Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer.

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.

Adsorption Thermodynamic and Kinetic Mechanism of Substrate-Induced Molecular Geometry Orientation.

N719 dye (cis-[Ru(4-carboxy-4'-carboxylate-2,2'-bipyridine)2(NCS)2]) contains two carboxylic acid/carboxylate groups and two isothiocyanato (NCS) ligands and exhibit different spatial adsorption orientations during adsorption on different substrate surfaces. However, the effect of spatially adsorption orientations on the adsorption process has been rarely reported. This paper presents a detailed study of the adsorption kinetics and thermodynamics of N719 molecules based on a quartz crystal microbalance under variable temperature conditions using TiO2 or Au substrate surfaces to induce changes in the geometrical orientation molecules. This work also reveals the adsorption properties of carboxylate groups and NCS ligands acting as anchoring groups. Research results have shown that the surface N719 molecular density of the TiO2 substrate is higher than that of the Au substrate. Adsorption kinetics have shown that the adsorption rate of N719 molecules on the Au substrate surface with NCS ligands as anchor groups is slightly higher than that of carboxylate as the anchor groups on the TiO2 substrate surface, and in the case of the former adsorption mode, the desorption is more pronounced. Under two different spatial orientation adsorption modes, both exhibit physical adsorption. The thermodynamics of molecular adsorption with different spatial orientations show that all adsorption processes are spontaneous and endothermic. This work is beneficial for understanding the mechanism of adsorption of dye molecules, dye molecule synthesis method, ligand selection, and improvement of device efficiency.

Plasma Cell Polarization to the Immunoglobulin G Phenotype in Hepatocellular Carcinomas Involves Epigenetic Alterations and Promotes Hepatoma Progression in Mice.

BACKGROUND & AIMS: Little is known about the composition and generation of plasma cell subsets in patients with hepatocellular carcinoma (HCC) and how these associate with outcomes. We investigated whether, or how, plasma cells differentiate and function in patients with HCC and mice with liver tumors. METHODS: We analyzed subset composition and distribution of plasma cells in HCC samples from 342 patients who underwent curative resection at the Cancer Center of Sun Yat-sen University in China; samples of non-tumor liver tissue were used as controls. We associated plasma cell profiles with patient outcomes. Tissue-derived leukocytes were analyzed by flow cytometry and real-time polymerase chain reaction. The ability of macrophages to regulate plasma cell differentiation was determined in ex vivo cultures of cells from human HCC tissues. C57BL/6 and BALB/c mice were given injections of Hepa1-6 cells, which formed hepatomas, or H22 cells, which formed ascitic hepatomas. Gene expression patterns were analyzed in human HCC, mouse hepatoma, and non-tumor tissues by real-time polymerase chain reaction. Mice with hepatomas were given injections of GSK126 (an inhibitor of histone H3 lysine 27 methyltransferase [EZH2]) and 5-AZA-dC (an inhibitor of DNA methyltransferases); tumor tissues were analyzed by immunofluorescence and immunohistochemistry for the presence of immune cells and cytokines. RESULTS: B cells isolated from HCCs had somatic hypermutations and class-switch recombinations to the IgG phenotype that were not observed in non-tumor tissues. Increased level of plasma cells correlated with poor outcomes of patients. Activated CD4+ T cells from HCCs stimulated C-X-C motif chemokine 10 (CXCL10) production by macrophages. CXCL10 bound CXC chemokine receptor 3 on B cells and signaled via extracellular signal-regulated kinase to cause them to become IgG-producing plasma cells. IgG activated Fc receptors on macrophages and induced them to produce interleukin 6, interleukin 10, and C-C motif chemokine ligand 20 (CCL20). In mice with hepatomas, depletion of B cells prevented generation of these macrophage, increased the anti-tumor T cell response, and reduced growth of hepatomas. However, these effects were lost after injection of CXC chemokine receptor 3-positive plasma cells. Human HCC and mouse hepatoma tissues had increased expression of DNA methyltransferase 1 and EZH2 compared with non-tumor tissues. Injection of mice with GSK126 and 5-AZA-dC induced expression of CXCL10 by tumor cells and caused plasma cell polarization, suppression of the anti-tumor T cell response, and hepatoma growth. CONCLUSIONS: Human HCC tissues contain B cells with class-switch recombinations to the IgG phenotype. Activated CD4+ T cells from HCCs stimulate CXCL10 production by macrophages; CXCL10 binds CXC chemokine receptor 3 on B cells and causes them to become IgG-producing plasma cells. IgG activates Fc receptor in macrophages to produce cytokines that reduce the anti-tumor immune response. In mice with hepatomas, depletion of B cells prevented generation of these macrophages, increased the anti-tumor T cell response, and reduced growth of hepatomas. This pathway involves increased expression of DNA methyltransferase 1 and EZH2 by HCC and hepatoma cells.

A kinetic/thermodynamic study of transparent co-adsorbents and colored dye molecules in visible light based on microgravimetric quartz-crystal microbalance on porous TiO2 films for dye-sensitized solar cells.

In this study, a quartz crystal microbalance (QCM) in situ method is used to study the kinetic and thermodynamic processes of the adsorption of ruthenium-based dyes (N719, N3, N749), and the co-adsorbent chenodeoxycholic acid (CDCA) on the TiO2 film surface. The results of the kinetic studies show that the adsorption rate of N749 is slightly higher than the other two dyes, and the adsorption rate of CDCA is more sensitive to temperature change. The adsorption mechanism of the dye and CDCA on the surface of TiO2 can be reasonably inferred based on the result of the activation energy. The isotherm adsorption model studies show that the ratio of the number of surface molecules (296 K) is n(N719) : n(N3) : n(N749) : n(CDCA) = 0.69 : 1.48 : 0.50 : 1. The Keq value of CDCA is about two orders of magnitude smaller than that of all the dye molecules, which indicates that the adsorption strength of CDCA is much weaker than that of the dye molecules. Thermodynamic studies show that the adsorption reaction is an endothermic reaction. The ΔS is ΔS(N3 = 143.11 J mol-1) > ΔS(N719 = 112.72 J mol-1) > ΔS(N749 = 109.43 J mol-1) > ΔS(CDCA = 96.14 J mol-1). The Gibbs free energy ΔG is negative, and indicates that the adsorption reaction of the four molecules on the surface of the TiO2 film is spontaneous. The results of this paper show that the tedious and lengthy experimental process of the traditional method can be simplified by QCM. In addition, the development of this study provides a certain theoretical and experimental basis for future studies on the interaction mechanism between dyes and co-adsorbents.

An in situ exchange mechanism for dye molecules and cations at the nano-semiconductor film/electrolyte interface.

This communication uses electrochemical quartz crystal microbalance (EQCM) in combination with the potentiostatic method to study the in situ exchange mechanism for dye molecules and cations on the nano-film surface under a constant potential. The relationship between dye molecule desorption mass and charge was analyzed. A theoretical model was established to obtain the important parameters of cation exchange number and apparent valence electron number during dye desorption, and the microscopic desorption mechanism of the dye is further revealed.

Different heart failure phenotypes of valvular heart disease: the role of mitochondrial dysfunction.

Valvular heart disease (VHD)-related heart failure (HF) is a special subtype of HF with an increasingly concerned heterogeneity in pathophysiology, clinical phenotypes, and outcomes. The mechanism of VHD-related HF involves not only mechanical damage to the valve itself but also valve lesions caused by myocardial ischemia. The interactions between them will lead to the occurrence and development of VHD-related HF subtypes. Due to the spatial (combination of different valvular lesions) and temporal effects (sequence of valvular lesions) of valvular damages, it can make the patient's condition more complicated and also make the physicians deal with a dilemma when deciding on a treatment plan. This indicates that there is still lack of deep understanding on the pathogenic mechanism of VHD-related HF subtypes. On the other hand, mitochondrial dysfunction (MitD) is not only associated with the development of numerous cardiac diseases such as atherosclerosis, hypertension, diabetes, and HF but also occurs in VHD. However, the role of MitD in VHD-related HF is still not fully recognized. In this comprehensive review, we aim to discuss the current findings and challenges of different valvular damages derived from HF subtypes as well as the role of MitD in VHD-related HF subtypes.

Scutellaria baicalensis Georgi regulates REV-ERBα/BMAL1 to protect against skin aging in mice.

Scutellaria baicalensis Georgi (SBG) is a traditional Chinese medicine widely used to treat disorders such as hypertension, dysentery and hemorrhaging. Here, we aimed to assess the pharmacological effects of SBG on skin aging and to investigate the underlying mechanisms. Mice with skin aging were established by treatment with D-galactose and ultraviolet-B. SBG (topical application) showed a protective effect on skin aging in mice, as evidenced by less formation of skin wrinkles, higher levels of SOD (superoxide dismutase) and HYP (hydroxyproline) as well as a lower level of MDA (malondialdehyde). In the meantime, skin MMP-1 and p53 expression were lower, epidermis was thinner and collagen amount was higher in SBG-treated mice. Anti-skin aging effects of SBG were also confirmed in NIH3T3 and HaCaT cells, as well as in mouse primary dermal fibroblasts and human primary epidermal keratinocytes. Furthermore, we found that loss of Rev-erbα (a known repressor of Bmal1) up-regulated skin BMAL1 (a clock component and a known anti-aging factor) and ameliorated skin aging in mice. Moreover, SBG dose-dependently increased the expression of BMAL1 in the skin of aged mice and in senescent NIT3H3 cells. In addition, based on a combination of Gal4 chimeric, luciferase reporter and expression assays, SBG was identified as an antagonist of REV-ERBα and thus an inducer of BMAL1 expression. In conclusion, SBG antagonizes REV-ERBα to up-regulate BMAL1 and to protect against skin aging in mice.

Long-acting microneedle patch loaded with adipose collagen fragment for preventing the skin photoaging in mice.

Skin photoaging is one of the most serious public health problems in the 21st century that may lead to thin, saggy, and structurally weakened skin. Adipokine therapy toward skin photoaging is always associated with poor permeability, biologic stability and the short in vivo release duration. Our laboratory previously extracted an extracellular matrix component of adipose tissue by purely physical methods, namely "adipose collagen fragment (ACF)", which holds promise for preventing skin photoaging. However, the injection treatment of ACF requires repeated preparation processes and injection procedures, which may be time-consuming and painful. Therefore, we describe the fabrication and assessment of a detachable ACF-microneedle (ACF-MN) patch that creates minimally invasive dermal microtrauma upon application. And we evaluated the morphology characterization, mechanical properties and puncture performance in vitro. The delivery efficiency of ACF from the patches was estimated in vitro and vivo. Then, the therapeutic efficacy was identified through applying ACF-MN patches into the dermis of UVA-induced photoaging mice and the related detection of skin photoaging was estimated. Our results demonstrated that ACF-MN exhibited well skin puncture performance and could release ACF component slowly. Meanwhile, this microneedle device loaded with ACF exhibited the treatment efficiency on skin photoaging in a mouse model. Therefore, implantation of the microtrauma-mediated, long-acting ACF-MN system can be utilized as a potential candidate for preventing skin photoaging in the clinic.

Has COVID-19 Changed China's Digital Trade?-Implications for Health Economics.

Digital technologies have played a significant role in the defense against the COVID-19 pandemic. This development raises the question of whether digital technologies have helped Chinese exports recover quickly and even grow. To answer this question, we study monthly data on Chinese exports to 40 countries/regions from January 2019 to June 2020 and covering 97 product categories. The study takes the COVID-19 outbreak as a natural experiment and treats digital trade products as the treatment group. Using a generalized difference-in-differences (DID) approach, we empirically investigate how this major global public health crisis and digital trade have influenced Chinese exports. Our empirical analysis reveals that the COVID-19 pandemic has inhibited China's export trade overall, digital trade has significantly promoted trade, and the supply mechanism has played a significant role in promoting the recovery of exports. Heterogeneity tests on destination countries/regions reveal that digital trade has significantly promoted exports to countries/regions with different income levels, with a more significant effect on low-risk destinations than on high-risk destinations. The sector heterogeneity test demonstrates that digital trade has enhanced the export recovery of sectors dealing in necessities for pandemic prevention. Other robustness tests, including parallel trend and placebo tests, support the above conclusions. Finally, we extend the research conclusions and discuss their implication for health economics and the practice of fighting COVID-19.

Experimental study of fat derived pellets promoting wound healing in rats.

To observe the effect of fat-derived pellets (FDP) on wound healing in rats, the inguinal fat of rats was obtained, and the FDP were obtained after centrifugation. The cell activity and growth factor secretion of FDP were measured. The wounds in rats were created, and FDP was used to treat the wounds of rats. The phenotype of macrophages and the expression of angiogenic factors expression in wounds were measured. The cell viability in FDP remains in high level after centrifugation and the expression of vascular endothelial growth factor (VEGF) and Basic Fibroblast Growth Factor (bFGF) from FDP was observed in vitro. The FDP significantly promoted the wound healing of rats compared with that in control groups. Moreover, the expression of M2 macrophages and VEGF in FDP group were significantly higher than that in the control group. FDP is a kind of stem cell product, which can be obtained from adipose tissue by physical centrifugation. The cytotherapeutic effect of FDP makes it a promising product for wound healing in clinics.