Active Targeted Janus Theranostic Nanoplatforms Enable Chemo-Photothermal Therapy to Inhibit the Growth of Breast Cancer.

Nanoscale structures have been developed to serve various functions in cancer therapy, encompassing areas such as diagnosis, biomedical visualization, tissue regeneration, and drug delivery. Based on biocompatible chitosan oligosaccharides (COS) and gold nanorods (GNRs), we designed the drug delivery systems (GNR@polyacrylic acid-Mn@COS Janus nanoparticles (JNPs)), which achieved paclitaxel (PTX) loaded on the side of GNRs, and the PAA-Mn domain served as magnetic resonance imaging contrast agents. This system was found to be effectively delivered to tumor sites through the enhanced permeability and retention (EPR) effect and the active target of the COS. The uniform JNPs selectively targeted cancer cells instead of normal cells through interacting with the COS on the surface of tumor cells, and the pH/NIR-responsive drug release behavior further enhanced their therapeutic effects. The in vivo effects of JNPs against tumors were evaluated using subcutaneous and orthotopic lung metastasis models, yielding promising outcomes for both tumor diagnosis and cancer treatment. In conclusion, the obtained JNPs hold great promise as a theranostic nanoplatform with synergistic chemotherapeutic and photothermal effects.

The protective effects of Mai-Luo-Ning injection against LPS-induced acute lung injury via the TLR4/NF-κB signalling pathway.

BACKGROUND: Acute lung injury (ALI) is a severe inflammatory disorder associated with high morbidity and mortality rates. Various therapeutic strategies for ALI have been proposed over the last few decades; however, the treatment options remain limited. Mai-Luo-Ning injection (MLN), a traditional Chinese medical formulation, has been extensively used for the treatment of respiratory diseases. Nevertheless, the effects of MLN on ALI remain unclear. PURPOSE: This study aimed to investigate the protective and therapeutic effects of MLN on lipopolysaccharide-induced ALI mouse models and RAW 264.7 cells, and further explore the underlying mechanism of these effects. METHODS: The therapeutic activity of MLN was evaluated using an in vivo ALI model and an in vitro model of RAW 264.7 macrophages. UHPLC-ESI-Q-TOF-MS/MS was used to investigate the chemical constituents of the MLN. The material basis and potential protective mechanism of MLN were analyzed using network pharmacology. The roles of MLN in inhibiting the Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB) signalling pathway were investigated via western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence staining. RESULTS: In vivo experiments demonstrated that MLN ameliorated LPS-induced histological changes in lung tissues and reduced lung wet/dry weight ratio, total protein concentration in the bronchoalveolar lavage fluid and myeloperoxidase activity. Furthermore, MLN downregulated the in vivo and in vitro expression of pro-inflammatory cytokines such as tumour necrosis factor-alpha, interleukin-6, and interleukin-1ß. Network pharmacology analysis revealed that MLN could act synergistically through multiple targets and pathways and exert a protective effect, possibly through inhibiting TLR4/ NF-κB signalling pathways. Western blotting and immunofluorescence experiments further confirmed that MLN could regulate the expression of TLR4, MyD88, phospho-IκB-α, and phospho-NF-κB p65 in the TLR4/NF-κB signalling pathway and decrease the translocation of phospho-NF-κB p65 into the nucleus. CONCLUSION: This study suggests that MLN has a potential protective effect against LPS-induced ALI, which might be associated with the inhibition of the TLR4/NF-κB signalling pathway. Therefore, MLN is worthy of further investigation as a potential candidate for the treatment of ALI in the future.

A Reasonable Evaluation of Chuanxiong Rhizoma Processing with Wine through Comparative Pharmacokinetic Study of Bioactive Components: Dominant Effect on Middle Cerebral Artery Occlusion Model Rats.

According to the ancient documents and Chinese herbal medicine processing experience, Chuanxiong Rhizoma was usually processed with yellow rice wine to improve efficacy. However, the relevant mechanisms are still unclear so far. In this study, a validated ultrahigh-performance liquid chromatography tandem mass spectrometry method was used to compare the pharmacokinetics of four representative components in middle cerebral artery occlusion rats after oral administration of raw and wine-processed Chuanxiong Rhizoma. The neurobehavioral scores and 2,3,5-triphenyltetrazolium chloride staining were employed to evaluate the model. Biological samples were prepared by protein precipitation with methanol. All analytes were separated on an ACQUITY BEH C18 column through gradient elution using acetonitrile and 0.01% of formic acid as mobile phase, and the flow rate was 0.3 mL/min. The results showed that the maximum plasma concentrations, the area values under the concentration-time curves of senkyunolide A, and ferulic acid in wine-processed Chuanxiong Rhizoma were all higher than in raw Chuanxiong Rhizoma, which were completely opposite to our previous studies in normal rats. Compared with normal rats, the theory that wine processing could enhance the efficacy of Chuanxiong Rhizoma may be better reflected in model rats.

Stability of motor cortex network states during learning-associated neural reorganizations.

A substantial reorganization of neural activity and neuron-to-movement relationship in motor cortical circuits accompanies the emergence of reproducible movement patterns during motor learning. Little is known about how this tempest of neural activity restructuring impacts the stability of network states in recurrent cortical circuits. To investigate this issue, we reanalyzed data in which we recorded for 14 days via population calcium imaging the activity of the same neural populations of pyramidal neurons in layer 2/3 and layer 5 of forelimb motor and premotor cortex in mice during the daily learning of a lever-press task. We found that motor cortex network states remained stable with respect to the critical network state during the extensive reorganization of both neural population activity and its relation to lever movement throughout learning. Specifically, layer 2/3 cortical circuits unceasingly displayed robust evidence for operating at the critical network state, a regime that maximizes information capacity and transmission and provides a balance between network robustness and flexibility. In contrast, layer 5 circuits operated away from the critical network state for all 14 days of recording and learning. In conclusion, this result indicates that the wide-ranging malleability of synapses, neurons, and neural connectivity during learning operates within the constraint of a stable and layer-specific network state regarding dynamic criticality, and suggests that different cortical layers operate under distinct constraints because of their specialized goals.NEW & NOTEWORTHY The neural activity reorganizes throughout motor learning, but how this reorganization impacts the stability of network states is unclear. We used two-photon calcium imaging to investigate how the network states in layer 2/3 and layer 5 of forelimb motor and premotor cortex are modulated by motor learning. We show that motor cortex network states are layer-specific and constant regarding criticality during neural activity reorganization, and suggests that layer-specific constraints could be motivated by different functions.

Selected Phytoestrogens Distinguish Roles of ERα Transactivation and Ligand Binding for Anti-Inflammatory Activity.

Estrogen receptor α (ERα) is a ligand-activated transcriptional activator that is also involved vascular inflammation and atherosclerosis. Whether different ligands may affect this activity has not been explored. We screened a panel of phytoestrogens for their role in ERα binding and transcriptional transcription, and correlated the findings to anti-inflammatory activities in vascular endothelial cells stably expressing either a wild-type or mutant form of ERα deficient in its membrane association. Taxifolin and silymarin were "high binders" for ERα ligand binding; quercetin and curcumin were "high activators" for ERα transactivation. Using these phytoestrogens as functional probes, we found, in endothelial cells expressing wild-type ERα, the ERα high activator, but not the ERα high binder, promoted ERα nuclear translocation, estrogen response element (ERE) reporter activity, and the downstream gene expression. In endothelial cells expressing membrane association-deficient mutant ERα, the ERα nuclear translocation was significantly enhanced by taxifolin and silymarin, which still failed to activate ERα. Inflammation response was examined using the systemic or vascular inflammation inducers lipopolysaccharide or oxidized low-density lipoprotein. In both cases, only the ERα high activator inhibited nuclear translocation of nuclear factor κB, JNK, and p38, and the production of inflammatory cytokines IL-1ß and TNFα. We confirm a threshold nuclear accumulation of ERα is necessary for its transactivation. The anti-inflammatory activity of phytoestrogens is highly dependent on ERα transactivation, less so on the ligand binding, and independent of its membrane association. A pre-examination of phytoestrogens for their mode of ERα interaction could facilitate their development as better targeted receptor modifiers.

Network pharmacology exploration reveals endothelial inflammation as a common mechanism for stroke and coronary artery disease treatment of Danhong injection.

Although Danhong injection (DHI) is the most widely prescribed Chinese medicine for both stroke and coronary artery disease (CAD), its underlying common molecular mechanisms remain unclear. An integrated network pharmacology and experimental verification approach was used to decipher common pharmacological mechanisms of DHI on stroke and CAD treatment. A compound-target-disease & function-pathway network was constructed and analyzed, indicating that 37 ingredients derived from DH (Salvia miltiorrhiza Bge., Flos Carthami tinctorii and DHI) modulated 68 common targets shared by stroke and CAD. In-depth network analysis results of the top diseases, functions, pathways and upstream regulators implied that a common underlying mechanism linking DHI's role in stroke and CAD treatment was inflammatory response in the process of atherosclerosis. Experimentally, DHI exerted comprehensive anti-inflammatory effects on LPS, ox-LDL or cholesterol crystal-induced NF-κB, c-jun and p38 activation, as well as IL-1ß, TNF-α, and IL-10 secretion in vascular endothelial cells. Ten of 14 predicted ingredients were verified to have significant anti-inflammatory activities on LPS-induced endothelial inflammation. DHI exerts pharmacological efficacies on both stroke and CAD through multi-ingredient, multi-target, multi-function and multi-pathway mode. Anti-endothelial inflammation therapy serves as a common underlying mechanism. This study provides a new understanding of DHI in clinical application on cardiovascular and cerebrovascular diseases.

Transformation of Cortex-wide Emergent Properties during Motor Learning.

Learning involves a transformation of brain-wide operation dynamics. However, our understanding of learning-related changes in macroscopic dynamics is limited. Here, we monitored cortex-wide activity of the mouse brain using wide-field calcium imaging while the mouse learned a motor task over weeks. Over learning, the sequential activity across cortical modules became temporally more compressed, and its trial-by-trial variability decreased. Moreover, a new flow of activity emerged during learning, originating from premotor cortex (M2), and M2 became predictive of the activity of many other modules. Inactivation experiments showed that M2 is critical for the post-learning dynamics in the cortex-wide activity. Furthermore, two-photon calcium imaging revealed that M2 ensemble activity also showed earlier activity onset and reduced variability with learning, which was accompanied by changes in the activity-movement relationship. These results reveal newly emergent properties of macroscopic cortical dynamics during motor learning and highlight the importance of M2 in controlling learned movements.

Bidirectional regulation of angiogenesis by phytoestrogens through estrogen receptor-mediated signaling networks.

Sex hormone estrogen is one of the most active intrinsic angiogenesis regulators; its therapeutic use has been limited due to its carcinogenic potential. Plant-derived phytoestrogens are attractive alternatives, but reports on their angiogenic activities often lack in-depth analysis and sometimes are controversial. Herein, we report a data-mining study with the existing literature, using IPA system to classify and characterize phytoestrogens based on their angiogenic properties and pharmacological consequences. We found that pro-angiogenic phytoestrogens functioned predominantly as cardiovascular protectors whereas anti-angiogenic phytoestrogens played a role in cancer prevention and therapy. This bidirectional regulation were shown to be target-selective and, for the most part, estrogen-receptor-dependent. The transactivation properties of ERα and ERß by phytoestrogens were examined in the context of angiogenesis-related gene transcription. ERα and ERß were shown to signal in opposite ways when complexed with the phytoestrogen for bidirectional regulation of angiogenesis. With ERα, phytoestrogen activated or inhibited transcription of some angiogenesis-related genes, resulting in the promotion of angiogenesis, whereas, with ERß, phytoestrogen regulated transcription of angiogenesis-related genes, resulting in inhibition of angiogenesis. Therefore, the selectivity of phytoestrogen to ERα and ERß may be critical in the balance of pro- or anti-angiogenesis process.

State Dependency of Chemosensory Coding in the Gustatory Thalamus (VPMpc) of Alert Rats.

The parvicellular portion of the ventroposteromedial nucleus (VPMpc) is the part of the thalamus that processes gustatory information. Anatomical evidence shows that the VPMpc receives ascending gustatory inputs from the parabrachial nucleus (PbN) in the brainstem and sends projections to the gustatory cortex (GC). Although taste processing in PbN and GC has been the subject of intense investigation in behaving rodents, much less is known on how VPMpc neurons encode gustatory information. Here we present results from single-unit recordings in the VPMpc of alert rats receiving multiple tastants. Thalamic neurons respond to taste with time-varying modulations of firing rates, consistent with those observed in GC and PbN. These responses encode taste quality as well as palatability. Comparing responses to tastants either passively delivered, or self-administered after a cue, unveiled the effects of general expectation on taste processing in VPMpc. General expectation led to an improvement of taste coding by modulating response dynamics, and single neuron ability to encode multiple tastants. Our results demonstrate that the time course of taste coding as well as single neurons' ability to encode for multiple qualities are not fixed but rather can be altered by the state of the animal. Together, the data presented here provide the first description that taste coding in VPMpc is dynamic and state-dependent. SIGNIFICANCE STATEMENT: Over the past years, a great deal of attention has been devoted to understanding taste coding in the brainstem and cortex of alert rodents. Thanks to this research, we now know that taste coding is dynamic, distributed, and context-dependent. Alas, virtually nothing is known on how the gustatory thalamus (VPMpc) processes gustatory information in behaving rats. This manuscript investigates taste processing in the VPMpc of behaving rats. Our results show that thalamic neurons encode taste and palatability with time-varying patterns of activity and that thalamic coding of taste is modulated by general expectation. Our data will appeal not only to researchers interested in taste, but also to a broader audience of sensory and systems neuroscientists interested in the thalamocortical system.

[GC-MS analysis of essential oils from seeds of Myristica fragrans in Chinese market].

OBJECTIVE: To analyze the constituents of the essential oils extracted from nine samples of commercial seeds of Myristica fragrans Houtt respectively and to provide qualities control foundations. METHOD: Water steam distillation and GC-MS were used. RESULT: 95-118 compounds were separated respectively. 79 Compounds being identified which were 95.18%-98.70% of the total essential oil. CONCLUSION: Myristicin (39.63%) and terpene series were the main compounds.