Phosphorylation at Ser 727 Increases STAT3 Interaction with PKCε Regulating Neuron-Glia Crosstalk via IL-6-Mediated Hyperalgesia In Vivo and In Vitro.

METHODS: A rat hyperalgesia model was induced using an intraplantar injection of Freund's complete adjuvant (FCA) or an intrathecal injection of IL-6. Mechanical allodynia was evaluated using von Frey filament tests after intrathecal injections of T-5224 (c-Fos/AP-1 inhibitor), minocycline (Mino, a specific microglia inhibitor), L-2-aminoadipic acid (LAA, an astroglial toxin), PKCε inhibitor peptide, APTSTAT3-9R (STAT3 inhibitor), or anti-IL-6 antibody. The c-Fos, GFAP, Iba-1, PKCε, STAT3, pSTAT3Tyr705 and pSTAT3Ser727, and IL-6 expression at the spinal cord level was assessed by Western blot analysis. The interactive effects of PKCε and STAT3 were determined using immunofluorescence staining and immunoprecipitation in vivo and in vitro. Interleukin-6 promoter activity was examined using luciferase assays. RESULTS: T-5224, Mino, and LAA attenuated FCA- or IL-6-mediated inflammatory pain, with a decrease in c-Fos, GFAP, Iba-1, PKCε, and IL-6 expression. PKCε inhibitor peptide and APTSTAT3-9R reversed FCA-induced nociceptive behavior, while decreasing pSTAT3Ser727, IL-6, c-Fos, GFAP, and Iba-1 expression and PKCε and STAT3 coexpression. Interleukin-6 promoter activity increased in the presence of PKCε and STAT3. The interaction with PKCε increased on phosphorylating STAT3 at Ser727 but not at Tyr705. CONCLUSION: STAT3 phosphorylation at Ser 727 and the interaction with PKCε contribute to hyperalgesia via the IL-6-mediated signaling pathway, thus regulating neuron-glia crosstalk during inflammatory pain.

New discoveries in the field of metabolism by applying single-cell and spatial omics.

Single-cell multi-Omics (SCM-Omics) and spatial multi-Omics (SM-Omics) technologies provide state-of-the-art methods for exploring the composition and function of cell types in tissues/organs. Since its emergence in 2009, single-cell RNA sequencing (scRNA-seq) has yielded many groundbreaking new discoveries. The combination of this method with the emergence and development of SM-Omics techniques has been a pioneering strategy in neuroscience, developmental biology, and cancer research, especially for assessing tumor heterogeneity and T-cell infiltration. In recent years, the application of these methods in the study of metabolic diseases has also increased. The emerging SCM-Omics and SM-Omics approaches allow the molecular and spatial analysis of cells to explore regulatory states and determine cell fate, and thus provide promising tools for unraveling heterogeneous metabolic processes and making them amenable to intervention. Here, we review the evolution of SCM-Omics and SM-Omics technologies, and describe the progress in the application of SCM-Omics and SM-Omics in metabolism-related diseases, including obesity, diabetes, nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). We also conclude that the application of SCM-Omics and SM-Omics approaches can help resolve the molecular mechanisms underlying the pathogenesis of metabolic diseases in the body and facilitate therapeutic measures for metabolism-related diseases. This review concludes with an overview of the current status of this emerging field and the outlook for its future.

Lactoferrin modification of berberine nanoliposomes enhances the neuroprotective effects in a mouse model of Alzheimer's disease.

Previous studies have shown that berberine has neuroprotective effects against Alzheimer's disease, including antagonizing tau phosphorylation, and inhibiting acetylcholinesterase activity and neural cell apoptosis. However, its low bioavailability and adverse reactions with conventional administration limit its clinical application. In this study, we prepared berberine nanoliposomes using liposomes characterized by low toxicity, high entrapment efficiency, and biodegradability, and modified them with lactoferrin. Lactoferrin-modified berberine nanoliposomes had uniform particle size and high entrapment efficiency. We used the lactoferrin-modified berberine nanoliposomes to treat a mouse model of Alzheimer's disease established by injection of amyloid-beta 1-42 into the lateral ventricle. Lactoferrin-modified berberine nanoliposomes inhibited acetylcholinesterase activity and apoptosis in the hippocampus, reduced tau over-phosphorylation in the cerebral cortex, and improved mouse behavior. These findings suggest that modification with lactoferrin can enhance the neuroprotective effects of berberine nanoliposomes in Alzheimer's disease.

Human clinical trial using diagnostic ultrasound and microbubbles to enhance neoadjuvant chemotherapy in HER2- negative breast cancer.

Background: In vivo and in vitro experiments have demonstrated that diagnostic ultrasound combined with microbubbles (USMB) can enhance tumor chemotherapy, but few clinical studies have explored the effect of USMB in human HER2-negative breast cancer. We aimed to compare USMB combined with neoadjuvant chemotherapy (NAC) with NAC alone in the treatment of human HER2-negative breast cancer. Methods: Patients (n=10) enrolled in the study were treated with TAC (taxane - (docetaxel), anthracycline - (epirubicin or doxorubicin liposomes), and cyclophosphamide) and ultrasound using a commercial clinical ultrasound scanner for 20 min after each chemotherapy session, followed by intermittent injections of SonoVue® to induce sonoporation and enhance therapeutic efficacy. Contrast-enhanced ultrasound (CEUS) was used to record tumor perfusion before and after ultrasound treatment. Results: After completion of chemotherapy, the maximum tumor diameter of patients in the combined treatment group (n=10) was significantly smaller than that in the control group (n=16) (p=0.017). Although the combined treatment group had higher overall response and clinical benefit rates than those in the control group, there was no statistically significant difference in RECIST between the combined treatment group and the control groups (p=0.590). More patients in the combination therapy group achieved pathologic complete response than in the control group (p=0.014). For combined treatment, CEUS revealed that the peak intensity, mean transit time, and area under the curve were higher after treatment than before treatment (p<0.001, p<0.001, p=0.003, respectively). Combined therapy did not cause additional toxicity or increase side effects. Conclusion: USMB and chemotherapy can be combined in a clinical setting using commercially available equipment, without additional toxicity, and may improve the efficacy of NAC in HER2-negative breast cancer.

Suggestions of management on emergency responses to epidemic outbreaks in outpatient or emergency departments of tertiary teaching hospitals.

Image, graphical abstract.

Fundamental Studies of Rapidly Fabricated On-Chip Passive Micromixer for Modular Microfluidics.

Micromixers play an important role in many modular microfluidics. Complex on-chip mixing units and smooth channel surfaces ablated by lasers on polymers are well-known problems for microfluidic chip fabricating techniques. However, little is known about the ablation of rugged surfaces on polymer chips for mixing uses. This paper provides the first report of an on-chip compact micromixer simply, easily and quickly fabricated using laser-ablated irregular microspheric surfaces on a polymethyl methacrylate (PMMA) microfluidic chip for continuous mixing uses in modular microfluidics. The straight line channel geometry is designed for sequential mixing of nanoliter fluids in about 1 s. The results verify that up to about 90% of fluids can be mixed in a channel only 500 µm long, 200 µm wide and 150 µm deep using the developed micromixer fabricating method under optimized conditions. The computational flow dynamics simulation and experimental result agree well with each other.

Amelioration of AOM/DSS-Induced Murine Colitis-Associated Cancer by Evodiamine Intervention is Primarily Associated with Gut Microbiota-Metabolism-Inflammatory Signaling Axis.

Evodiamine (EVO), an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth.、Evodia rutaecarpa (Juss.) Benth. Var. bodinieri (Dode) Huang or Evodia rutaecarpa (Juss.) Benth. Var. officinalis (Dode) Huang, has anti-inflammatory and anti-tumor activities. Our previous study found that EVO attenuates colitis by regulating gut microbiota and metabolites. However, little is known about its effect on colitis-associated cancer (CAC). In this study, the protective effects of EVO on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis and tumor mice were observed, and the underlying potential mechanism was clarified. The results suggested that EVO ameliorated AOM/DSS-induced colitis by inhibiting the intestinal inflammation and improving mucosal barrier function. And EVO significantly reduced the number and size of AOM/DSS-induced colorectal tumors along with promoted apoptosis and inhibited proliferation of epithelial cell. Moreover, EVO promoted the enrichment of SCFAs-producing bacteria and reduced the levels of the pro-inflammatory bacteria, which contributes to the changes of microbiota metabolism, especially tryptophan metabolism. Furthermore, inflammatory response (like Wnt signaling pathway、Hippo signaling pathway and IL-17 signaling pathway) were effectively alleviated by EVO. Our study demonstrated that the protective therapeutic action of EVO on CAC is to inhibit the development of intestinal inflammation-cancer by regulating gut microbiota metabolites and signaling pathways of colon intestinal epithelial, which may represent a novel agent for colon cancer prevention via manipulation of gut microbiota.