TEAD2 initiates ground-state pluripotency by mediating chromatin looping.

The transition of mouse embryonic stem cells (ESCs) between serum/LIF and 2i(MEK and GSK3 kinase inhibitor)/LIF culture conditions serves as a valuable model for exploring the mechanisms underlying ground and confused pluripotent states. Regulatory networks comprising core and ancillary pluripotency factors drive the gene expression programs defining stable naïve pluripotency. In our study, we systematically screened factors essential for ESC pluripotency, identifying TEAD2 as an ancillary factor maintaining ground-state pluripotency in 2i/LIF ESCs and facilitating the transition from serum/LIF to 2i/LIF ESCs. TEAD2 exhibits increased binding to chromatin in 2i/LIF ESCs, targeting active chromatin regions to regulate the expression of 2i-specific genes. In addition, TEAD2 facilitates the expression of 2i-specific genes by mediating enhancer-promoter interactions during the serum/LIF to 2i/LIF transition. Notably, deletion of Tead2 results in reduction of a specific set of enhancer-promoter interactions without significantly affecting binding of chromatin architecture proteins, CCCTC-binding factor (CTCF), and Yin Yang 1 (YY1). In summary, our findings highlight a novel prominent role of TEAD2 in orchestrating higher-order chromatin structures of 2i-specific genes to sustain ground-state pluripotency.

Chiral cysteine-copper ion-based assemblies for improved phototherapy.

Phototherapy, encompassing photothermal therapy and photodynamic therapy, is gaining attention as an appealing cancer treatment modality. To enhance its clinical implementation, a comprehensive exploration of the pivotal factors influencing phototherapy is warranted. In this study, the L/d-cysteine (Cys)-copper ion (Cu2+) chiral nanoparticles, through the assembly of L/d-Cys-Cu2+ coordination complexes, were constructed. We found that these nanoparticles interacted with chiral liposomes in a chirality-dependent manner, with d-Cys-Cu2+ nanoparticles exhibiting more than three times stronger binding affinity than l-Cys-Cu2+ nanoparticles. Furthermore, we demonstrated that the d-Cys-Cu2+ nanoparticles were more efficiently internalized by Hela cells in contrast with l-Cys-Cu2+. On this basis, indocyanine green (ICG), acting as both photothermal and photodynamic agent, was encapsulated into L/d-Cys-Cu2+ nanoparticles. Experimental results showed that the l-Cys-Cu2+-ICG and d-Cys-Cu2+-ICG nanoparticles displayed almost identical photothermal performance and singlet oxygen (1O2) generation capability in aqueous solution. However, upon laser irradiation, the d-Cys-Cu2+-ICG nanoparticles achieved enhanced anti-tumor effects compared to l-Cys-Cu2+-ICG due to their chirality-promoted higher cellular uptake efficiency. These findings highlight the crucial role of chirality in phototherapy and provide new perspectives for engineering cancer therapeutic agents.

Study on the correlation between B vitamins and breast cancer.

BACKGROUND: Relevant studies suggest that serum vitamin level is related to the risk of breast cancer, and dietary pattern and drug supplementation can significantly affect the level of vitamin in the body. Therefore, intervention of vitamin level in the body is expected to be a potential strategy to reduce the risk of breast cancer. However, the current epidemiological findings of serum vitamin levels and breast cancer risk are inconsistent, and the relationship between serum vitamin and breast cancer is still controversial. In this study, we compared the serum vitamin expression levels of healthy people, benign breast patients, and breast cancer patients, and evaluated the relationship between B vitamin levels and breast cancer risk. METHODS: The study used liquid chromatography-tandem mass spectrometry to determine the serum vitamin levels of 520 people who attended Yunnan Cancer Hospital from September 2020 to December 2020. After screening by exclusion criteria, 38 patients with benign breast diseases, 87 patients with breast cancer and 91 healthy controls were finally included. The kruskal-wallis H test was used to compare the differences in serum vitamin levels of subjects. Χ2 test was used to evaluate the relationship between B vitamin level and age,BMI,TNM staging,Ki-67,Her-2,surgery and chemotherapy, and other baseline characteristics and through binary logistic regression analysis, calculating odds ratio and 95% confidence interval (CI) to evaluate the relationship between B vitamins and breast cancer risk. CONCLUSION: The levels of VitB1 and VitB5 in the serum of breast cancer patients and patients with benign breast diseases were higher than those in the healthy control group, while the expression levels of VitB3 in breast cancer patients were lower than those in the healthy control group and the breast benign disease groups. The level of VitB1 was positively correlated with breast cancer risk. The VitB3 level was negatively correlated with breast cancer risk. The VitB5 level is not significantly related to the risk of breast cancer.

Engineering goat milk-derived extracellular vesicles for multiple bioimaging-guided and photothermal-enhanced therapy of colon cancer.

Multimodal image-guided photothermal therapy (PTT) has great application potential in cancer treatment due to its advantages of low side effects and good efficacy. There is an urgent need for PTT nanocarriers with high loading efficiency and modified surfaces. Goat milk-derived extracellular vesicles (GMVs) an ideal PTT nanoplatforms due to their anti-inflammatory ability, tumor retention ability, high yield, and high biosafety. This study used GMVs to design a theranostic nanoprobe for positron emission tomography/computer tomography/near-infrared fluorescence (PET/CT/NIRF) imaging and image-guided PTT for colon cancer. The key genes, important biological processes, and important signaling pathways of indocyanine green (ICG)-mediated PTT and N3-GMV@ICG-mediated PTT were analyzed. The nanoprobe triggered anti-tumor immune and inflammation responses to enhance PTT. In addition, the nanoprobe could attenuate PTT-induced inflammation benefiting from the anti-inflammatory efficacy of GMVs. Therefore, our findings conceptually advanced the diagnosis and treatment of colon cancer. We believed that the nanoprobe had broad clinical transformation prospects, and GMVs might be ideal nanocarriers for constructing integrated diagnostic and PTT probes.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

[Research progress on mechanism and preventive measures of retrograde ejaculation after benign prostatic hyperplasia surgery].

Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly men. It's first-line therapy is drugs. But with the progression of the disease or side effects of drugs, surgical treatment will become a better choice. However, either transurethral resection of the prostate, the standard procedure, or enucleation or resection of the prostate based on various laser platforms or plasma technologies cause a high incidence of retrograde ejaculation in their postoperative follow-up. In the past, retrograde ejaculation was usually regarded as the cost of benign prostatic hyperplasia surgery. In recent years, with the continuous improvement of surgical skills and the emergence of new techniques, retrograde ejaculation has aroused the attention of clinicians. This article mainly introduces the mechanism of retrograde ejaculation after benign prostatic hyperplasia surgery and the methods to reduce the incidence of retrograde ejaculation after surgery. These methods mainly include various modified surgery, as well as novel minimally invasive techniques such as prostate embolization and prostatic urethral lift.

Clinical efficacy of acupuncture combined with Western medicine in the treatment of mild to moderate Alzheimer disease: A protocol of a randomized controlled trial.

BACKGROUND: Alzheimer disease (AD) is a common cause of dementia, and there are still a lack of treatment options to reverse or prevent disease progression. Existing evidence shows that acupuncture has advantages in the treatment of AD, but whether the efficacy of acupuncture belongs to the placebo effect remains controversial, and there is no strict placebo-controlled clinical study to evaluate the efficacy and safety of acupuncture combined with Western medicine in the treatment of AD. METHODS: This is a prospective randomized, a single-blind, sham-acupuncture controlled trial to study the clinical efficacy of acupuncture combined with Western medicine in the treatment of mild to moderate AD. Participants will be randomly divided into treatment and control groups. The treatment group using acupuncture combined with donepezil hydrochloride orally, and the control group using sham acupuncture combined with donepezil hydrochloride orally, followed up for 24 weeks after 24 weeks of continuous treatment. Outcome measures included: AD assessment scale-cognitive subscale, mini-mental state examination, activities of daily living, neuropsychiatric inventory questionnaire, serum superoxide dismutase, and homocysteine levels. Finally, SPASS 21.0 software was used for statistical analysis of the data. DISCUSSION: This study will evaluate the efficacy of acupuncture combined with Western medicine in improving cognitive function and activities of daily living in AD patients. The results of this study will verify whether the efficacy of acupuncture in the treatment of AD belongs to the placebo effect, which will also provide a reference for the clinical use of acupuncture combined with Western medicine in the treatment of AD. TRIAL REGISTRATION: The TCTR identification number is TCTR20220817004.

Yolk-shell Fe3O4@Carbon@Platinum-Chlorin e6 nanozyme for MRI-assisted synergistic catalytic-photodynamic-photothermal tumor therapy.

HYPOTHESIS: Tumor treatments based on phototherapy, such as photodynamic therapy (PDT) and photothermal therapy (PTT), are promising anticancer strategies. However, their dependence on light also poses several limitations for their application. Therefore, the establishment of a multifunctional nanotheranostic platform based on light therapy is needed to improve applicability of the technology. EXPERIMENTS: We designed yolk-shell magnetic Fe3O4@Carbon@Platinum-Chlorin e6 nanoparticles (MCPtCe6), which may be used for Magnetic resonance imaging (MRI) and synergistic catalytic-photodynamic-photothermal (catalytic-PDT-PTT) tumor therapy. FINDINGS: We designed to compound multiple nanozymes and solve the drawbacks of single nanozyme and give additional functionalization to nanozymes for tumor therapy. Fe3O4 has T2 weighted MRI ability. The designed yolk-shell structure can disperse Fe3O4 in the carbon shell layer, which in turn can act as a carrier for PtNPs and improve the dispersion of both Fe3O4 and Pt. Pt nanoparticles attached to the surface of N-doped carbon spheres enhanced the catalytic ability of the nanozyme to generate reactive oxygen species (ROS). The covalently linked photosensitizer chlorin e6 (Ce6) on the Fe3O4@C@Pt (MCPt) nanozyme is essential for the therapeutic effects of PDT. MCPtCe6 can be specifically activated by the microenvironment through an enzyme-like catalytic process and extend PDT/PTT in acidic and H2O2-rich microenvironments. The results showed that MCPtCe6 had a high photothermal conversion efficiency (η = 28.28%), indicating its feasibility for PTT. Further cellular and animal studies have revealed that catalytic-PDT-PTT therapy can effectively inhibit tumors both in vitro and in vivo.

Construction and regulation of aqueous-based Cerberus droplets by vortex mixing.

HYPOTHESIS: The emerging aqueous-based Cerberus emulsion droplets with multi-domains behave as an excellent platform to design cyto-mimetic compartmentalization for fabrication of anisotropic biomimetic materials and microreactors. However, the ultralow water/water interfacial tension impedes fabrication of aqueous Cerberus droplets in batch-scale and precisely topology regulation especially under lack of deep understanding of w/w interface properties. EXPERIMENTS: Aqueous-based ternary phase diagram composed by salt, hydrophilic polymer and fluorocarbon compound is determined. Different emulsions employing the multiple aqueous solutions as internal phase and vegetable oil as continuous phase, are prepared by traditional vortex mixing based on the diagram. The construction mechanism of (W1 + W2 + W3)/O Cerberus droplets and relationship between droplet topology and the diagram are investigated. FINDINGS: Diverse categories of aqueous-based emulsions from single emulsions, Janus emulsions, to Cerberus emulsions are delicately controlled in the same system based on the diagram. Various morphologies of Cerberus droplets such as linear and fan-like configurations are obtained, although spreading coefficient based on interfacial tension indicates preference of onion-like configuration. The viscosity plays an unexpected role in the construction of Cerberus droplets due to highly sensitive water/water interfaces within the droplets. Moreover, an empirical equation is perfectly applied, which endows quantitative prediction and control of lobe volume ratio within Cerberus droplets.

YY1 safeguard multidimensional epigenetic landscape associated with extended pluripotency.

Although extended pluripotent stem cells (EPSCs) have the potential to form both embryonic and extraembryonic lineages, how their transcriptional regulatory mechanism differs from that of embryonic stem cells (ESCs) remains unclear. Here, we discovered that YY1 binds to specific open chromatin regions in EPSCs. Yy1 depletion in EPSCs leads to a gene expression pattern more similar to that of ESCs than control EPSCs. Moreover, Yy1 depletion triggers a series of epigenetic crosstalk activities, including changes in DNA methylation, histone modifications and high-order chromatin structures. Yy1 depletion in EPSCs disrupts the enhancer-promoter (EP) interactions of EPSC-specific genes, including Dnmt3l. Yy1 loss results in DNA hypomethylation and dramatically reduces the enrichment of H3K4me3 and H3K27ac on the promoters of EPSC-specific genes by upregulating the expression of Kdm5c and Hdac6 through facilitating the formation of CCCTC-binding factor (CTCF)-mediated EP interactions surrounding their loci. Furthermore, single-cell RNA sequencing (scRNA-seq) experiments revealed that YY1 is required for the derivation of extraembryonic endoderm (XEN)-like cells from EPSCs in vitro. Together, this study reveals that YY1 functions as a key regulator of multidimensional epigenetic crosstalk associated with extended pluripotency.

Supramolecular Core-Shell Nanoassemblies with Tumor Microenvironment-Triggered Size and Structure Switch for Improved Photothermal Therapy.

Photothermal therapy (PTT) is demonstrated to be an effective methodology for cancer treatment. However, the relatively low photothermal conversion efficiency, limited tumor accumulation, and penetration still remain to be challenging issues that hinder the clinical application of PTT. Herein, the core-shell hierarchical nanostructures induced by host-guest interaction between water-soluble pillar[5]arene (WP5) and polyethylene glycol-modified aniline tetramer (TAPEG) are constructed. The pH-responsive performance endows the core-shell nanostructures with size switchable property, with an average diameter of 200 nm in the neutral pH and 60 nm in the acidic microenvironment, which facilitates not only tumor accumulation but also tumor penetration. Moreover, the structure switch of WP5⊃TAPEG under acidic microenvironment and the dual mechanism regulated extending of п conjugate, inclusion in the hydrophobic cavity of WP5 and the dense distribution in the core-shell structured assemblies, dramatically enhance the absorption in the near-infrared-II region and, further, the photothermal conversion efficiency (60.2%). The as-designed intelligent nanoplatform is demonstrated for improved antitumor efficacy via PTT.

Registration of intervention trials of Traditional Chinese Medicine for four neurological diseases on Chinese Clinical Trial Registry and ClinicalTrials.gov: a narrative review.

OBJECTIVE: To analyze the current status of clinical trial registration of Traditional Chinese Medicine (TCM) for the treatment of neurological diseases. METHODS: Interventional clinical trials of TCM treatment for ischemic stroke, hemorrhagic stroke, vascular cognitive impairment, tension-type headache before September 22, 2020 on the platform of Chinese Clinical Trial Registry (ChiCTR), and ClinicalTrials.gov were searched. Two researchers independently selected the literature and extracted data. RESULTS: A total of 180 interventional clinical trials were included for analysis. Out of 180 trials, 127 were from ChiCTR and 53 from ClinicalTrials.gov. The countries primary sponsoring the included trials were China (176, 97.8%), and the common categories of primary sponsors were hospital (131, 72.8%). Among the study design, the largest proportion of allocation was randomized (172, 95.6%), interventional model assignment was parallel (163, 90.6%), masking was double blind 49 (27.2%), and the sample size was ≤ 400 (144, 80.0%). The trials were most carried out at a single center (102, 56.7%). Among the included studies, 112 (62.2%) registered on ChiCTR attached the ethical approval documents. In terms of trial stages, 50 (27.7%) studies were in phase IV. The mostly used intervention was Chinese herbal medicines (99, 55%), acupuncture (68, 37.8%) was the second. By searching the registration number on China National Knowledge Infrastructure Database and PubMed, 38 (21.1%) registered trials were published, including 25 protocol studies and 14 research results with one (NCT02275949) published both the protocol and the results. CONCLUSIONS: Irregular and inadequate reporting, untimely update and publication, insufficient information on traditional medicine unique characteristics, and lack of international collaborations are the problems existing in the interventional clinical registration trials of traditional medicine treatment on neurological diseases. More efforts need to be made from the above aspects to standardize and improve the registration of traditional medicine trials.

Gold nanorod@void@polypyrrole yolk@shell nanostructures: Synchronous regulation of photothermal and drug delivery performance for synergistic cancer therapy.

Synergistic therapy has been emerging as new trend for effective tumor treatment due to synchronous function and cooperative reinforcement of multi therapeutic modalities. Herein, gold nanorods (GNRs) encapsulated into polypyrrole (PPy) shell with tunable void space (GNRs@Void@PPy) showing yolk@shell nanostructures were innovatively designed. The exploitation of dual near-infrared (NIR) absorptive species offered synergistic enhancement of photothermal performance. In addition, the manipulation of the void space between them provided additional benefits of high drug encapsulation efficiency (92.6%) and, interestingly, tumor microenvironment and NIR irradiation triggered targeted drug releasing. Moreover, the GNRs@Void@PPy exhibited excellent biocompatibility, and optimal curative effect by chemo-photothermal synergistic therapy was achieved through both in vitro and in vivo antitumor activity investigation.

Selenium Deficiency Causes Inflammatory Injury in the Bursa of Fabricius of Broiler Chickens by Activating the Toll-like Receptor Signaling Pathway.

The aim of our study was to observe the effect of selenium (Se) deficiency on inflammatory injury in the bursa of Fabricius of broiler chickens and to determine the role of the Toll-like receptor (TLR)/myeloid differential protein-88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway during this process. Here, we revealed that severe inflammatory injury occurred in the broiler bursa of Fabricius with Se deficiency via histopathology. Moreover, the ultrastructural pathological results showed that the nuclear, mitochondrial, endoplasmic reticulum and cytomembrane structures were damaged to varying degrees. Additionally, interleukin-2 (IL-2), interleukin-6 (IL-6), and interferon (IFN-γ) mRNA expression was markedly upregulated in the broiler bursa of Fabricius with Se deficiency. Furthermore, TLR, toll-interleukin-1 receptor domain-containing adapter-inducing interferon-ß (TRIF), MyD88, and NF-κB mRNA expression was also markedly elevated in the broiler bursa of Fabricius with Se deficiency. The above results suggested that Se deficiency increases the expression of numerous proinflammatory cytokines and is probably due to the activation of the TLR/MyD88/NF-κB signaling pathway, which causes inflammatory injury in the bursa of Fabricius of broiler chickens. Our findings provide a theoretical reference for further studying the underlying mechanism of Se deficiency-induced inflammatory injury in the bursa of Fabricius of broiler chickens.

[Expert consensus on clinical application of Compound Congrong Yizhi Capsules in treatment of vascular dementia].

Compound Congrong Yizhi Capsules is widely used in clinic for the long-term treatment and synergistic treatment of vascular cognitive impairment. After years of clinical observation, it has an obvious curative effect on the treatement of vascular cognitive impairment and has been recommended by multiple guidelines, consensuses, and series. This consensus was formulated for the treatment of vascular dementia. On the basis of summarizing the application experience of clinicians, and combined with the existing evidence-based evidence, 11 recommendations/consensus recommendations were finally reached through the nominal group method. The indications, usage and dosage, course of treatment, medication time, concomitant medication, and precautions of Congrong Yizhi Capsules in the treatment of vascular dementia were proposed, and the safety of the clinical application was described. This consensus is applicable to the use of Compound Congrong Yizhi Capsules in the treatment of patients with vascular dementia, and can be used by clinicians from the departments of encephalopathy(neurology), geriatrics, and traditional Chinese medicine in general hospitals. This consensus has been approved by China Association of Chinese Medicine, with the number of GS/CACM 298-2022.

Promoting biomethane production from propionate with Fe2O3@carbon nanotubes composites.

Using a batch anaerobic system constructed with 60 mL serum bottles, potential of a composite material with Fe2O3 nanoparticles decorated on carbon nanotubes (CNTs) to enhance biomethane production was investigated. The composites (Fe2O3@CNTs) with well dispersed Fe2O3 nanoparticles (4.5 nm) were fabricated by a facile thermal decomposition method in a muffle furnace under nitrogen atmosphere. Compared with Fe2O3, Fe2O3@CNTs showed a large specific surface area and good electrical conductivity. Supplementation of Fe2O3@CNTs to the propionate-degrading enrichments enhanced the methane production rate, which was 10.4-fold higher than that in the control experiment without material addition. The addition of Fe2O3@CNTs also not only showed a clearly electrochemical response to flavin and cytochrome C, but also reduced the electron transfer resistance when compared to the control. Comparative analysis showed that Fe2O3 in Fe2O3@CNTs played a key role in initiating electrochemical response and triggering rapid methane production, while CNTs functioned as rapid electron conduits to facilitate electron transfer from iron-reducing bacteria (e.g., Acinetobacter, Syntrophomonas, and Geobacter) to methanogens (e.g. Methanosarcina).

Selenium Deficiency Induces Autophagy in Chicken Bursa of Fabricius Through ChTLR4/MyD88/NF-κB Pathway.

To explore the role of ChTLR4/MyD88/NF-κB signaling pathway on autophagy induced by selenium (Se) deficiency in the chicken bursa of Fabricius, autophagosome formation in the bursa of Fabricius was observed by transmission electron microscopy. Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the expression of ChTLR4 and its signaling pathway molecules (MyD88, TRIF, and NF-κB), inflammatory factors (IL-1ß, IL-8, and TNF-α), and autophagy-related factors (ATG5, Beclin1, and LC3-II) in the Se-deficient chicken bursa of Fabricius at different ages. The results showed that ChTLR4/MyD88/NF-κB signaling pathway was activated in the chicken bursa of Fabricius and autophagy was induced at the same time by Se deficiency. In order to verify the relationship between the autophagy and ChTLR4/MyD88/NF-κB signaling pathway, HD11 cells were used to establish the normal C group, low Se group, and low Se + TLR4 inhibitor (TAK242) group. The results demonstrated that autophagy could be hindered when the TLR4 signaling pathway was inhibited under Se deficiency. Furthermore, autophagy double-labeled adenovirus was utilized to verify the integrity of autophagy flow induced by Se deficiency in HD11 cells. The results showed that it appeared to form a complete autophagy flow under the condition of Se deficiency and could be blocked by TAK242. In summary, we found that Se deficiency was involved in the chicken bursa of Fabricius autophagy occurring by activating the ChTLR4/MyD88/NF-κB pathway.

The antitumor effect of the combination of aconitine and crude monkshood polysaccharide on hepatocellular carcinoma.

Aconitine, the main component in Radix Aconiti Lateralis Preparata, not only exerts the anti-tumor effect on Hepatocellular Carcinoma (HCC) but also damages on immune system. In the present study, Crude Monkshood Polysaccharide (CMP), another one natural composition component originated from the same herbal with aconitine, combined with aconitine to investigate the effects on HCC and immunity in vitro and in vivo. The combination of CMP and aconitine enhanced the ability of the immunocyte to kill the tumor cell in vitro and had an additive effect on anti-HCC in vivo. Aconitine-CMP in combination improved the spleen weights, spleen index, thymus weights, thymus index. Elevated CD4+ T and CD8+ T cells and macrophages in spleen, decreased serum IL-6 level and increased serum IFN-γ and TNF-α levels were observed in mice treated with the combination of aconitine and CMP compare with control group (P<0.05). Our results showed that the combination of aconitine and CMP exerts anti-tumor effect by directly killing tumor cells and enhancing the anti-tumor immune responses, which further implies that chemotherapy drugs combined with Chinese medicine immunopotentiator maybe a feasible and effective strategy for HCC.

Polydopamine-based nanoplatform for photothermal ablation with long-term immune activation against melanoma and its recurrence.

The high risk of tumor recurrence presents a big challenge in melanoma therapy. Photothermal therapy (PTT) has merged as a powerful weapon against tumor in recent years, which produces tumor-associated antigens (TAA) and recruits dendritic cells (DCs) to tumor sites through immunogenic cell death (ICD) for immune activation. However, due to the lack of activation signals of DCs, the immune effect induced by PTT is not sufficient to inhibit the recurrence and proliferation of tumor. To efficiently cooperate PTT and immunotherapy to circumvent tumor recurrence, here we constructed a polydopamine (PDA) based core-shell nanoplatform loading CpG ODNs to elicit robust photothermal ablation and antitumor immune responses. Cationized polydopamine coated with hyaluronic acid (HA) shell was proven an efficient photothermal agent that increased the surface temperature of tumor by 16 °C and induced ICD. CpG ODNs effectively induced maturation of DCs by elevating the expression of co-stimulating markers. PTT combined with CpG ODNs achieved a remarkable synergistic treatment effect in the maturation of DCs and activation of T cells in melanoma-bearing mice model compared with PTT or CpG ODNs alone. Furthermore, in a tumor recurrence model, photothermal-immune combination therapy increased the infiltration of CTLs in distant tumor compared with PTT or CpG ODNs alone. The combination therapy overcame insufficient immunity at distant tumor caused by PTT alone and relieved immunosuppression microenvironment of the tumor. Hence, the PDA based core-shell nanoplatform presents a potent photo-immunotherapy against proliferation and recurrence of melanoma. STATEMENT OF SIGNIFICANCE: In order to solve the insufficient immunity induced by photothermal therapy (PTT), CpG ODNs were utilized to enhance the weak immune response mediated by PTT through inducing DCs maturation. Hence, we designed a polydopamine (PDA) based core-shell nanoplatform loading CpG ODNs followed by hyaluronic acid named PPP/CpG/HA to elicit robust photothermal ablation and antitumor immune responses. CpG ODNs were delivered to the tumor site through the targeting effect of the HA shell. The core-shell nanoplatform achieved a remarkable synergistic treatment effect in the maturation of DCs and activation of T cells, thereby overcoming insufficient immunity at distant tumor caused by PTT alone. The core-shell nanoplatform presents a potent photo-immunotherapy against proliferation and recurrence of melanoma.

Therapeutic Targets and Mechanism of Xingpi Jieyu Decoction in Depression: A Network Pharmacology Study.

BACKGROUND: Depression is a common mental disease that lacks effective therapeutic drugs with good curative effects and few adverse reactions. Traditional Chinese medicine (TCM) has the advantages of multiple components, multiple channels, and fewer adverse reactions in the treatment of depression. Although Xingpi Jieyu Decoction (XPJYD) demonstrates a good therapeutic effect on depression, the pharmacological mechanism underlying its antidepressant effect is still unclear. METHODS: We used a network pharmacology strategy, including the construction and analysis of a complex drug-disease network, to explore the complex mechanism of XPJYD treatment of depression. In addition, molecular docking technology was used to preliminarily study the binding ability of the potential active components and core therapeutic targets of XPJYD. RESULTS: The network pharmacology results showed 42 targets of XPJYD that are involved in depression. PPI network analysis demonstrated that the top 10 core targets were AKT1, VEGFA, MAPK8, FOS, ESR1, NR3C1, IL6, HIF1A, NOS3, and AR. The molecular docking results showed that the binding energies of beta sitosterol with AR, FOS, AKT1, VEGFA, NR3C1, and NOS3 were less than -7.0 kcal·mol-1, indicating a good docking effect. The GO enrichment analysis results showed that the XPJYD antidepression mechanism mainly involves the following biological processes such as apoptotic signaling pathway, cellular response to lipid, inflammatory response, and others. The KEGG analysis results indicated that XPJYD may regulate 13 pathways such as PI3K-Akt signaling pathway and estrogen signaling pathway in the treatment of depression. CONCLUSIONS: This study reflects the characteristics of the mechanism of action by which XPJYD treats depression, which includes multiple components, multiple targets, and multiple pathways, and provides a biological basis for further verification and a novel perspective for drug discovery in depression.