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.

Flavonoids, the key active compounds in Epimedii Folium, have both protective and toxic effects on the liver. Their hepatoprotective effects are associated with reducing lipid accumulation and oxidative stress, which contribute to the management of various liver conditions. In contrast, the mechanisms driving Epimedii Folium-induced hepatotoxicity are less understood but likely involve oxidative stress and pyroptosis. Pharmacokinetic studies, especially on icaritin, indicate that it undergoes isopentenyl dehydrogenation, glycosylation, and glucuronidation in vivo, contributing to its pharmacological effects. However, intermediate metabolites of icaritin may interact with biomolecules, potentially leading to liver toxicity. This review offers a detailed examination of the dual effects of Epimedii Folium flavonoids on liver function, emphasizing recent discoveries in their hepatoprotective and hepatotoxic pathways. We also summarize and discuss the pharmacokinetics of these flavonoids, highlighting how their metabolism affects therapeutic efficacy and toxicity. Lastly, we propose strategies to mitigate liver injury, providing new perspectives on the safe use of Epimedii Folium.

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

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.

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.

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.

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.

Astragali Radix(AR)is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer(NK)cells.However,owing to the complexity of its composition,the specific active ingredients in AR that act on NK cells are not clear yet.Cell membrane chromatography(CMC)is mainly used to screen the active ingredients in a complex system of herbal medicines.In this study,a new comprehensive two-dimensional(2D)NK-92MI CMC/C18 column/time-of-flight mass spectrometry(TOFMS)system was established to screen for potential NK cell acti-vators.To obtain a higher column efficiency,3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column.In total,nine components in AR were screened from this system,which could be washed out from the NK-92MI/CMC column after 10 min,and they showed good affinity for NK-92MI/CMC column.Two representative active compounds of AR,isoastragaloside Ⅰ and astragaloside Ⅳ,promoted the killing effect of NK cells on K562 cells in a dose-dependent manner.It can thus suggest that isoastragaloside Ⅰ and astragaloside Ⅳ are the main immunomodulatory compo-nents of AR.This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.