Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation.

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.

In vivo acute and subacute toxicities of phenolic extract from rambutan (Nephelium lappaceum) peels by oral administration.

Acute and subacute studies of rambutan peel phenolic (RPP) extract were conducted by oral administration on Kunming mice and Sprague-Dawley (SD) rats, respectively. Acute toxicity study (14 days) results revealed that the LD50 value of RPP extract was more than 5000 mg/kg bw in vivo. For the subacute study, four different doses were administered to SD rats by daily gavage for 28 days. Subacute toxicity study results indicated that RPP extract did not show any obvious adverse effect at doses of 312 and 625 mg/kg bw. The bw gain was significantly inhibited at 2500 mg/kg bw of RPP extract. RPP extract at doses of 1250 and 2500 mg/kg bw showed toxicities to liver, kidney, and spleen in SD rats according to the results of hematological and biochemical analyses. Furthermore, RPP extract at 2500 mg/kg bw showed toxicity on different tissues according to the results of histopathological analyses.

Metal Chelating, Inhibitory DNA Damage, and Anti-Inflammatory Activities of Phenolics from Rambutan (Nephelium lappaceum) Peel and the Quantifications of Geraniin and Corilagin.

Whereas the preparation and biological properties of rambutan peel phenolics (RPP) were explored in our previous studies, the metal chelating, inhibitory DNA damage, and anti-inflammatory activities of RPP were evaluated and the important phenolics of RPP quantified in this study. Results showed that RPP had high Fe2+ and Cu2+-chelating activities with EC50 of 0.80 mg/mL and 0.13 mg/mL, respectively. RPP effectively decreased the production of hydroxyl radical with IC50 of 62.4 µg/mL. The protective effects of RPP against AAPH-induced DNA damage were also explored. RPP efficiently inhibited peroxyl radical-induced plasmid DNA strand breakage. The anti-inflammatory effects of RPP were determined using a lipopolysaccharide (LPS)-induced RAW 264.7 cell model. RPP significantly inhibited the production of nitric oxide (NO) and controlled the levels of inducible NO synthase mRNA in LPS-induced RAW 264.7 cells. The inhibitory activity increased in a dose-dependent manner. The above bioactivity of RPP was associated with its phenolic content and phenolic profiles. Furthermore, the contents of geraniin and corilagin in RPP were determined by an ultra-high performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS), showing 140.02 and 7.87 mg/g extract dry weight. Thus, RPP has potential applications as a novel nutraceutical and functional food in health promotion.

Healthy Indoor Environments: The Need for a Holistic Approach.

Indoor environments have a large impact on health and well-being, so it is important to understand what makes them healthy and sustainable. There is substantial knowledge on individual factors and their effects, though understanding how factors interact and what role occupants play in these interactions (both causative and receptive) is lacking. We aimed to: (i) explore interactions between factors and potential risks if these are not considered from holistic perspective; and (ii) identify components needed to advance research on indoor environments. The paper is based on collaboration between researchers from disciplines covering technical, behavioural, and medical perspectives. Outcomes were identified through literature reviews, discussions and workshops with invited experts and representatives from various stakeholder groups. Four themes emerged and were discussed with an emphasis on occupant health: (a) the bio-psycho-social aspects of health; (b) interaction between occupants, buildings and indoor environment; (c) climate change and its impact on indoor environment quality, thermal comfort and health; and (d) energy efficiency measures and indoor environment. To advance the relevant research, the indoor environment must be considered a dynamic and complex system with multiple interactions. This calls for a transdisciplinary and holistic approach and effective collaboration with various stakeholders.

Curcumin improves LPS-induced preeclampsia-like phenotype in rat by inhibiting the TLR4 signaling pathway.

INTRODUCTION: Abnormal inflammation mediated by Toll-like receptor 4 (TLR4) signaling pathway contributes to preeclampsia (PE). Because curcumin can inhibit TLR4 signaling pathway, we investigated its effects on a PE rat model. METHODS: Twenty-one pregnant rats were randomly divided into three groups: 1) seven rats were injected 0.5 µg/kg lipopolysaccharide (LPS) on gestational day (GD) 5 to create a PE model (LPS-treated group), 2) seven rats were injected with a similar dosage of LPS and further treated with curcumin (0.36 mg/kg) (LPS-curcumin-treated group), 3) seven rats received saline (control group). Blood pressure and urinary protein level were observed. Immunostaining and periodic acid-Schiff staining of placenta were conducted. TLR4 and downstream Nuclear Factor-κB (NF-κB) expressions of placenta were analyzed by Western blot and immunohistochemistry. IL-6 and MCP-1 in rat serum and placenta were determined by ELISA and qRT-PCR. RESULTS: Compared to LPS-treated group, LPS-curcumin-treated group had decreased blood pressure and urinary protein level, similar to control group. Furthermore, deficient trophoblast invasion and spiral artery remodeling induced by LPS were improved by curcumin. Increased TLR4, NF-κB and IL-6, MCP-1 protein expressions in LPS-treated group were significantly decreased after curcumin administration. DISCUSSION: Curcumin improves the PE-like phenotype in rat model by reducing abnormal inflammation related to TLR4 signaling pathway.

High-kappa oxide nanoribbons as gate dielectrics for high mobility top-gated graphene transistors.

Deposition of high-kappa dielectrics onto graphene is of significant challenge due to the difficulties of nucleating high quality oxide on pristine graphene without introducing defects into the monolayer of carbon lattice. Previous efforts to deposit high-kappa dielectrics on graphene often resulted in significant degradation in carrier mobility. Here we report an entirely new strategy to integrate high quality high-kappa dielectrics with graphene by first synthesizing freestanding high-kappa oxide nanoribbons at high temperature and then transferring them onto graphene at room temperature. We show that single crystalline Al(2)O(3) nanoribbons can be synthesized with excellent dielectric properties. Using such nanoribbons as the gate dielectrics, we have demonstrated top-gated graphene transistors with the highest carrier mobility (up to 23,600 cm(2)/V x s) reported to date, and a more than 10-fold increase in transconductance compared to the back-gated devices. This method opens a new avenue to integrate high-kappa dielectrics on graphene with the preservation of the pristine nature of graphene and high carrier mobility, representing an important step forward to high-performance graphene electronics.

[Influence of Qingxiang San on substance P, somatostatin in rats model with the spleen and stomach wet heat syndrome].

OBJECTIVE: To observe the influence of Qingxiang San (QS) on substance P (SP), somatostatin (SS) in rats model of spleen and stomach wet heat syndrome. METHODS: 24 rats were divided into 3 groups (each group 8 rats) randomly: the normal control group (NCG), wet heat group (WHG), QS group (QSG). We set up the spleen and stomach wet heat syndrome of rats model by the composite factors such as greasy and sweet food, wet and hot environment, pathogen and so on. Then the contents of SP, SS were detected by radioimmuno assay. RESULTS: The content of SP, SS in WHG were obviously lower than NCG (P<0.01); QSG compared with WHG, the content of SP, SS increased (P<0.01); The content of SP obviously increased when QSG compared with NCG (P<0.01); About the content of SS, there was no significant difference between QSG and NCG (P>0.05), illustrating that QS can increase the content of SP, SS which had decreased. CONCLUSION: QS can regulate the content of SP and SS and increase them which had decreased.