EBP1 promotes the malignant biological behaviors of kidney renal clear cell carcinoma through activation of p38/HIF-1α signaling pathway.

BACKGROUND: Kidney Renal Clear Cell Carcinoma (KIRC) is a common malignant tumor of the urinary system, and its incidence is increasing. ERBB3 binding protein (EBP1) is upregulated in various cancers. However, the connection between EBP1 and KIRC has not been reported. METHODS: The expression of EBP1 in normal kidney tissue and KIRC tissue was analyzed through database and tissue microarray. EBP1 was knocked down in KIRC cell lines, and its impact on KIRC proliferation was assessed through CCK-8, soft agar assay, and flow cytometry. Scratch and transwell assays were used to evaluate the influence of EBP1 on KIRC invasion and migration. Nude mice tumor experiment were conducted to examine the effect of EBP1 on tumor tissue. Database analysis explored potential pathways involving EBP1, and validation was performed through Western blot experiments and p38 inhibitor. RESULTS: EBP1 is upregulated in KIRC and significantly correlates with clinical staging, pathological grading, and lymph node metastasis in patients. The mechanism research showed that knocking down EBP1 inhibited KIRC proliferation, invasion, and migration and inhibited p38 phosphorylation and the expression of hypoxia-inducible factor-1α (HIF-1α) in KIRC. p-38 inhibitor (SB203580) inhibits p38 phosphorylation and HIF-1α expression and suppresses cell viability in a concentration-dependent manner, but has no effect on EBP1 expression. HEK 293T cells overexpressing EBP1 showed increased expression of phosphorylated p38 and HIF-1α and enhanced cell viability, however, SB203580 inhibited this effect of EBP1. CONCLUSION: EBP1 may promote the occurrence and development of KIRC by regulating the expression of p38/HIF-1α signaling pathway.

NaOAc-Assisted Aerobic Oxidation Protocol for the Synthesis of Pentacoordinate Chalcogenyl Spirophosphoranes with P-Se/P-S Bonds under Open Air.

The NaOAc-assisted aerobic oxidation reaction of pentacoordinate hydrospirophosphoranes and dichalcogenyl compounds with open air as a green oxidant has been developed under mild conditions. A series of novel pentacoordinate spirophosphoranes with P-Se/P-S bonds were synthesized in excellent yields. The reaction mechanism was determined by 31P nuclear magnetic resonance tracing experiments, high-resolution mass spectrometry tracing experiments, and X-ray diffraction analysis. The method features a broad substrate scope, good functional group tolerance, and a high degree of atomic utilization and is meaningful for the synthesis of bioactive chalcogenphosphate compounds with chalcogen and phosphorus moieties.

Investigation of the Asymmetric Addition Reactions Induced by Pentacoordinated Hydrospirophosphorane Substrate.

Pentacoordinated bisaminoacyl hydrospirophosphoranes were first found to induce the asymmetric addition reactions as a novel chiral organic framework. Asymmetric addition reactions of bisaminoacyl hydrospirophosphoranes with aromatic aldehyde and in situ generated imine were investigated, and the corresponding α-hydroxyspirophosphonates and α-amino spirophosphonates were obtained. The addition reaction of hydrospirophosphoranes with ΔP configuration showed better stereoselectivity than that with ΛP configuration, not only for the addition reaction to aromatic aldehyde but also to in situ generated imine. Furthermore, the stereochemical mechanisms of asymmetric addition reactions induced by pentacoordinated hydrospirophosphorane were proposed by 31P NMR tracing experiment and X-ray diffraction analysis.

ERBB3 binding protein 1 promotes the progression of malignant melanoma through activation of the Wnt/ ß-catenin signaling pathway.

BACKGROUND: Malignant melanoma (MM) is highly metastatic and has the highest mortality rate in patients with skin cancer. The ERBB3 binding protein 1 (Ebp1) has been linked to the onset and progression of a number of malignancies. However, the role of Ebp1 in MM has not yet been reported. METHODS: Multiple databases were analyzed for comparing the expression of Ebp1 in normal skin and MM. Ebp1 expression was knocked down in A375 and B16 cells, and the impact of Ebp1 on the cell growth was tested by CCK-8, plate clone colony, and cell cycle assays. Scratch, transwell, and in vivo caudal vein lung metastasis tests were also used to confirm the effects of Ebp1 on melanoma cells migration, invasion, and metastasis. Furthermore, the possible molecular mechanism of Ebp1 was predicted by set enrichment analysis and verified by western blotting. RESULTS: Ebp1 expression was substantially higher in MM than it was in normal skin, and Ebp1 was linked to the clinical stage and lymph node metastases of patients with MM. Knockdown of Ebp1 inhibited cell proliferation, migration, and invasion. In vivo experiments further verified that the knockdown of Ebp1 had an obvious inhibitory effect on lung metastasis in nude mice. Knockdown of Ebp1 reduced vimentin, N-cadherin, slug, and snail expression while increasing E-cadherin expression. Furthermore, knockdown of Ebp1 reduced the expression of ß-catenin, as well as its downstream targets CyclinD1 and p-GSK3ß; however, a Wnt/ß-catenin agonist could reverse this effect. CONCLUSION: Ebp1 may promote the proliferation and metastasis of melanoma cells through activation of the Wnt/ß-catenin pathway.

Investigation of the Stereochemical Mechanism of the Nucleophilic Substitution Reaction at Pentacoordinate Phosphorus of Spirophosphorane.

The stereochemical mechanism of the nucleophilic substitution reaction at pentacoordinate phosphorus (P-V) atom is rarely studied. Here, we report the Atherton-Todd-type reaction of pentacoordinate hydrospirophosphorane with phenolic compounds in detail. The stereochemical mechanism of nucleophilic substitution at P-V atom was proposed by 31P NMR tracing experiment, X-ray diffraction analysis, and density functional theory calculations. The first step of the Atherton-Todd-type reaction is the formation of halogenated spirophosphorane intermediate with retention of configuration at phosphorus definitely. The second step is a nucleophilic substitution reaction at P-V atom of halogenated spirophosphorane. When using CCl4 as a halogenating agent, the reaction of chlorinated spirophosphorane proceeds via SN2(P-V) mechanism, and the backside attack of P-Cl bond is the main pathway. For chlorinated spirophosphorane with ΔP configuration, the completely P-inverted product is normally obtained. As for chlorinated spirophosphorane with ΛP configuration, which has larger steric hindrance behind P-Cl bond, the proportion of P-retained products apparently increases and a pair of diastereoisomers is acquired. Furthermore, if CBr4 is used as a halogenating agent, the nucleophilic substitution reaction of brominated spirophosphorane may go through a SN1(P-V) mechanism to afford a pair of diastereoisomers.

The occurrence and removal of organophosphate ester flame retardants/plasticizers in a municipal wastewater treatment plant in the Pearl River Delta, China.

The occurrence, distribution and main removal pathway of seven widely used organophosphate esters (OPs) in a municipal wastewater treatment plant (WWTP) located in the Pearl River Delta were investigated. Their daily discharge load into the Pearl River via effluent was also estimated. All the target analytes were detected in wastewater, suspended particle and dewatered sludge, with tri-n-butyl phosphate (TBP) and tris(2-butoxyethyl) phosphate (TBEP) as the main components. The total concentrations of TBP and TBEP were 21271.8 ng L(-1) and 4349.4 ng L(-1), 3105.1 ng L(-1) and 494.5 ng L(-1) in influent wastewater and final effluent, respectively. These results indicated that non-chlorinated OPs were removed efficiently in the WWTP, while chlorinated OPs passed through the WWTP unchanged due to their resistance to current wastewater treatment technology. Approximate 91.4 g of non-chlorinated OPs and 23.4 g of chlorinated OPs per day were discharged into the Pearl River via effluent, 2.4 g of non-chlorinated OPs and 0.6 g of chlorinated OPs entered the environment following sludge disposal.

Salidroside alleviates cholestasis-induced liver fibrosis by inhibiting hepatic stellate cells via activation of the PI3K/AKT/GSK-3ß signaling pathway and regulating intestinal flora distribution.

Salidroside (SAL), a phenylpropanoid bioactive compound, has various pharmacological properties, including antioxidant, anti-inflammatory, and hepatoprotective effects. However, the pharmacological effects and mechanisms of action of SAL on cholestatic liver injury are unclear. This study investigated the mechanism and effects of salidroside (SAL) on intestinal flora distribution and hepatic stellate cell (HSC) activation in cholestatic hepatic fibrosis. Bile duct ligation was used to cause cholestasis BALB/c mice. The therapeutic efficacy of SAL in liver fibrosis was assessed via serum/tissue biochemical analyses and liver tissue hematoxylin and eosin and Masson staining. Inflammation and oxidative stress were analyzed using enzyme-linked immunosorbent assay and western blotting. HSC were activated in vitro using lipopolysaccharide, and the effects of SAL on HSC migration and inflammatory factor expression were detected via scratch, transwell, and western blotting assays. The effects of SAL on the PI3K/AKT/GSK-3ß pathway in vivo and in vitro were detected using western blotting. 16sRNA sequencing was used to detect the effect of SAL on the diversity of the intestinal flora. Ileal histopathology and western blotting were used to detect the protective effect of SAL on the intestinal mucosal barrier. SAL reduces liver inflammation and oxidative stress and protects against liver fibrosis with cholestasis. It inhibits HSC activation and activates the PI3K/AKT/GSK-3ß pathway in vitro and in vivo. Additionally, SAL restores the abundance of intestinal flora, which contributes to the repair of the intestinal mucosal barrier, inhibits endotoxin translocation, and indirectly inhibits HSC activation, reversing the course of cholestatic liver fibrosis. SAL inhibits HSC activation through the PI3K/AKT/GSK-3ß pathway and improves intestinal flora distribution, thereby protecting and reversing the progression of hepatic fibrosis.

Dazhu Hongjingtian injection attenuated alcohol-induced depressive symptoms by inhibiting hippocampus oxidative stress and inflammation through Nrf2/HO-1/NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Alcoholic depression, a disorder of the central nervous system, is characterized by alcohol abuse, which causes blood-brain barrier disruption and oxidative damage in the brain. The rhizome of Rhodiola crenulate, from which Dazhu Hongjingtian Injection (DZHJTI) is derived, has been traditionally employed in ethnopharmacology to treat neurological disorders due to its neuroprotective, anti-inflammatory, and antioxidant properties. However, the exact mechanism by which DZHJTI alleviates alcoholic depression remains unclear. AIM OF THE STUDY: This study aimed to investigate the antidepressant effects of DZHJTI and its underlying mechanisms in a mouse model of alcohol-induced depression. MATERIALS AND METHODS: A model of alcoholic depression was established using C57BL/6J mice, and the effects of DZHJTI on depression-like behaviors induced by alcohol exposure were assessed through behavioral experiments. Histopathological examination was conducted to observe nerve cell damage and microglial activation in the hippocampal region. Oxidative stress indices in the hippocampus, inflammatory factors, and serum levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) were measured using ELISA. Expression of proteins related to the Nrf2/HO-1/NLRP3 signaling pathway was determined by Western blot analysis. RESULTS: DZHJTI attenuated depression-like behaviors, neuronal cell damage, oxidative stress levels, inflammatory responses, and microglial activation. It also restored levels of brain-derived neurotrophic factor, brain myelin basic protein, DA, and 5-HT in mice with chronic alcohol exposure. After DZHJTI treatment, the expressions of Nuclear Respiratory Factor 2 (Nrf2) and Heme Oxygenase-1 (HO-1) increased in the hippocampus, whereas the levels of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD, cleaved caspase-1, interleukin (IL)-1ß, and IL-18 decreased. CONCLUSIONS: DZHJTI ameliorates alcohol-induced depressive symptoms in mice through its antioxidant and anti-inflammatory effects, involving mechanisms associated with the Nrf2/HO-1/NLRP3 signaling pathway. This study highlights the potential of DZHJTI as a therapeutic option for alcohol-related depression and suggests the scope for future research to further elucidate its mechanisms and broader clinical applications.

A molecularly defined amygdala-independent tetra-synaptic forebrain-to-hindbrain pathway for odor-driven innate fear and anxiety.

Fear-related disorders (for example, phobias and anxiety) cause a substantial public health problem. To date, studies of the neural basis of fear have mostly focused on the amygdala. Here we identify a molecularly defined amygdala-independent tetra-synaptic pathway for olfaction-evoked innate fear and anxiety in male mice. This pathway starts with inputs from the olfactory bulb mitral and tufted cells to pyramidal neurons in the dorsal peduncular cortex that in turn connect to cholecystokinin-expressing (Cck+) neurons in the superior part of lateral parabrachial nucleus, which project to tachykinin 1-expressing (Tac1+) neurons in the parasubthalamic nucleus. Notably, the identified pathway is specifically involved in odor-driven innate fear. Selective activation of this pathway induces innate fear, while its inhibition suppresses odor-driven innate fear. In addition, the pathway is both necessary and sufficient for stress-induced anxiety-like behaviors. These findings reveal a forebrain-to-hindbrain neural substrate for sensory-triggered fear and anxiety that bypasses the amygdala.

Distinct Circuits From the Central Lateral Amygdala to the Ventral Part of the Bed Nucleus of Stria Terminalis Regulate Different Fear Memory.

BACKGROUND: The ability to differentiate stimuli that predict fear is critical for survival; however, the underlying molecular and circuit mechanisms remain poorly understood. METHODS: We combined transgenic mice, in vivo transsynaptic circuit-dissecting anatomical approaches, optogenetics, pharmacological methods, and electrophysiological recording to investigate the involvement of specific extended amygdala circuits in different fear memory. RESULTS: We identified the projections from central lateral amygdala (CeL) protein kinase C δ (PKCδ)-positive neurons and somatostatin (SST)-positive neurons to GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons in the ventral part of the bed nucleus of stria terminalis (vBNST). Prolonged optogenetic activation or inhibition of the PKCδCeL-vBNST pathway specifically reduced context fear memory, whereas the SSTCeL-vBNST pathway mainly reduced tone fear memory. Intriguingly, optogenetic manipulation of vBNST neurons that received the projection from PKCδCeL neurons exerted bidirectional regulation of context fear, whereas manipulation of vBNST neurons that received the projection from SSTCeL neurons could bidirectionally regulate both context and tone fear memory. We subsequently demonstrated the presence of δ and κ opioid receptor protein expression within the CeL-vBNST circuits, potentially accounting for the discrepancy between prolonged activation of GABAergic circuits and inhibition of downstream vBNST neurons. Finally, administration of an opioid receptor antagonist cocktail on the PKCδCeL-vBNST or SSTCeL-vBNST pathway successfully restored context or tone fear memory reduction induced by prolonged activation of the circuits. CONCLUSIONS: Together, these findings establish a functional role for distinct CeL-vBNST circuits in the differential regulation and appropriate maintenance of fear.

C3aR in the medial prefrontal cortex modulates the susceptibility to LPS-induced depressive-like behaviors through glutamatergic neuronal excitability.

Complement activation and prefrontal cortical dysfunction both contribute to the pathogenesis of major depressive disorder (MDD), but their interplay in MDD is unclear. We here studied the role of complement C3a receptor (C3aR) in the medial prefrontal cortex (mPFC) and its influence on depressive-like behaviors induced by systematic lipopolysaccharides (LPS) administration. C3aR knockout (KO) or intra-mPFC C3aR antagonism confers resilience, whereas C3aR expression in mPFC neurons makes KO mice susceptible to LPS-induced depressive-like behaviors. Importantly, the excitation and inhibition of mPFC neurons have opposing effects on depressive-like behaviors, aligning with increased and decreased excitability by C3aR deletion and activation in cortical neurons. In particular, inhibiting mPFC glutamatergic (mPFCGlu) neurons, the main neuronal subpopulation expresses C3aR, induces depressive-like behaviors in saline-treated WT and KO mice, but not in LPS-treated KO mice. Compared to hypoexcitable mPFCGlu neurons in LPS-treated WT mice, C3aR-null mPFCGlu neurons display hyperexcitability upon LPS treatment, and enhanced excitation of mPFCGlu neurons is anti-depressant, suggesting a protective role of C3aR deficiency in these circumstances. In conclusion, C3aR modulates susceptibility to LPS-induced depressive-like behaviors through mPFCGlu neuronal excitability. This study identifies C3aR as a pivotal intersection of complement activation, mPFC dysfunction, and depression and a promising therapeutic target for MDD.

Unexpected insertion of CO2 into the pentacoordinate P-N bond: Atherton-Todd-type reaction of hydrospirophosphorane with amines.

The Atherton-Todd-type reaction of pentacoordinate hydrospirophosphoranes with amines was investigated, and a novel CO2 insertion reaction into the pentacoordinate P-N bond under mild conditions was developed. The mechanism and stereochemistry of the CO2 insertion reaction between hydrospirophosphoranes and secondary amines were proposed via a carbon-13 labeling experiment, a (31)P NMR tracing experiment, and X-ray diffraction analysis. The chlorinated spirophosphorane intermediate was first generated with stereoretention of the configuration at phosphorus and subsequently was attacked by a carbamate anion formed from CO2 and a secondary amine. It was found that rear attack of nucleophilic substitution with stereoinversion at pentacoordinate phosphorus was the preferred route, although front attack happened for sterically hindered reactants. The configuration of the CO2 insertion product depended mainly upon the original phosphorus configuration of the hydrospirophosphoranes.

Glutamine ameliorates hyperoxia-induced hippocampal damage by attenuating inflammation and apoptosis via the MKP-1/MAPK signaling pathway in neonatal rats.

Glutamine (Gln) is an immunomodulatory protein that mediates oxidative stress, inflammation, and apoptosis, but has not been reported in the treatment of hyperoxia (Hyp)-induced brain injury. The aim of this study was to determine whether Gln could improve hyp-induced brain injury in neonatal rats to and later learning and memory dysfunction, and to explore its possible mechanisms. We prepared a model of neonatal rat brain injury caused by normobaric hyperoxia while administered with Gln for 7 days for evaluation. Learning memory function was assessed with the Morris water maze test. Histological analysis, protein expression analysis, oxidative stress and inflammation level analysis were performed using hippocampal tissue. Gln treatment significantly reduced brain tissue water content, oxidative stress levels, microglia activation and inflammatory factor expression, and attenuated tissue damage and apoptosis in the hippocampal region. Gln ameliorates hyp-induced learning, memory impairment in neonatal rats in water maze test. It also increased MKP-1 protein expression and decreased p-p38, p-ERK and p-JNK. Therefore, it is hypothesized that Gln may exert neuroprotective effects by increasing MKP-1 expression to negatively regulate MAPK signaling, with potential cognitive improvement in hyp-induced brain injury.

Neurocircuitry underlying the antidepressant effect of retrograde facial botulinum toxin in mice.

BACKGROUNDS: Botulinum toxin type A (BoNT/A) is extensively applied in spasticity and dystonia as it cleaves synaptosome-associated protein 25 (SNAP25) in the presynaptic terminals, thereby inhibiting neurotransmission. An increasing number of randomized clinical trials have suggested that glabellar BoNT/A injection improves depressive symptoms in patients with major depressive disorder (MDD). However, the underlying neuronal circuitry of BoNT/A-regulated depression remains largely uncharacterized. RESULTS: Here, we modeled MDD using mice subjected to chronic restraint stress (CRS). By pre-injecting BoNT/A into the unilateral whisker intrinsic musculature (WIM), and performing behavioral testing, we showed that pre-injection of BoNT/A attenuated despair- and anhedonia-like phenotypes in CRS mice. By applying immunostaining of BoNT/A-cleaved SNAP25 (cl.SNAP25197), subcellular spatial localization of SNAP25 with markers of cholinergic neurons (ChAT) and post-synaptic membrane (PSD95), and injection of monosynaptic retrograde tracer CTB-488-mixed BoNT/A to label the primary nucleus of the WIM, we demonstrated that BoNT/A axonal retrograde transported to the soma of whisker-innervating facial motoneurons (wFMNs) and subsequent transcytosis to synaptic terminals of second-order neurons induced central effects. Furthermore, using transsynaptic retrograde and monosynaptic antegrade viral neural circuit tracing with c-Fos brain mapping and co-staining of neural markers, we observed that the CRS-induced expression of c-Fos and CaMKII double-positive neurons in the ventrolateral periaqueductal grey (vlPAG), which sent afferents to wFMNs, was down-regulated 3 weeks after BoNT/A facial pre-administration. Strikingly, the repeated and targeted silencing of the wFMNs-projecting CaMKII-positive neurons in vlPAG with a chemogenetic approach via stereotactic injection of recombinant adeno-associated virus into specific brain regions of CRS mice mimicked the antidepressant-like action of BoNT/A pre-treatment. Conversely, repeated chemogenetic activation of this potential subpopulation counteracted the BoNT/A-improved significant antidepressant behavior. CONCLUSION: We reported for the first time that BoNT/A inhibited the wFMNs-projecting vlPAG excitatory neurons through axonal retrograde transport and cell-to-cell transcytosis from the injected location of the WIM to regulate depressive-like phenotypes of CRS mice. For the limited and the reversibility of side effects, BoNT/A has substantial advantages and potential application in MDD.

Levels and distribution of synthetic musks and polycyclic aromatic hydrocarbons in sludge collected from Guangdong Province.

The levels and distribution of six polycyclic musks, three nitromusks and 15 polycyclic aromatic hydrocarbons (PAHs) were investigated in sludge collected from 19 municipal wastewater treatment plants (WWTPs) in six cities in Guangdong Province, China. PAHs were detected in all of the sludge samples, and the levels of the total 15 PAHs ranged from 177.2-4421.8 µg/kg dry weight (dw). Four polycyclic musks, 4-acetyl-1,1-dimethyl-6-tert-butylindan (ADBI), 6-acetyl-1,1,2,3,3,5-hexamethylindan (AHMI), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta (g) -2-benzopyran (HHCB) and 7-acetyl -1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydro naphthalene (AHTN), were found in these samples. The total concentrations of polycyclic musks varied from 794.4-12960.3 µg/kg dw, with HHCB and AHTN being the main components. Of the three nitromusks, 2,6-dinitro-3-methoxy-4-tert- butyl - toluene (MA) was only found in one sludge sample at the limit of detection (LOD) level, while 1-tert-butyl-3,5-dimethyl-2,4,6-trinitrobenzene (Musk xylene, MX) and 4-acetyl-1-tert-butyl-3,5-dimethyl-2,6-dinitrobenzene (Musk ketone, MK) were found at levels ranging from the LOD to 65.8 µg/kg dw and LOD to 172.7 µg/kg dw, respectively, in most of the sludge samples. The PAHs, polycyclic musks and nitro musks were also shown to have various distribution patterns, possibly due to their different wastewater sources and wastewater treatment technology.

(+)-Borneol inhibits the generation of reactive oxygen species and neutrophil extracellular traps induced by phorbol-12-myristate-13-acetate.

Background and purpose: Neutrophil extracellular traps (NETs) are special web-like structures that can be generated in both infectious and noninfectious diseases. Previous studies showed that reactive oxygen species (ROS) were crucial in the formation of NETs (NETosis). The purpose of this study is to evaluate the effect of (+)-borneol, an antioxidant, on NETosis. Methods: Human neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) to induce NETosis in vitro. Neutrophils treated with (+)-borneol at three different time points (-30 min, 0, and 30 min) associated with PMA stimulation were used to examine the effect of (+)-borneol on the formation of NETs. The ROS generation of neutrophils was also measured to explore the potential mechanism of the inhibitory effect of (+)-borneol on NETosis. Results: (+)-Borneol pretreatment inhibited NETosis induced by PMA. Immunofluorescence staining visualized and confirmed the inhibitory effect. (+)-Borneol inhibited the burst of ROS in neutrophils caused by PMA. Suppressing NADPH oxidase or protein kinase C (PKC) eliminated the effect of (+)-borneol on NETosis. Moreover, inhibiting Toll-like receptor 2 (TLR2) led to increased NETosis which can be inhibited by (+)-borneol. Conclusion: (+)-Borneol decreases the ROS level in activated neutrophils and inhibits NETosis triggered by PMA stimulation in vitro. (+)-Borneol therapy may be effective in some NET-dependent conditions.

Effects of cGMP/Akt/GSK-3ß signaling pathway on atrial natriuretic peptide secretion in rabbits with rapid atrial pacing.

Atrial natriuretic peptide (ANP) plays a pivotal role in the regulation of the cardiovascular system. The ANP level increases during atrial fibrillation (AF), suggesting that AF may provoke ANP secretion, but its potential mechanism is still unclear. In the present study, the potential mechanisms of rapid atrial pacing (RAP) regulating ANP secretion was explored. Rabbits were subjected to burst RAP, ANP secretion increased whereas cyclic guanosine monophosphate (cGMP) concentrations decreased during RAP. The p-Akt and p-GSK-3ß levels decreased in atrial tissues. Natriuretic peptide receptor A (NPR-A) protein and particulate guanylate cyclase (PGC) activity were detected. The sensitivity of NPR-A to ANP decreased, leading to the decrease of PGC activity. Also, the isolated atrial perfusion system were made in the rabbit model, cGMP was shown to inhibit ANP secretion, and the Akt inhibitor LY294002 (LY) and GSK-3ß inhibitor SB216763 (SB) attenuated the inhibitory effects of cGMP on ANP secretion and enhanced the inhibitory effects of cGMP on atrial dynamics. In conclusion, NPR-A interacts with ANP to regulate PGC expression, and influence the expression of cGMP during RAP, which involves in the Akt/GSK-3ß signaling pathway. From the aforementioned points we conclude that cGMP regulates ANP secretion by the Akt/GSK-3ß signaling pathway during atrial pacing.

Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset.

Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.

Inferring the Individual Psychopathologic Deficits With Structural Connectivity in a Longitudinal Cohort of Schizophrenia.

The prediction of schizophrenia-related psychopathologic deficits is exceedingly important in the fields of psychiatry and clinical practice. However, objective association of the brain structure alterations to the illness clinical symptoms is challenging. Although, schizophrenia has been characterized as a brain dysconnectivity syndrome, evidence accounting for neuroanatomical network alterations remain scarce. Moreover, the absence of generalized connectome biomarkers for the assessment of illness progression further perplexes the prediction of long-term symptom severity. In this paper, a combination of individualized prediction models with quantitative graph theoretical analysis was adopted, providing a comprehensive appreciation of the extent to which the brain network properties are affected over time in schizophrenia. Specifically, Connectome-based Prediction Models were employed on Structural Connectivity (SC) features, efficiently capturing individual network-related differences, while identifying the anatomical connectivity disturbances contributing to the prediction of psychopathological deficits. Our results demonstrated distinctions among widespread cortical circuits responsible for different domains of symptoms, indicating the complex neural mechanisms underlying schizophrenia. Furthermore, the generated models were able to significantly predict changes of symptoms using SC features at follow-up, while the preserved SC features suggested an association with improved positive and overall symptoms. Moreover, cross-sectional significant deficits were observed in network efficiency and a progressive aberration of global integration in patients compared to healthy controls, representing a group-consensus pathological map, while supporting the dysconnectivity hypothesis.

Gas-phase fragmentation of protonated 3-phenoxy imidazo[1,2-a] pyridines using tandem mass spectrometry and computational chemistry.

Imidazo[1,2-a] pyridine is one of the pharmaceutically important scaffolds and has been widely studied due to its extensive biological activities. In this work, electrospray ionization tandem mass spectrometry (ESI-MS/MS) in positive mode was used to study the gas-phase fragmentation behavior of a series of 3-phenoxy imidazo[1,2-a] pyridines. Proposed fragmentation pathways were supported by ESI-MS/MS data and computational thermochemistry. Homolytic cleavage of the 3-phenoxy C-O bond was the characteristic fragmentation of 3-phenoxy imidazo [1,2-a] pyridines. The eliminations of the one substituted phenoxy radical and CO produced other diagnostic ions for 3-phenoxy imidazo [1,2-a] pyridines, which were useful to identify the 3-phenoxy group and imidazo [1,2-a] pyridine scaffold. The results contribute to the further understanding of the gas-phase fragmentation of 3-phenoxy imidazo [1,2-a] pyridines and the identification of other analogs using tandem mass spectrometry techniques.