Purpose: Leptin interacts not only with leptin receptor (LEPR) but also engages with other receptors. While the pro-oncogenic effects of the adrenergic receptor β2 (ADRB2) are well-established, the role of leptin in activating ADRB2 in triple-negative breast cancer (TNBC) remains unclear. Materials and Methods: The pro-carcinogenic effects of LEPR were investigated using murine TNBC cell lines, 4T1 and EMT6, and a tumor-bearing mouse model. Expression levels of LEPR, NADPH oxidase 4 (NOX4), and ADRB2 in TNBC cells and tumor tissues were analyzed via western blot and quantitative real-time polymerase chain reaction. Changes in reactive oxygen species (ROS) levels were assessed using flow cytometry and MitoSox staining, while immunofluorescence double-staining confirmed the co-localization of LEPR and ADRB2. Results: LEPR activation promoted NOX4-derived ROS and mitochondrial ROS production, facilitating TNBC cell proliferation and migration, effects which were mitigated by the LEPR inhibitor Allo-aca. Co-expression of LEPR and ADRB2 was observed on cell membranes, and bioinformatics data revealed a positive correlation between the two receptors. Leptin activated both LEPR and ADRB2, enhancing intracellular ROS generation and promoting tumor progression, which was effectively countered by a specific ADRB2 inhibitor ICI118551. In vivo, leptin injection accelerated tumor growth and lung metastases without affecting appetite, while treatments with Allo-aca or ICI118551 mitigated these effects. Conclusion This study demonstrates that leptin stimulates the growth and metastasis of TNBC through the activation of both LEPR and ADRB2, resulting in increased ROS production. These findings highlight LEPR and ADRB2 as potential biomarkers and therapeutic targets in TNBC.

Purpose: Leptin interacts not only with leptin receptor (LEPR) but also engages with other receptors. While the pro-oncogenic effects of the adrenergic receptor β2 (ADRB2) are well-established, the role of leptin in activating ADRB2 in triple-negative breast cancer (TNBC) remains unclear. Materials and Methods: The pro-carcinogenic effects of LEPR were investigated using murine TNBC cell lines, 4T1 and EMT6, and a tumor-bearing mouse model. Expression levels of LEPR, NADPH oxidase 4 (NOX4), and ADRB2 in TNBC cells and tumor tissues were analyzed via western blot and quantitative real-time polymerase chain reaction. Changes in reactive oxygen species (ROS) levels were assessed using flow cytometry and MitoSox staining, while immunofluorescence double-staining confirmed the co-localization of LEPR and ADRB2. Results: LEPR activation promoted NOX4-derived ROS and mitochondrial ROS production, facilitating TNBC cell proliferation and migration, effects which were mitigated by the LEPR inhibitor Allo-aca. Co-expression of LEPR and ADRB2 was observed on cell membranes, and bioinformatics data revealed a positive correlation between the two receptors. Leptin activated both LEPR and ADRB2, enhancing intracellular ROS generation and promoting tumor progression, which was effectively countered by a specific ADRB2 inhibitor ICI118551. In vivo, leptin injection accelerated tumor growth and lung metastases without affecting appetite, while treatments with Allo-aca or ICI118551 mitigated these effects. Conclusion This study demonstrates that leptin stimulates the growth and metastasis of TNBC through the activation of both LEPR and ADRB2, resulting in increased ROS production. These findings highlight LEPR and ADRB2 as potential biomarkers and therapeutic targets in TNBC.

Purpose: Leptin interacts not only with leptin receptor (LEPR) but also engages with other receptors. While the pro-oncogenic effects of the adrenergic receptor β2 (ADRB2) are well-established, the role of leptin in activating ADRB2 in triple-negative breast cancer (TNBC) remains unclear. Materials and Methods: The pro-carcinogenic effects of LEPR were investigated using murine TNBC cell lines, 4T1 and EMT6, and a tumor-bearing mouse model. Expression levels of LEPR, NADPH oxidase 4 (NOX4), and ADRB2 in TNBC cells and tumor tissues were analyzed via western blot and quantitative real-time polymerase chain reaction. Changes in reactive oxygen species (ROS) levels were assessed using flow cytometry and MitoSox staining, while immunofluorescence double-staining confirmed the co-localization of LEPR and ADRB2. Results: LEPR activation promoted NOX4-derived ROS and mitochondrial ROS production, facilitating TNBC cell proliferation and migration, effects which were mitigated by the LEPR inhibitor Allo-aca. Co-expression of LEPR and ADRB2 was observed on cell membranes, and bioinformatics data revealed a positive correlation between the two receptors. Leptin activated both LEPR and ADRB2, enhancing intracellular ROS generation and promoting tumor progression, which was effectively countered by a specific ADRB2 inhibitor ICI118551. In vivo, leptin injection accelerated tumor growth and lung metastases without affecting appetite, while treatments with Allo-aca or ICI118551 mitigated these effects. Conclusion This study demonstrates that leptin stimulates the growth and metastasis of TNBC through the activation of both LEPR and ADRB2, resulting in increased ROS production. These findings highlight LEPR and ADRB2 as potential biomarkers and therapeutic targets in TNBC.

Retrograde adeno-associated viruses (AAVs) are capable of infecting the axons of projection neurons and serve as a powerful tool for the anatomical and functional characterization of neural networks. However, few retrograde AAV capsids have been shown to offer access to cortical projection neurons across different species and enable the manipulation of neural function in non-human primates (NHPs). Here, we report the development of a novel retrograde AAV capsid, AAV-DJ8R, which efficiently labeled cortical projection neurons after local administration into the striatum of mice and macaques. In addition, intrastriatally injected AAV-DJ8R mediated opsin expression in the mouse motor cortex and induced robust behavioral alterations. Moreover, AAV-DJ8R markedly increased motor cortical neuron firing upon optogenetic light stimulation after viral delivery into the macaque putamen. These data demonstrate the usefulness of AAV-DJ8R as an efficient retrograde tracer for cortical projection neurons in rodents and NHPs and indicate its suitability for use in conducting functional interrogations.
Animals ; Haplorhini ; Axons ; Motor Neurons ; Interneurons ; Macaca ; Dependovirus/genetics* ; Genetic Vectors

Objective To study the pharmacokinetics of HMS-01 in mice and provide support for subsequent studies. Methods Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to establish a sensitive and specific method for the determination of the concentration of HMS-01 in plasma and other biological samples. The pharmacokinetics of HMS-01 in C57BL/6J mice were studied by the established method. To obtain the basic pharmacokinetic parameters, three doses of HMS-01 were given orally and one dose of HMS-01 was given intravenously. Results The pharmacokinetic results of mice showed that the intestinal absorption of HMS-01 was fast, the oral bioavailability of HMS-01 in mice was moderate (50% to 70%). The exposure levels (AUC and c_max) of HMS-01 in mice increased with the increase of dosage, while the AUC was linearly correlated with the increase of dosage. After intravenous administration of HMS-01, the half-life period in mice was about 1 h which was not long. The plasma clearance rate (CL_total.p) was 2.8 L/h·kg, which was similar to the hepatic blood flow of mice. The apparent volume of distribution (V_SS) was 5 L/kg, which was much larger than the total mouse fluid. There were significant differences in AUC and F (P<0.05), but no significant differences in parameters such as c_max,AUC_0−∞,t_1/2,CL_tot,p,MRT,Vss in male and female mice which were given 30 and 60mg/kg HWS-01 orally. Conclusion The pharmacokinetic process of HMS-01 in mice showed gender differences, and the area under the curve of blood concentration time and bioavailability of female mice were higher than that of male mice. As oral bioavailability was reasonable, further in vivo studies on HMS-01 in mice with heart failure by oral administration could be considered to provide evidence.

Heart failure (HF) is a global public health problem with high morbidity and mortality. Numerous studies have shown that HF is caused by severe disturbance of energy metabolism, resulting in insufficient cardiac energy supply. This lack of energy could lead to a failure of the heart to pump blood and a failure of energy metabolism in other organs throughout the body. Currently, therapeutics of HF work by reducing heart rate and cardiac preload and afterload, symptomatic treatment, or delaying the progression of the disease. However, drugs targeting heart energy metabolism have not been developed. the main characteristics of cardiac energy metabolism, metabolic changes during HF were summarized and drugs that improve cardiac function through energy metabolism were discussed, which could provide a new research direction for the development and application of drugs in treatment of heart failure.

Diabetic nephropathy (DN) is a common microvascular complication of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)，which is also the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the treatment methods are limited at present. More and more evidences have indicated that inflammatory response is involved in the pathogenesis and progression of DN. Several anti-inflammatory strategies that target specific inflammatory mediators (transcription factors, pro-inflammatory cytokines, chemokines, adhesion molecules) and intracellular signaling pathways have shown benefits in the DN rodent model. The mechanisms related to inflammation in the development and progression of DN were summarized and new strategies to prevent or treat DN based on inflammation were briefly discussed in this review.

Objective: To classify the characteristics of circadian type among clinical nurses and examine their relationships with presenteeism and work-related flow. Methods: Using a cross-sectional design, 568 nurses were recruited through convenience sampling in January 2021 from three hospitals in Shandong Province, China. The data were collected using self-report measures, including the 11-item Circadian Type Inventory, Stanford Presenteeism Scale-6, and Work-Related Flow Inventory. Latent class analysis was performed to identify any clustering of circadian types. One-way analysis was performed to compare the differences between presenteeism and work-related flow in different circadian types. Results: Four latent classes were identified, including high response class (14.4%), high flexible class (20.1%), high languid class (51.1%), and low response class (14.4%). Regarding presenteeism, the high languid class had higher scores than others. Regarding work-related flow, the scores of high flexible class were higher than those of high languid class, while the differences in all three dimensions were statistically significant. Conclusion Although the shift work mode is not expected to change, nursing managers could use circadian type as a predictive index to select and employ individuals for shift work to enhance work performance and provide sufficient support to staff who are intolerant to shift work.

P-glycoprotein (P-gp) highly expressed in cancer cells can lead to multidrug resistance (MDR) and the combination of anti-cancer drugs with P-gp inhibitor has been a promising strategy to reverse MDR in cancer treatment. In this study, we established a label-free and detergent-free system combining surface plasmon resonance (SPR) biosensor with styrene maleic acid (SMA) polymer membrane proteins (MPs) stabilization technology to screen potential P-gp inhibitors. First, P-gp was extracted from MCF-7/ADR cells using SMA polymer to form SMA liposomes (SMALPs). Following that, SMALPs were immobilized on an SPR biosensor chip to establish a P-gp inhibitor screening system, and the affinity between P-gp and small molecule ligand was determined. The methodological investigation proved that the screening system had good specificity and stability. Nine P-gp ligands were screened out from 50 natural products, and their affinity constants with P-gp were also determined. The in vitro cell verification experiments demonstrated that tetrandrine, fangchinoline, praeruptorin B, neobaicalein, and icariin could significantly increase the sensitivity of MCF-7/ADR cells to Adriamycin (Adr). Moreover, tetrandrine, praeruptorin B, and neobaicalein could reverse MDR in MCF-7/ADR cells by inhibiting the function of P-gp. This is the first time that SMALPs-based stabilization strategy was applied to SPR analysis system. SMA polymer can retain P-gp in the environment of natural lipid bilayer and thus maintain the correct conformation and physiological functions of P-gp. The developed system can quickly and accurately screen small molecule ligands of complex MPs and obtain affinity between complex MPs and small molecule ligands without protein purification.

Objective:To explore the diagnostic value of ultrasound in posterior fossa anomalies (PFA) at 11-13 + 6 gestational weeks by measuring brainstem (BS), brainstem-to-occipital bone (BSOB) diameter and BS/BSOB ratio. Methods:A total of 209 normal fetuses (control group) were randomly selected from Beijing Obstetrics and Gynecology Hospital, Capital Medical University, between March 2018 and November 2021. Reference ranges for BS, BSOB diameter and BS/BSOB ratio were obtained on the mid-sagittal view of the fetal profile and the relationship of three parameters and crown-rump length (CRL) was investigated. The intra- and inter-observer reliabilities were determined by intraclass correlation coefficient (ICC) in 30 normal fetuses. Fourteen fetuses diagnosed with PFA in the same period including 10 cases of cystic posterior fossa malformations (cPFM) and 4 cases of open spine bifida (OSB) were retrospectively selected to compare BS, BSOB diameter and the BS/BSOB ratio with control group.Results:BS and BSOB diameters were successfully obtained in all control fetuses (100%), and the intra- and inter-observer reliabilities for BS and BSOB diameters were good (ICC=0.877, 0.846 and 0.939, 0.895). In the control group, BS and BSOB diameter linearly correlated with CRL ( r=0.867, 0.794; all P<0.001), while the BS/BSOB ratio was 0.75 (0.71, 0.79). There were significant differences of BSOB diameter and BS/BSOB ratio between control group and PFA group (all P<0.05). Except for one isolated vermian hypoplasia (VH), the BSOB diameters in 9 (90%) cases of cPFM were above the 95th percentile of the calculated normal range and were below the 5th percentile in 4(100%) cases of OSB.Except for one isolated VH, the BS/BSOB ratio in 9 (90%) cases of cPFM was below the 5th percentile of the calculated normal range. The BS/BSOB ratio in 4 (100%) cases of OSB was above the 95th percentile of the calculated normal range. Conclusions:The measurements of BS and BSOB diameter are feasible with good repeatability. Abnormal BSOB diameter and BS/BSOB ratio are suggestive for PFA. The posterior fossa of isolated VH can be normal in the first trimester.