[Current situation of acupuncture and moxibustion patents in China and abroad].

The patents of acupuncture and moxibustion in China and abroad was analyzed, aiming to provide support for the innovative development of acupuncture industry. With the China Think Tank of Patent of Traditional Chinese Medicine and the PatSnap database as data sources, based on the mathematical statistics method, the application trend, legal status, patent types, transformation and distribution of major technical fields of acupuncture patents in China and abroad were analyzed. As a result, a total of 53,422 acupuncture patents were screened, involving 49 countries and 4 organizations. The patent types were mainly utility model patents. Although the application number of acupuncture patent had increased rapidly, the average patent conversion rate was generally low, approximately 4%. In the context of global economic integration, the acupuncture industry is developing at a high speed. It is suggested to take advantage of the "Belt and Road Initiative" to improve the international acceptance of acupuncture and moxibustion, adhere to the principle of attaching equal importance to the number and quality of patents, promote the in-depth cooperation of industry-university-research, and promote high-quality development of acupuncture and moxibustion.

[Advantages and application prospects of heat-sensitive moxibustion robot].

Moxibustion therapy is a unique health resource in China, which is advantageous by its irreplaceable effectiveness in treatment, disease prevention and healthcare. But, moxibustion therapy used in primary care institutions in China is far from the due role of this therapy played in medical practice. The authors believe that the heat-sensitive moxibustion (HSM) robot should be developed by integrating the manipulation of moxibustion therapy with modern artifical intelligence technology so that moxibustion therapy can be operated precisely and easily, deqi of moxibustion be effectively stimulated and the cost of its manual manipulation be reduced. Eventually, the technology of moxibustion therapy can be popularized in the primary care institutions to serve the health of the people. This paper introduces the creation of HSM technology, the research and development (R&D) of HSM robot, and its advantages, as well as the application prospects. It is anticipated that the R&D of HSM robot may speed up the development of moxibustion therapy worldwide.

Record-high CO2 emissions from boreal fires in 2021.

Extreme wildfires are becoming more common and increasingly affecting Earth's climate. Wildfires in boreal forests have attracted much less attention than those in tropical forests, although boreal forests are one of the most extensive biomes on Earth and are experiencing the fastest warming. We used a satellite-based atmospheric inversion system to monitor fire emissions in boreal forests. Wildfires are rapidly expanding into boreal forests with emerging warmer and drier fire seasons. Boreal fires, typically accounting for 10% of global fire carbon dioxide emissions, contributed 23% (0.48 billion metric tons of carbon) in 2021, by far the highest fraction since 2000. 2021 was an abnormal year because North American and Eurasian boreal forests synchronously experienced their greatest water deficit. Increasing numbers of extreme boreal fires and stronger climate-fire feedbacks challenge climate mitigation efforts.

Ultra-Low Pt Doping and Pt-Ni Pair Sites in Amorphous/Crystalline Interfacial Electrocatalyst Enable Efficient Alkaline Hydrogen Evolution.

Noble metal doping can achieve an increase in mass activity (MA) without sacrificing catalysis efficiency and stability, so that alkaline hydrogen evolution reaction (HER) performance of the catalyst can be optimized to the maximum degree. However, its excessively large ionic radius makes it difficult to achieve either interstitial doping or substitutional doping under mild conditions. Herein, a hierarchical nanostructured electrocatalyst with enriched amorphous/crystalline interfaces for high-efficiency alkaline HER is reported, which is composed of amorphous/crystalline (Co, Ni)11 (HPO3 )8 (OH)6 homogeneous hierarchical structure with an ultra-low doped Pt (Pt-a/c-NiHPi). Benefiting from the structural flexibility of the amorphous component, extremely low Pt (0.21 wt.%, totally 3.31 µg Pt on 1 cm-2 NF) are stably doped on it via a simple two-phase hydrothermal method. The DFT calculations show that due to the strongly electron transfer between the crystalline/amorphous components at the interfaces, electrons finally concentrate toward Pt and Ni in the amorphous components, thus the electrocatalyst has near-optimal energy barriers and adsorption energy for H2 O* and H* . With the above benefits, the obtained catalyst exhibits an exceptionally high MA (39.1 mA µg-1 Pt ) at 70 mV, which is almost the highest level among the reported Pt-based electrocatalysts for alkaline HER.

Novel model predicts diastolic cardiac dysfunction in type 2 diabetes.

OBJECTIVE: Diabetes mellitus complicated with heart failure has high mortality and morbidity, but no reliable diagnoses and treatments are available. This study aimed to develop and verify a new model nomogram based on clinical parameters to predict diastolic cardiac dysfunction in patients with Type 2 diabetes mellitus (T2DM). METHODS: 3030 patients with T2DM underwent Doppler echocardiography at the First Affiliated Hospital of Shenzhen University between January 2014 and December 2021. The patients were divided into the training dataset (n = 1701) and the verification dataset (n = 1329). In this study, a predictive diastolic cardiac dysfunction nomogram is developed using multivariable logical regression analysis, which contains the candidates selected in a minor absolute shrinkage and selection operator regression model. Discrimination in the prediction model was assessed using the area under the receiver operating characteristic curve (AUC-ROC). The calibration curve was applied to evaluate the calibration of the alignment nomogram, and the clinical decision curve was used to determine the clinical practicability of the alignment map. The verification dataset was used to evaluate the prediction model's performance. RESULTS: A multivariable model that included age, body mass index (BMI), triglyceride (TG), creatine phosphokinase isoenzyme (CK-MB), serum sodium (Na), and urinary albumin/creatinine ratio (UACR) was presented as the nomogram. We obtained the model for estimating diastolic cardiac dysfunction in patients with T2DM. The AUC-ROC of the training dataset in our model was 0.8307, with 95% CI of 0.8109-0.8505. Similar to the results obtained with the training dataset, the AUC-ROC of the verification dataset in our model was 0.8083, with 95% CI of 0.7843-0.8324, thus demonstrating robust. The function of the predictive model was as follows: Diastolic Dysfunction = -4.41303 + 0.14100*Age(year)+0.10491*BMI (kg/m2) +0.12902*TG (mmol/L) +0.03970*CK-MB (ng/mL) -0.03988*Na(mmol/L) +0.65395 * (UACR > 30 mg/g) + 1.10837 * (UACR > 300 mg/g). The calibration plot diagram of predicted probabilities against observed DCM rates indicated excellent concordance. Decision curve analysis demonstrated that the novel nomogram was clinically useful. CONCLUSION: Diastolic cardiac dysfunction in patients with T2DM can be predicted by clinical parameters. Our prediction model may represent an effective tool for large-scale epidemiological study of diastolic cardiac dysfunction in T2DM patients and provide a reliable method for early screening of T2DM patients with cardiac complications.KEY MESSAGESThis study used clinical parameters to predict diastolic cardiac dysfunction in patients with T2DM. This study established a nomogram for predicting diastolic cardiac dysfunction by multivariate logical regression analysis. Our predictive model can be used as an effective tool for large-scale epidemiological study of diastolic cardiac dysfunction in patients with T2DM and provides a reliable method for early screening of cardiac complications in patients with T2DM.

Genetic diversity of virus auxiliary metabolism genes associated with phosphorus metabolism in Napahai plateau wetland.

Viruses play important roles in ecosystems by interfering with the central metabolic pathways of the host during infection via the expression of auxiliary metabolic genes (AMGs), altering the productivity of ecosystems and thus affecting geochemical cycling. In this study, the genetic diversity of phosphorus metabolism AMGs phoH, phoU and pstS was investigated by phylogenetic analysis, PCoA analysis, and alpha diversity analysis based on metagenomic data. It was found that the majority of the sequences were unique to Napahai plateau wetland. It was shown that the genetic diversity of phoH, phoU and pstS genes was independent of both habitats and host origins. In addition, the metabolic pathway of AMGs associated with the phosphorus cycling was identified based on metagenomic data. When phosphorus is deficient, virus utilizes AMGs to affect the metabolic pathway, contributing to higher phosphorus levels in the host and facilitating virus survival, replication, and propagation in the host cell.

Removal, migration, and distribution of naphthalene in bioretention facilities: the influences of particulate matter.

Particulate matter (PM), as an important carrier of carrying and transporting runoff pollutants, can significantly affect the behavior and removal efficiency of pollutants in bioretention facilities. In order to control the pollution caused by naphthalene in bioretention facilities, the removal efficiency and migration characteristics of naphthalene were systematically investigated under the influences of PM. The results showed that the removal efficiency of naphthalene was 74 ~ 97% in bioretention facilities under the influences of PM. With the higher concentration, the lower rainfall return period, and the longer antecedent drying period, the removal efficiency of naphthalene in each medium layer were higher. Furthermore, the PM could increase the naphthalene adsorption capacity onto medium in the first 10 cm depth, which showed more than 80% removal efficiency and lower mobility of naphthalene. The removal efficiency of naphthalene was significantly higher (90 ~ 97%), when the particle size and concentration of PM were 0 ~ 45 µm and 500 mg/L, respectively. This study investigated the important role of PM for naphthalene removal in bioretention facilities, and provided effective guidelines for runoff pollution control, design of stormwater facilities, and assessment risk of naphthalene.

A Model-Informed Approach to Accelerate the Clinical Development of Janagliflozin, an Innovative SGLT2 Inhibitor.

AIM: To apply model-informed drug development (MIDD) approach to support the decision making in drug development and accelerate the clinical development of janagliflozin, an orally selective SGLT2 inhibitor. METHOD: We previously developed a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model of janagliflozin based on preclinical data to optimize dose design in the first-in-human (FIH) study. In the current study, we used clinical PK/PD data of the FIH study to validate the model and then simulate the PK/PD profiles of multiple ascending dosing (MAD) study in healthy subjects. Besides, we developed a population PK/PD model of janagliflozin to predict steady-state urinary glucose excretion (UGE [UGE,ss]) in healthy subjects in the Phase 1 stage. This model was subsequently used to simulate the UGE, ss in patients with type 2 diabetes mellitus (T2DM) based on a unified PD target (ΔUGEc) across healthy subjects and patients with T2DM. This unified PD target was estimated from our previous work of model-based meta-analysis (MBMA) for the same class of drugs. The model-simulated UGE,ss in patients with T2DM was validated by data from the clinical Phase 1e study. Finally, at the end of the Phase 1 study, we simulated the 24-week hemoglobin A1c (HbA1c) level in patients with T2DM of janagliflozin based on the quantitative UGE/FPG/HbA1c relationship informed by our previous MBMA study for the same class of drugs. RESULTS: The pharmacologically active dose (PAD) levels of multiple ascending dosing (MAD) study were estimated to be 25, 50,100 mg once daily (QD) for 14 days based on the effective PD target of approximately 50 g daily UGE in healthy subjects. Besides, our previous MBMA analysis for the same class of drugs has provided a unified effective PD target of ΔUGEc approximately 0.5-0.6 g/(mg/dL) in both healthy subjects and patients with T2DM. In this study, the model-simulated steady-state ΔUGEc (ΔUGEc,ss) of janagliflozin in patients with T2DM were 0.52, 0.61 and 0.66 g/(mg/dL) for 25, 50, 100 mg QD dose levels. Finally, we estimated that HbA1c at 24 weeks would decrease 0.78 and 0.93 from baseline for the 25 and 50 mg QD dose groups. CONCLUSIONS: The application of MIDD strategy adequately supported the decision making at each stage of janagliflozin development process. A waiver of Phase 2 study was successfully approved for janagliflozin based on these model-informed results and suggestions. This MIDD strategy of janagliflozin could be further utilized to support the clinical development of other SGLT2 inhibitors.

SOX9 Modulates the Transformation of Gastric Stem Cells Through Biased Symmetric Cell Division.

BACKGROUND & AIMS: Transformation of stem/progenitor cells has been associated with tumorigenesis in multiple tissues, but stem cells in the stomach have been hard to localize. We therefore aimed to use a combination of several markers to better target oncogenes to gastric stem cells and understand their behavior in the initial stages of gastric tumorigenesis. METHODS: Mouse models of gastric metaplasia and cancer by targeting stem/progenitor cells were generated and analyzed with techniques including reanalysis of single-cell RNA sequencing and immunostaining. Gastric cancer cell organoids were genetically manipulated with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) for functional studies. Cell division was determined by bromodeoxyuridine-chasing assay and the assessment of the orientation of the mitotic spindles. Gastric tissues from patients were examined by histopathology and immunostaining. RESULTS: Oncogenic insults lead to expansion of SOX9+ progenitor cells in the mouse stomach. Genetic lineage tracing and organoid culture studies show that SOX9+ gastric epithelial cells overlap with SOX2+ progenitors and include stem cells that can self-renew and differentiate to generate all gastric epithelial cells. Moreover, oncogenic targeting of SOX9+SOX2+ cells leads to invasive gastric cancer in our novel mouse model (Sox2-CreERT;Sox9-loxp(66)-rtTA-T2A-Flpo-IRES-loxp(71);Kras(Frt-STOP-Frt-G12D);P53R172H), which combines Cre-loxp and Flippase-Frt genetic recombination systems. Sox9 deletion impedes the expansion of gastric progenitor cells and blocks neoplasia after Kras activation. Although Sox9 is not required for maintaining tissue homeostasis where asymmetric division predominates, loss of Sox9 in the setting of Kras activation leads to reduced symmetric cell division and effectively attenuates the Kras-dependent expansion of stem/progenitor cells. Similarly, Sox9 deletion in gastric cancer organoids reduces symmetric cell division, organoid number, and organoid size. In patients with gastric cancer, high levels of SOX9 are associated with recurrence and poor prognosis. CONCLUSION: SOX9 marks gastric stem cells and modulates biased symmetric cell division, which appears to be required for the malignant transformation of gastric stem cells.

Molecular Engineering of pH-Responsive NIR Oxazine Assemblies for Evoking Tumor Ferroptosis via Triggering Lysosomal Dysfunction.

Ferroptosis, a newly discovered form of regulated cell death, is emerging as a promising approach to tumor therapy. However, the spatiotemporal control of cell-intrinsic Fenton chemistry to modulate tumor ferroptosis remains challenging. Here, we report an oxazine-based activatable molecular assembly (PTO-Biotin Nps), which is capable of triggering the lysosomal dysfunction-mediated Fenton pathway with excellent spatiotemporal resolution via near-infrared (NIR) light to evoke ferroptosis. In this system, a pH-responsive NIR photothermal oxazine molecule was designed and functionalized with a tumor-targeting hydrophilic biotin-poly(ethylene glycol) (PEG) chain to engineer well-defined nanostructured assemblies within a single-molecular framework. PTO-Biotin Nps possesses a selective tropism to lysosome accumulation inside tumor cells, accommodated by its enhanced photothermal activity in the acidic microenvironment. Upon NIR light activation, PTO-Biotin Nps promoted lysosomal dysfunction and induced cytosolic acidification and impaired autophagy. More importantly, photoactivation-mediated lysosomal dysfunction via PTO-Biotin Nps was found to markedly enhance cellular Fenton reactions and evoke ferroptosis, thereby improving antitumor efficacy and mitigating systemic side effects. Overall, our study demonstrates that the molecular engineering approach of pH-responsive photothermal oxazine assemblies enables the spatiotemporal modulation of the intrinsic ferroptosis mechanism, offering a novel strategy for the development of metal-free Fenton inducers in antitumor therapy.

Etiology and clinical characteristics of primary epistaxis.

Background: Primary epistaxis (rupture of nasal artery vessels) is a common emergency, but the related factors are still controversial. This study collected the data on primary epistaxis patients and healthy people undergoing a physical examination at the same center to explore and classify primary epistaxis by its characteristics. Methods: Primary epistaxis was divided into septal epistaxis and non-septal epistaxis, and logistic regression was performed to determine the risk factors. Results: In total, 196 cases of septal epistaxis and 127 cases of non-septal epistaxis, and the control group was 182 healthy subjects. There were significant differences in sex, drinking history, hypertension history and hyperlipidemia between the bleeding group and the control group, but no correlation with smoking, diabetes, cardiovascular and cerebrovascular events, or anticoagulant drug use. In the age group of 26-40 years it was related to alcohol consumption and hypertension, for those aged 41-55 years it was related to hypertension, in the age group of 56-70 years it was related to hypertension, high triglyceride and high apolipoprotein B levels, and no related factors were found in the age group >70 years. The risk factors for non-septal cases were increased low-density lipoprotein (LDL) [P=0.035; odds ratio (OR), 2.450; 95% confidence interval (CI): 1.067-5.624], male sex (P=0.002; OR, 3.136; 95% CI: 1.501-6.554), and younger age (P=0.000; OR, 0.941; 95%CI: 0.920-0.962). All patients with nosebleed underwent nasal endoscopy and the bleeding site was successfully located and treated with electrocoagulation. No further bleeding or serious complications occurred after 6 months of follow-up. Conclusions: Primary epistaxis is more common in males and is related to alcohol consumption, hypertension, and hyperlipidemia. In the young age groups, male sex, and increased LDL were high risk factors for non-septal hemorrhage in winter and spring. Nasal endoscopy and electrocoagulation are safe and effective.

Vault-correlated efficacy and safety of Implantable Collamer Lens V4c implantation for myopia in patients with shallow anterior chamber depth.

INTRODUCTION: To evaluate efficacy and safety outcomes after implantation of the Visian Implantable Collamer Lens (ICL V4c) in myopia patients with shallow anterior chamber depth (ACD). METHODS: This retrospective study followed 163 eyes of 94 patients for at least 24 months. Uncorrected distance visual acuity, corrected distance visual acuity, intraocular pressure (IOP), manifest refraction, vault, endothelial cell density (ECD), anterior chamber angle (ACA), anterior chamber volume (ACV) and the distance from the corneal endothelium to the central ICL (C-ICL) were measured during follow-ups. Spearman's correlation and logistic regression were used to identify variables correlated with changes in ECD and potential risk factors for ineffective outcomes, respectively. RESULTS: All surgeries were performed safely. High IOP of 9 eyes and anterior capsular opacity of 5 eyes were observed. The last follow-up ACA had a significant difference between the high and normal IOP groups (P = 0.0003). The mean ECD and vault was 2855.76 ± 270.82 cells/mm2 and 388.01 ± 135.28 µm at the last follow-up, respectively. The vault and C-ICL were significantly associated with ΔECD (all P < 0.01). Furthermore, the vault was most responsible for the ECD loss. Twenty-two eyes had unsatisfactory postoperative UDVA, and the low vault at the last follow-up was a significant risk factor for this ineffective outcome (P < 0.001, OR = 14.739). CONCLUSIONS: ICL V4c implantation in patients with shallow ACD achieved stable visual outcomes. The vault is related to postoperative visual acuity and ECD loss, which needs to be paid attention during follow-up.

The safflower MBW complex regulates HYSA accumulation through degradation by the E3 ligase CtBB1.

The regulatory mechanism of the MBW (MYB-bHLH-WD40) complex in safflower (Carthamus tinctorius) remains unclear. In the present study, we show that the separate overexpression of the genes CtbHLH41, CtMYB63, and CtWD40-6 in Arabidopsis thaliana increased anthocyanin and procyanidin contents in the transgenic plants and partially rescued the trichome reduction phenotype of the corresponding bhlh41, myb63, and wd40-6 single mutants. Overexpression of CtbHLH41, CtMYB63, or CtWD40-6 in safflower significantly increased the content of the natural pigment hydroxysafflor yellow A (HYSA) and negatively regulated safflower petal size. Yeast two-hybrid, functional, and genetic assays demonstrated that the safflower E3 ligase CtBB1 (BIG BROTHER 1) can ubiquitinate CtbHLH41, marking it for degradation through the 26S proteasome and negatively regulating flavonoid accumulation. CtMYB63/CtWD40-6 enhanced the transcriptional activity of CtbHLH41 on the CtDFR (Dihydroflavonol 4-reductase) promoter. We propose that the MBW-CtBB1 regulatory module may play an important role in coordinating HYSA accumulation with other response mechanisms. This article is protected by copyright. All rights reserved.

Extraction of Ursolic Acid from Apple Peel with Hydrophobic Deep Eutectic Solvents: Comparison between Response Surface Methodology and Artificial Neural Networks.

Extracting ursolic acid (UA) from plant resources using organic solvents is incompatible with food applications. To address this, in this study, 15 edible hydrophobic deep eutectic solvents (HDESs) were prepared to extract UA from apple peel, the extraction conditions were optimized, and the optimization strategies were compared. It was found that the solubility of UA in the HDESs can be 9 times higher than the traditional solvent such as ethanol. The response surface optimization concluded that temperature had the greatest effect on the extraction and the optimized test conditions obtained as follows: temperature of 49 °C, time of 32 min, solid-liquid ratio of 1:16.5 g/mL, respectively. Comparing the response surface methodology (RSM) and artificial neural networks (ANN), it was concluded that ANN has more accurate prediction ability than RSM. Overall, the HDESs are more effective and environmentally friendly than conventional organic solvents to extract UA. The results of this study will facilitate the further exploration of HDES in various food and pharmaceutical applications.

Joint effects of recent stressful life events and adverse childhood experiences on perinatal comorbid anxiety and depression.

BACKGROUND: Stressful life events (SLEs) and adverse childhood experiences (ACEs) have been reported to be associated with perinatal depression (PND) or perinatal anxiety (PNA) alone; however, in most cases, majority of PND and PNA coexist and could lead to more serious health consequences. The independent effect of recent SLEs and their joint effects with ACEs on perinatal comorbid anxiety and depression (CAD) remain inadequately explored. METHODS: Based on a longitudinal study, 1082 participants receiving prenatal care in Ma'anshan, China were included. Women were recruited in the first trimester (T1: ≤14+ 6 weeks) and followed up at 15 ~ 27 weeks (T2), 28 ~ 40 weeks (T3), and postpartum (T4). Depression and anxiety status were assessed at all time points, while recent SLEs and ACEs were measured at T1. Logistic regression was conducted to examine the associations of SLEs with the risks of CAD at different time points, as well as their joint effects with ACEs on CAD. RESULTS: Approximately 38.5% of women experienced at least one SLE, which was significantly associated with higher risks of CAD at all time points (p < 0.05). As the number of SLEs increased, the risk of CAD increased (p for trend < 0.05). Specific types of SLEs were associated with CAD in different periods, while only interpersonal events were consistently associated with risks of CAD throughout the whole perinatal period. The joint effects of SLEs with ACEs on CAD were identified throughout the perinatal period, with the highest observed in the first trimester (aOR = 7.47, 95% CI: 3.73-14.95; p for trend < 0.001). CONCLUSION: Our study demonstrated independent associations of recent SLEs and their joint effects with ACEs with risks of perinatal CAD. SLEs combined with ACEs should be recognized as a major risk factor for perinatal CAD and managed at the earliest time to prevent and control CAD.

[Research on ontology construction of acupuncture effect based on ISO/TS 16843-6: 2022].

In order to specify the information expression of acupuncture effect and realize the knowledge reuse and sharing, in view of animal experiments and clinical trials, the relevant knowledge of acupuncture effect is allocated. Using seven-step method and Protégé5.5.0 tool, the ontology of acupuncture effect is constructed on the base of ISO/TS 16843-6: 2022. A total of 199 classes are constructed, including 7 categories (acupuncture point, acupuncture therapy, needling method, biological process, genes and gene products, disorder, and anatomic structure), 12 object properties, 1 108 instances and 5 123 axioms. A semantic network with the characteristics of acupuncture and moxibustion is established and the structured expression for the knowledge of acupuncture effects is obtained, which lays the foundation for the innovation and development in the field of acupuncture and moxibustion.

Microstructural Analysis of Cancellous Bone in Fluorosis Rats.

Skeletal fluorosis likely alters bone structural properties on the cortical and cancellous tissue levels in view that fluorine ion replaces bone mineral composition. Our previous study showed high bone turnover occurred in cortical bone of skeletal fluorosis. Therefore, this study further analyzed the microstructure of cancellous bone in fluorosis rats. Rats were randomly assigned into three groups: the control, low-dose fluoride group (10 mgF-/kg·day), and high-dose fluoride group (20 mgF-/kg·day). Rats were orally administered with fluoride for 1, 2, and 3 months of periods. The trabecular bone parameters of tibia were detected with micro CT and analyzed with software. The activities of glutathione peroxidase (GPX), superoxide dismutase (SOD), and the content of malondialdehyde (MDA) in serum were measured. Results showed that severity of dental fluorosis rose with the increase of dose and prolongation of fluoride exposure. Meantime, the poorer connectivity and less trabecular bone network were observed in cancellous bone of rats treated with fluoride. Data analysis indicated that fluoride treatment significantly decreased bone volume and connectivity degree, but amplified trabecular space in 1 and 2 months of periods. Intriguingly, trabecular thickness significantly decreased in 1-month high-dose fluoride group, but returned to the control in 3 months of period. Fluoride treatment mainly inhibited the GPX activity and increased the MDA level to activate oxidative stress. This study confirmed that excessive fluoride impaired cancellous bone and caused redox imbalance.

Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex.

Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. Methods: We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. Results: Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non-monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. Conclusions: These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience.

Intrahippocampal injection of IL-1ß upregulates Siah1-mediated degradation of synaptophysin by activation of the ERK signaling in male rat.

Interleukin-1ß (IL-1ß) has been described to exert important effect on synapses in the brain. Here, we explored if the synapses in the hippocampus would be adversely affected following intracerebral IL-1ß injection and, if so, to clarify the underlying molecular mechanisms. Adult male Sprague-Dawley rats were divided into control, IL-1ß, IL-1ß + PD98059, and IL-1ß + MG132 groups and then sacrificed for detection of synaptophysin (syn) protein level, synaptosome glutamate release, and synapse ultrastructure by western blotting, glutamate kit and electron microscopy, respectively. These rats were tested by Morris water maze for learning and memory ability. It was determined by western blotting whether IL-1ß exerted the effect of on syn and siah1 expression in primary neurons via extracellular regulated protein kinases (ERK) signaling pathway. Intrahippocampal injection of IL-1ß in male rats and sacrificed at 8d resulted in a significant decrease in syn protein, damage of synapse structure, and abnormal release of neurotransmitters glutamate. ERK inhibitor and proteosome inhibitor treatment reversed the above changes induced by IL-1ß both in vivo and in vitro. In primary cultured neurons incubated with IL-1ß, the expression level of synaptophysin was significantly downregulated coupled with abnormal glutamate release. Furthermore, use of PD98059 had confirmed that ERK signaling pathway was implicated in synaptic disorders caused by IL-1ß treatment. The present results suggest that exogenous IL-1ß can suppress syn protein level and glutamate release. A possible mechanism for this is that IL-1ß induces syn degradation that is regulated by the E3 ligase siah1 via the ERK signaling pathway.