-Met on H(2)O(2)-induced oxidative damage in mitochondria. Our study demonstrated that L-Met protected H(2)O(2)-induced injury in CHO cells. Cytoprotections of L-Met at low concentrations (1-5mM) were abolished by dimethyl sulfoxide (DMSO), a competitive inhibitor of MsrA function, suggesting that these effects may involve the participation of MsrA. Overexpression of MsrA in CHO cells protected mitochondria from H(2)O(2)-induced downtrend of membrane potential and production of mitochondrial superoxide. Pre-treatment with L-Met (1mM) produced a similar effect on the mitochondrial protection against H(2)O(2). Furthermore, it was observed that topical application of L-Met can prevent 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced oxidative damage in the skin of mice. These results suggest that anti-oxidation activity of L-Met may promise a new strategy for the prevention of oxidative stress-induced damage., (Copyright © 2012 Elsevier Ltd. All rights reserved.)