Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects.

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

Therapeutic vaccine-induced plasma cell differentiation is defective in the presence of persistently high HBsAg levels.

BACKGROUND & AIMS: Mechanisms behind the impaired response of antigen-specific B cells to therapeutic vaccination in chronic hepatitis B virus (HBV) infection remain unclear. The development of vaccines or strategies to overcome this obstacle is vital for advancing the management of chronic hepatitis B. METHODS: A mouse model, denominated as E6F6-B, was engineered to feature a knock-in of a B-cell receptor (BCR) that specifically recognizes HBsAg. This model served as a valuable tool for investigating the temporal and spatial dynamics of humoral responses following therapeutic vaccination under continuous antigen exposure. Using a suite of immunological techniques, we elucidated the differentiation trajectory of HBsAg-specific B cells post-therapeutic vaccination in HBV carrier mice. RESULTS: Utilizing the E6F6-B transfer model, we observed a marked decline in antibody-secreting cells 2 weeks after vaccination. A dysfunctional and atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138- BCMA-) emerged, manifested by sustained BCR signaling. By deploying an antibody to purge persistent HBsAg, we effectively prompted the therapeutic vaccine to provoke conventional plasma cell differentiation. This resulted in an enhanced anti-HBs antibody response and facilitated HBsAg clearance. CONCLUSIONS: Sustained high levels of HBsAg limit the ability of therapeutic hepatitis B vaccines to induce the canonical plasma cell differentiation necessary for anti-HBs antibody production. Employing a strategy combining antibodies with vaccines can surmount this altered humoral response associated with atypical pre-plasma cells, leading to improved therapeutic efficacy in HBV carrier mice. IMPACT AND IMPLICATIONS: Therapeutic vaccines aimed at combatting HBV encounter suboptimal humoral responses in clinical settings, and the mechanisms impeding their effectiveness have remained obscure. Our research, utilizing the innovative E6F6-B mouse transfer model, reveals that the persistence of HBsAg can lead to the emergence of an atypical pre-plasma cell population, which proves to be relevant to the potency of therapeutic HBV vaccines. Targeting the aberrant differentiation process of these atypical pre-plasma cells stands out as a critical strategy to amplify the humoral response elicited by HBV therapeutic vaccines in carrier mouse models. This discovery suggests a compelling avenue for further study in the context of human chronic hepatitis B. Encouragingly, our findings indicate that synergistic therapy combining HBV-specific antibodies with vaccines offers a promising approach that could significantly advance the pursuit of a functional cure for HBV.

Sensory nerves directly promote osteoclastogenesis by secreting peptidyl-prolyl cis-trans isomerase D (Cyp40).

Given afferent functions, sensory nerves have recently been found to exert efferent effects and directly alter organ physiology. Additionally, several studies have highlighted the indirect but crucial role of sensory nerves in the regulation of the physiological function of osteoclasts. Nonetheless, evidence regarding the direct sensory nerve efferent influence on osteoclasts is lacking. In the current study, we found that high levels of efferent signals were transported directly from the sensory nerves into osteoclasts. Furthermore, sensory hypersensitivity significantly increased osteoclastic bone resorption, and sensory neurons (SNs) directly promoted osteoclastogenesis in an in vitro coculture system. Moreover, we screened a novel neuropeptide, Cyp40, using an isobaric tag for relative and absolute quantitation (iTRAQ). We observed that Cyp40 is the efferent signal from sensory nerves, and it plays a critical role in osteoclastogenesis via the aryl hydrocarbon receptor (AhR)-Ras/Raf-p-Erk-NFATc1 pathway. These findings revealed a novel mechanism regarding the influence of sensory nerves on bone regulation, i.e., a direct promoting effect on osteoclastogenesis by the secretion of Cyp40. Therefore, inhibiting Cyp40 could serve as a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.

Temporospatial inhibition of Erk signaling is required for lymphatic valve formation.

Intraluminal lymphatic valves (LVs) and lymphovenous valves (LVVs) are critical to ensure the unidirectional flow of lymphatic fluid. Morphological abnormalities in these valves always cause lymph or blood reflux, and result in lymphedema. However, the underlying molecular mechanism of valve development remains poorly understood. We here report the implication of Efnb2-Ephb4-Rasa1 regulated Erk signaling axis in lymphatic valve development with identification of two new valve structures. Dynamic monitoring of phospho-Erk activity indicated that Erk signaling is spatiotemporally inhibited in some lymphatic endothelial cells (LECs) during the valve cell specification. Inhibition of Erk signaling via simultaneous depletion of zygotic erk1 and erk2 or treatment with MEK inhibitor selumetinib causes lymphatic vessel hypoplasia and lymphatic valve hyperplasia, suggesting opposite roles of Erk signaling during these two processes. ephb4b mutants, efnb2a;efnb2b or rasa1a;rasa1b double mutants all have defective LVs and LVVs and exhibit blood reflux into lymphatic vessels with an edema phenotype. Importantly, the valve defects in ephb4b or rasa1a;rasa1b mutants are mitigated with high-level gata2 expression in the presence of MEK inhibitors. Therefore, Efnb2-Ephb4 signaling acts to suppress Erk activation in valve-forming cells to promote valve specification upstream of Rasa1. Not only do our findings reveal a molecular mechanism of lymphatic valve formation, but also provide a basis for the treatment of lymphatic disorders.

Intranasal influenza-vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response in hamsters.

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants and "anatomical escape" characteristics threaten the effectiveness of current coronavirus disease 2019 (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. Here we investigate immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants in hamsters. Intranasal delivery of dNS1-RBD induces innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrains the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (Il6, Il1b, and Ifng) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden.

Combination therapy of therapeutic antibody and vaccine or entecavir in HBV carrier mice.

Chronic infection with the hepatitis B virus (HBV) is a leading causes of liver cirrhosis and hepatocellular carcinoma. However, managing HBV treatments is challenging due to the lack of effective monotherapy. Here, we present two combination approaches, both of which aim to target and enhance the clearance of HBsAg and HBV-DNA. The first approach involves the use of antibodies to continuously suppress HBsAg, followed by the administration of a therapeutic vaccine in a sequential manner. This approach results in better therapeutic outcomes compared to the use of these treatments individually. The second approach involves combining antibodies with ETV, which effectively overcomes the limitations of ETV in suppressing HBsAg. Thus, the combination of therapeutic antibodies, therapeutic vaccines, and other existing drugs is a promising strategy for the development of novel strategies to treat hepatitis B.

Deterministic manipulation of steering between distant quantum network nodes.

Multipartite Einstein-Podolsky-Rosen (EPR) steering is a key resource in a quantum network. Although EPR steering between spatially separated regions of ultracold atomic systems has been observed, deterministic manipulation of steering between distant quantum network nodes is required for a secure quantum communication network. Here, we propose a feasible scheme to deterministically generate, store, and manipulate one-way EPR steering between distant atomic cells by a cavity-enhanced quantum memory approach. While optical cavities effectively suppress the unavoidable noises in electromagnetically induced transparency, three atomic cells are in a strong Greenberger-Horne-Zeilinger state by faithfully storing three spatially separated entangled optical modes. In this way, the strong quantum correlation of atomic cells guarantees one-to-two node EPR steering is achieved, and can perserve the stored EPR steering in these quantum nodes. Furthermore, the steerability can be actively manipulated by the temperature of the atomic cell. This scheme provides the direct reference for experimental implementation for one-way multipartite steerable states, which enables an asymmetric quantum network protocol.

Microgroove Cues Guiding Fibrogenesis of Stem Cells via Intracellular Force.

Groove patterns are widely used in material surface modifications. However, the independent role of ditches/ridges in regulating fibrosis of soft tissues is not well-understood, especially the lack of linkage evidence in vitro and in vivo. Herein, two kinds of combinational microgroove chips with the gradient ditch/ridge width were fabricated by photolithography technology, termed R and G groups, respectively. In group R, the ridge width was 1, 5, 10, and 30 µm, with a ditch width of 30 µm; in group G, the groove width was 5, 10, 20, and 30 µm, and the ridge width was 5 µm. The effect of microgrooves on the morphology, proliferation, and expression of fibrous markers of stem cells was systematically investigated in vitro. Moreover, thicknesses of fibrous capsules were evaluated after chips were implanted into the muscular pouches of rats for 5 months. The results show that microgrooves have almost no effect on cell proliferation but significantly modulate the morphology of cells and focal adhesions (FAs) in vitro, as well as fibrosis differentiation. In particular, the differentiation of stem cells is attenuated after the intracellular force caused by stress fibers and FAs is interfered by drugs, such as rotenone and blebbistatin. Histological analysis shows that patterns of high intracellular force can apparently stimulate soft tissue fibrosis in vivo. This study not only reveals the specific rules and mechanisms of ditch/ridge regulating stem cell behaviors but also offers insight into tailoring implant surface patterns to induce controlled soft tissue fibrosis.

The expression profile of 79 genes from 107 viruses revealed new insights into disease susceptibility in rats, mice, and muskrats.

The coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread over the world, resulting in a global severe pneumonia pandemic. Both the cell receptor angiotensin-converting enzyme 2 (ACE2) and the breakdown of S protein by transmembrane serine protease 2 (TMPRSS2) are required by SARS-CoV-2 to enter the host cells. Similarly, the expression level of viral receptor genes in various organs determines the likelihood of viral infection. Several animal species have been found to be infected by the SARS-CoV-2, such as minks, posing an enormous threat to humans. Because the mice and rats were closely related to human and the fact that rats and mice have a risk of infection by SARS-CoV-2 with specific variants, we investigated the expression patterns of 79 receptor genes from 107 viruses, including SARS-CoV-2, in 14 organs of the rat and mouse, and 5 organs of the muskrat, to find the most likely host organs to become infected with certain viruses. The findings of this study are anticipated to aid in prevention of zoonotic infections spread by rats, mice, muskrats, and other rodents.

Tanshinone IIA inhibits hypoxia/reoxygenation-induced cardiomyocyte apoptosis and autophagy by regulating ABCE1 / 中华危重病急救医学

OBJECTIVE@#To investigate the effects of tanshinone IIA on apoptosis and autophagy induced by hypoxia/reoxygenation in H9C2 cardiomyocytes and its mechanism.@*METHODS@#H9C2 cardiomyocytes in logarithmic growth phase were divided into control group, hypoxia/reoxygenation model group and tanshinone IIA low-dose, medium-dose and high-dose groups (50, 100, 200 mg/L tanshinone IIA were treated after hypoxia/reoxygenation respectively). The dose with good therapeutic effect was selected for follow-up study. The cells were divided into control group, hypoxia/reoxygenation model group, tanshinone IIA+pcDNA3.1-NC group and tanshinone IIA+pcDNA3.1-ABCE1 group. The cells were transfected with the overexpressed plasmids pcDNA3.1-ABCE1 and pcDNA3.1-NC and then treated accordingly. Cell counting kit-8 (CCK-8) was used to detect H9C2 cell activity in each group. The apoptosis rate of cardiomyocytes was detected by flow cytometry. The ATP-binding cassette transporter E1 (ABCE1), apoptosis-related proteins Bcl-2 and Bax, caspase-3, autophagy-related proteins Beclin-1, microtubule-associated protein 1 light chain 3 (LC3II/I) and p62 mRNA expression level of H9C2 cells in each group were detected by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The protein expression levels of the above indexes in H9C2 cells were detected by Western blotting.@*RESULTS@#(1) Cell activity and ABCE1 expression: tanshinone IIA inhibited the activity of H9C2 cells induced by hypoxia/reoxygenation, and the effect was significant at medium-dose [(0.95±0.05)% vs. (0.37±0.10)%, P < 0.01], mRNA and protein expression of ABCE1 were significantly reduced [ABCE1 mRNA (2-ΔΔCt): 2.02±0.13 vs. 3.74±0.17, ABCE1 protein (ABCE1/GAPDH): 0.46±0.04 vs. 0.68±0.07, both P < 0.05]. (2) Expression of apoptosis-related proteins: medium-dose of tanshinone IIA inhibited the apoptosis of H9C2 cells induced by hypoxia/reoxygenation [apoptosis rate: (28.26±2.52)% vs. (45.27±3.07)%, P < 0.05]. Compared with the hypoxia/reoxygenation model group, medium-dose of tanshinone IIA significantly down-regulated the protein expression of Bax and caspase-3 in H9C2 cells induced by hypoxia/reoxygenation, and significantly up-regulated the protein expression of Bcl-2 [Bax (Bax/GAPDH): 0.28±0.03 vs. 0.47±0.03, caspase-3 (caspase-3/GAPDH): 0.31±0.02 vs. 0.44±0.03, Bcl-2 (Bcl-2/GAPDH): 0.53±0.02 vs. 0.37±0.05, all P < 0.05]. (3) Expression of autophagy-related proteins: compared with the control group, the positive rate of LC3 in the hypoxia/reoxygenation model group was significantly increased, while the positive rate of LC3 in the medium-dose of tanshinone IIA group was significantly decreased [(20.67±3.09)% vs. (42.67±3.86)%, P < 0.01]. Compared with hypoxia/reoxygenation model group, medium-dose of tanshinone IIA significantly down-regulated Beclin-1, LC3II/I and p62 protein expressions [Beclin-1 (Beclin-1/GAPDH): 0.27±0.05 vs. 0.47±0.03, LC3II/I ratio: 0.24±0.05 vs. 0.47±0.04, p62 (p62/GAPDH): 0.21±0.03 vs. 0.48±0.02, all P < 0.05]. (4) Expression of apoptosis and autophagy related proteins after transfection with overexpressed ABCE1 plasmid: compared with tanshinone IIA+pcDNA3.1-NC group, the protein expression levels of Bax, caspase-3, Beclin-1, LC3II/I and p62 in tanshinone IIA+pcDNA3.1-ABCE1 group were significantly up-regulated, while the protein expression level of Bcl-2 was significantly down-regulated.@*CONCLUSIONS@#100 mg/L tanshinone IIA could inhibit autophagy and apoptosis of cardiomyocytes by regulating the expression level of ABCE1. So, it protects H9C2 cardiomyocytes injury induced by hypoxia/reoxygenation.

Oral Chinese patent medicines for acute myocardial infarction after percutaneous coronary intervention: A protocol for systematic review and network meta-analysis.

BACKGROUND: Acute myocardial infarction (AMI) is a serious and fatal heart disease with one of the highest mortality rates in the world. In some countries, percutaneous coronary intervention (PCI) is the preferred reperfusion strategy after AMI, but it cannot achieve safe and effective treatment of AMI after PCI remains a challenging clinical problem. The potential of oral Chinese patent medicines to treat AMI after PCI has been demonstrated, but which type of oral Chinese patent medicines may be preferred remains controversial. The aim of this network meta-analysis was to investigate the efficacy and safety of multiple oral Chinese patent medicines in the treatment of AMI after PCI. METHODS: We will conduct a literature search from China National Knowledge Infrastructure, formerly Chinese Biomedical Database (SinoMed), Wanfang Data, Chongqing VIP, PubMed, Embase, Web of Science and Cochrane Library (The Cochrane Database of Systematic Reviews) from their inception until to November 1, 2022, with language restricted to Chinese and English. Then, the study selection process will follow the Preferred Reporting Items for Meta-Analyses guideline, and the quality assessment will be conducted with Cochrane Collaboration's tool. Pairwise and network meta-analysis will be conducted using the WinBUGS V.1.4.3.37 and STATA V.13. Additionally, sensitivity analysis, subgroup analysis, quality assessment, Small-study effects and publication bias will be performed. ETHICS AND DISSEMINATION: This work is based on published research and therefore does not require ethical approval. This review will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020188065.

Effect of muscone on anti-apoptotic ability of muskrat prostate primary cells.

Muskrat is a small fur animal with a pair of scent glands that can secrete muskrat musk during breeding season. The consensus is muskrat musk functions as a pheromone, but we hypothesized it has a broader role. In previous research, we found the presence of muscone in muskrat musk. To study whether the muscone can affect the apoptosis of muskrat prostate, we carried out the following investigations. Primary muskrat prostate cells were cultured and treated with muscone. Then we drew cell proliferation curves by applying the CCK-8 and used TdT-mediated dUTP nick end labeling (TUNEL) to detect apoptosis. Levels of mRNA transcription and protein expression of Bcl-2 as well as Bax were detected by qRT-PCR and the Western blot. Meanwhile, we collected tissue samples of muskrat prostates and froze sections to analyze the fluorescence signal intensity of BCL-2 and BAX via immunofluorescence. Under the treatment of 30 µmol/L muscone, the proliferation rate of the experimental group exceeded that of the control group, and the proportion of cells undergoing apoptosis was lower in the experimental group. The qRT-PCR and Western blot result showed that, in the experimental group, the ratio of Bcl-2 to Bax mRNA transcription levels increased by 2.85 times and their corresponding protein expression ratio increased by 2.37 times (P < 0.05). Immunofluorescence results were consistent with the cell experiment's results. The fluorescence signal intensity of BCL-2 was higher in the breeding season than nonbreeding season but vice versa for BAX. Based on these results, we speculate that the muscone could regulates prostate development by inhibiting apoptosis.

A 3D bioprinted nano-laponite hydrogel construct promotes osteogenesis by activating PI3K/AKT signaling pathway.

Development of nano-laponite as bioinks based on cell-loaded hydrogels has recently attracted significant attention for promoting bone defect repairs and regeneration. However, the underlying mechanisms of the positive function of laponite in hydrogel was not fully explored. In this study, the effect of 3D bioprinted nano-laponite hydrogel construct on bone regeneration and the potential mechanism was explored in vitro and in vivo. In vitro analyses showed that the 3D construct protected encapsulated cells from shear stresses during bioprinting, promoted cell growth and cell spreading, and BMSCs at a density of 107/mL exhibited an optimal osteogenesis potential. Osteogenic differentiation and ectopic bone formation of BMSCs encapsulated inside the 3D construct were explored by determination of calcium deposition and x-ray, micro-CT analysis, respectively. RNA sequencing revealed that activation of PI3K/AKT signaling pathway of BMSCs inside the laponite hydrogel significantly upregulated expression of osteogenic related proteins. Expression of osteogenic proteins was significantly downregulated when the PI3K/AKT pathway was inhibited. The 3D bioprinted nano-laponite hydrogel construct exhibited a superior ability for bone regeneration in rat bones with defects compared with groups without laponite as shown by micro-CT and histological examination, while the osteogenesis activity was weakened by applications of a PI3K inhibitor. In summary, the 3D bioprinted nano-laponite hydrogel construct promoted bone osteogenesis by promoting cell proliferation, differentiation through activation of the PI3K/AKT signaling pathway.

High-performance cavity-enhanced quantum memory with warm atomic cell.

High-performance quantum memory for quantized states of light is a prerequisite building block of quantum information technology. Despite great progresses of optical quantum memories based on interactions of light and atoms, physical features of these memories still cannot satisfy requirements for applications in practical quantum information systems, since all of them suffer from trade-off between memory efficiency and excess noise. Here, we report a high-performance cavity-enhanced electromagnetically-induced-transparency memory with warm atomic cell in which a scheme of optimizing the spatial and temporal modes based on the time-reversal approach is applied. The memory efficiency up to 67 ± 1% is directly measured and a noise level close to quantum noise limit is simultaneously reached. It has been experimentally demonstrated that the average fidelities for a set of input coherent states with different phases and amplitudes within a Gaussian distribution have exceeded the classical benchmark fidelities. Thus the realized quantum memory platform has been capable of preserving quantized optical states, and is ready to be applied in quantum information systems, such as distributed quantum logic gates and quantum-enhanced atomic magnetometry.

Experiment and simulation of flexible CNT/SA/PDMS electromagnetic shielding composite.

Flexible electromagnetic shielding composites have a great potential for wide range applications. In this study, two flexible composites were produced by plating Ni nanoparticles on carbon nanotubes (CNTs) or infiltrating carbon nanofibers/polydimethylsiloxane (CNF/PDMS) polymer into CNT/sodium alginate (CNT/SA) sponge skeleton (CNT/SA/CNF/PDMS composites). The composites are tested under the X band in the frequency range of 8.2 - 12.4 GHz, the electromagnetic interference shielding effectiveness (EMI-SE) values of the above two composites are almost as twice as that of CNT/SA/PDMS composite at a same CNT loading. Introducing nano-sized Ni particles on CNT improved the microwave absorption capacity of the composite, while adding CNF on the PDMS matrix enhanced the conductivity of these composites. Under 10% strain, both flexible composites show stable conductivity. Simulation and calculation results shown that increasing the cladding rate of Ni nanoparticles on the surface of CNT, reducing the average size of Ni particles, and increasing the loading of CNF in PDMS matrix can significantly improve conductivity and then EMI performance of the materials. All of these could benefit for the design of flexible electromagnetic shielding composites.

Mechanisms of Dihuang (Rehmanniae Radix) in treating diabetic nephropathy complicated with depression based on network pharmacology / 数字中医药（英文）

@#Objective To predict the molecular mechanism of Dihuang (Rehmanniae Radix) in the treatment of diabetic nephropathy (DN) complicated with depression based on network pharmacology. Methods The components of Dihuang (Rehmanniae Radix) were identified from the Integrated Pharmacology-based Research Platform of Traditional Chinese Medicine (TCMIP), Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and relevant literature. The component targets were detected by combining the SwissTargetPrediction and PubChem databases. Disease targets were collected from the Therapeutic Target Database (TTD), DisGeNET, and Ensembl databases with “diabetic nephropathy” and “depression” as keywords. The disease-component targets were mapped using Venny 2.1.0 to obtain potential targets. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and Cytoscape 3.7.2. The co-expression genes of the key targets were collected based on the COXPRESdb 7.3. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed for potential targets using R language. Target-component docking was verified and evaluated using Discovery Studio 4.5. Results According to the databases and literature reports, Dihuang (Rehmanniae Radix) contained 65 active components, and had 155 related targets for the treatment of DN complicated with depression. PPI screening showed that the key targets included serine/threonine protein kinase 1 (AKT1), signal transducer and activator transcription 3 (STAT3), interleukin 6 (IL-6), mitogen-activated protein kinase 1 (MAPK1), and vascular endothelial growth factor A (VEGFA), etc. GO enrichment analysis mainly involved biological processes, such as lipid metabolism, protein secretion regulation, cell homeostasis, and phosphatidylinositol 3 kinase activity. KEGG pathway enrichment analysis included the role of the AGE-RAGE signaling pathway in diabetic complements, insulin resistance (IR), neurotrophin signal path, Toll-like receptor signaling pathway, relaxin signaling pathway, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), etc. Molecular docking showed that the target had high affinity for stachyose, manninotriose, verbascose, nigerose, etc. Conclusion Based on network parmacology, this study preliminarily predict the effects of Dihuang (Rehmanniae Radix) in treating DN complicated with depression by regulating inflammation, glucose metabolism, nution nerve, etc.

Exploring the therapeutic mechanism of Longqi Fang for diabetic kidney disease based on network pharmacology and verification in rats / 南方医科大学学报

OBJECTIVE@#To study the therapeutic mechanism of Longqi Fang (LQF) for diabetic kidney disease (DKD) based on GEO database and network pharmacology.@*METHODS@#LQF and DKD targets were obtained using the databases including GEO, TCMSP, CNKI, ChemDraw, and SwissTarget Prediction, and LQF-DKD intersection targets were obtained with VENNY. String was used for protein-protein interaction (PPI) analysis, and R package for KEGG and GO enrichment analysis. Cytoscape 3.7.2 software Network graphs were constructed. The results of network pharmacology analysis were verified in SD rat models of DKD by daily treatment of the rats with LQF at low (1 g/kg), medium (2 g/kg), and high (2 g/kg) doses, and kidney pathology was observed with HE staining and the changes in renal function were assessed. Western blotting was used to detect the expression levels of NF-κB and p-NF-κB proteins.@*RESULTS@#We identified 760 main targets of LQF, and obtained 1026 differential genes using GEO database and 61 LQF-DKD intersection targets using Venny database. The core targets obtained through PPI network analysis included Myc, EGF, CASP3, VEGFA, CCL2, SPP1, VCAM1 and ICAM1. Go analysis showed that LQF affects mainly nuclear receptor activity and ligand activated transcription factor activity. KEGG analysis showed that LQF affects inflammatory signaling pathways by interfering with NF-κB, TNF, and PI3K-AKT. In rat models of DKD, treatment with LQF resulted in significant improvements of the renal functions (P < 0.05) and glomerular and tubular structure and arrangement in a dose-dependent manner. Western blotting results showed that LQF dose-dependently downregulated NF-κB and p-NF-κB expressions in the rat models.@*CONCLUSION@#The therapeutic mechanism of LQF for DKD involves multiple components, targets and signal pathways that mediate an inhibitory effect on NF-κB signaling pathway to protect the renal function.

Case Report: Primary Bilateral Minimally Invasive Adenocarcinoma of the Lungs in an 11-Year-Old Child: A Rare Case.

There are many types of benign and malignant tissue, but primary lung tumor is very rare in children and often remains undiagnosed until after distant metastasis has occurred. Few cases of early lung adenocarcinoma in children have been reported. However, this case concerns an 11-year-old child with primary bilateral minimally invasive adenocarcinoma. As far as we know, this is the youngest reported case of its type.

[Exploration of emulsifying material basis of Angelicae Sinensis Radix volatile oil based on partial least squares and hydrophile-lipophile balance value].

This study explores the emulsifying material basis of Angelicae Sinensis Radix volatile oil (ASRVO) based on partial least squares (PLS) method and hydrophile-lipophile balance (HLB) value.The turbidity of ASRVO emulsion samples from Gansu,Yunnan,and Qinghai was determined and the chemical components in the emulsion were analyzed by GC-MS.The PLS model was established with the chemical components as the independent variable and the turbidity as the dependent variable and evaluated with indexes R~2X and R~2Y.The chemical components which were in positive correlation with the turbidity were selected and the HLB values were calculated to determine the emulsification material basis of ASRVO.The PLS models for the 81 emulsion samples had high R~2X and R~2Y values,which showed good fitting ability.Seven chemical components,2-methoxy-4-vinylphenol,trans-ligustilide,3-butylidene-1(3H)-isobenzofuranone,dodecane,1-methyl-4-(1-methylethylidene)-cyclohexene,trans-beta-ocimene,and decane,had positive correlation with turbidity.Particularly,the HLB value of 2-methoxy-4-vinylphenol was 4.4,which was the HLB range of surfactants to be emulsifiers and 2-methoxy-4-vinylphenol was positively correlated with turbidity of the ASRVO emulsion samples from the main producing area.Therefore,2-methoxy-4-vinylphenol was the emulsifying material basis of ASRVO.The selected emulsifying substances can lay a foundation for exploring the emulsification mechanism and demulsification solution of ASRVO.

Biological sealing and integration of a fibrinogen-modified titanium alloy with soft and hard tissues in a rat model.

Percutaneous or transcutaneous devices are important and unique, and the corresponding biological sealing at the skin-implant interface is the key to their long-term success. Herein, we investigated the surface modification to enhance biological sealing, using a metal sheet and screw bonded by biomacromolecule fibrinogen mediated via pre-deposited synthetic macromolecule polydopamine (PDA) as a demonstration. We examined the effects of a Ti-6Al-4V titanium alloy modified with fibrinogen (Ti-Fg), PDA (Ti-PDA) or their combination (Ti-PDA-Fg) on the biological sealing and integration with skin and bone tissues. Human epidermal keratinocytes (HaCaT), human foreskin fibroblasts (HFF) and preosteoblasts (MC3T3-E1), which are closely related to percutaneous implants, exhibited better adhesion and spreading on all the three modified sheets compared with the unmodified alloy. After three-week subcutaneous implantation in Sprague-Dawley (SD) rats, the Ti-PDA-Fg sheets could significantly attenuate the soft tissue response and promote angiogenesis compared with other groups. Furthermore, in the model of percutaneous tibial implantation in SD rats, the Ti-PDA-Fg screws dramatically inhibited epithelial downgrowth and promoted new bone formation. Hence, the covalent immobilization of fibrinogen through the precoating of PDA is promising for enhanced biological sealing and osseointegration of metal implants with soft and hard tissues, which is critical for an orthopedic percutaneous medical device.