Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. ...However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC).
The distribution, phenotype, and function of MAIT cells in patients with HCC were evaluated by both flow cytometry (FCM) and
bioassays. Transcriptomic analysis of MAIT cells was also performed. Prognostic significance of tumor-infiltrating MAIT cells was validated in four independent cohorts of patients with HCC.
Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7
CD45RA
CD45RO
CD95
effector memory phenotype with lower costimulatory and effector capabilities. Tumor-educated MAIT cells significantly upregulated inhibitory molecules like PD-1, CTLA-4, TIM-3, secreted significantly less IFNγ and IL17, and produced minimal granzyme B and perforin while shifting to produce tumor-promoting cytokines like IL8. Transcriptome sequencing confirmed that tumor-derived MAIT cells were reprogrammed toward a tumor-promoting direction by downregulating genes enriched in pathways of cytokine secretion and cytolysis effector function like
and
and by upregulating genes like
, and
(
). High infiltration of MAIT cells in HCC significantly correlated with an unfavorable clinical outcome, revealed by FCM, qRT-PCR, and multiplex IHC analyses, respectively.
HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.
.
The aim of this study was to well understand the dynamic changes of physicochemical properties of polysaccharides from loquat leaves (LLP) during in vitro simulated saliva-gastrointestinal digestion ...and fecal fermentation and its related impacts on human gut microbiota. Results showed that the contents of reducing sugar of LLP slightly increased during the gastrointestinal digestion, and its molecular weight also slightly decreased, suggesting that LLP could be slightly degraded under the gastrointestinal digestion conditions. Moreover, during the fecal fermentation, the molecular weight of the indigestible LLP (LLP-I) significantly decreased, and the molar ratio of constituent monosaccharides of LLP-I, such as glucuronic acid, galacturonic acid, galactose, and arabinose, significantly changed, indicating that LLP-I could be degraded and consumed by human gut microbiota. Indeed, some beneficial bacteria such as Megasphaera, Megamonas, Bifidobacterium, Phascolarctobacterium, and Desulfovibrio significantly increased, suggesting that LLP-I could change the composition and abundance of gut microbiota. LLP-I could also promote the production of health-promoting short chain fatty acids. Results from this study are benefical to well understand the in vitro digestion and fecal fermentation behaviors of LLP, and LLP can be developed as a potential prebiotic in the functional food industry.
•Polysaccharides from loquat leaves (LLP) could be slightly degraded during in vitro digestion.•The indigestible LLP (LLP-I) could be degraded and consumed by human gut microbiota.•Some beneficial bacteria, such as Megasphaera, Megamonas, and Bifidobacterium, increased•LLP-I could also promote the production of health-promoting short chain fatty acids.
Neuropathic pain (NeP) is a major health concern. Due to the complex pathological mechanisms, management of NeP is challenging. Emodin, a natural anthraquinone derivative, exerts excellent analgesic ...effects. However, its mechanisms of action are still poorly understood. In this study, we investigated the mechanisms underlying pain‐relief effects of emodin in the cerebral cortex using proteomic and metabolomic approaches. After 15 days of emodin administration, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values in the emodin groups were significantly higher than those in the chronic constriction injury (CCI) group (p < .05), suggesting emodin treatment could reverse CCI‐induced hyperalgesia. Emodin treatment evoked the expression alteration of 402 proteins (153 up‐regulated and 249 down‐regulated) in the CCI models, which were primarily involved in PI3K/AKT signaling pathway, gamma‐aminobutyric acid (GABA) receptor signaling, complement and coagulation cascades, cGMP/PKG signaling pathway, MAPK signaling pathway, and calcium signaling pathway. In parallel, emodin intervention regulated the abundance alteration of 27 brain metabolites (20 up‐regulated and 7 down‐regulated) in the CCI rats, which were primarily implicated in carbon metabolism, biosynthesis of amino acids, pentose phosphate pathway, and glucagon signaling pathway. After a comprehensive analysis and western blot validation, we demonstrated that emodin alleviated NeP mainly through regulating GABAergic pathway and PI3K/AKT/NF‐κB pathway.
Herein, we report the first Ni-catalyzed enantioselective deaminative alkylation of amino acid and peptide derivatives with unactivated olefins. Key for success was the discovery of a new sterically ...encumbered bis(oxazoline) ligand backbone, thus offering a de novo technology for accessing enantioenriched sp 3 –sp 3 linkages via sp 3 C–N functionalization. Our protocol is distinguished by its broad scope and generality across a wide number of counterparts, even in the context of late-stage functionalization. In addition, an enantioselective deaminative remote hydroalkylation reaction of unactivated internal olefins is within reach, thus providing a useful entry point for forging enantioenriched sp 3 –sp 3 centers at remote sp 3 C–H sites.
To expand the chemical space of chiral N‐oxides and chiral furan‐containing ligands, herein we designed and synthesized a new class of rigid‐featured tertiary amine‐derived C2‐symmetric chiral ...furan‐N,N′‐dioxide (Fu‐2NO) ligands from optically pure l‐prolinamides/hydroxylprolinamides in operationally simple two steps and up to 57 % overall yield. The newly developed rigid‐featured chiral Fu‐2NO ligands possesses two pyrroloimidazolone‐based N‐oxides as non‐flat chiral walls, and afforded the opportunity for fine‐tuning the ligand electronic and conformational properties by judicious choice of the substituent in the nonligating nitrogen atom. More importantly, The Fu‐2NO ligands can tolerate air and moisture such that no special handling is needed for their storage, and can be applied in the Ni(II)‐catalyzed asymmetric Friedel‐Crafts alkylation reaction of indole.
Here, we demonstrate that the first example of harmaline scaffolds serving as acceptor/acceptor-based N-C-C synthons triggered the ring opening and skeletal reconstruction of 3-vinyl benzofuranones ...for the construction of a library of skeletally diverse polycyclic harmaline scaffolds. These products were smoothly afforded in up to 77% yield, >20 : 1 dr under catalyst-free conditions, and expanded the chemical space of biologically significant harmaline derivative species. All synthetic compounds showed cytotoxic activity against tumor cells, especially compound
3at
, which exhibited selective cytotoxicity against A549 cells and lower cytotoxicity against normal cells MRC-5 and HK-2. In further mechanism research,
3at
inhibited A549 cell proliferation through the G1 phase arrest, induced A549 cell apoptosis through internal and external apoptosis pathways, and suppressed the migration and invasion abilities of A549 cells. These data indicated that compound
3at
is the most effective compound in the series and can serve as a promising precursor for drug development.
This is the first example of harmaline scaffolds as acceptor/acceptor-based N-C-C synthons and evaluation of
3at
as an anticancer agent.
The development of chiral ligands to fine-tune stereocontrol in asymmetric catalysis is of great demand. To diversify the Py-2NO ligand library recently developed by our group, herein, we synthesized ...six new Py-2NO ligands, determined the absolute configuration
via
X-ray crystallographic study of ligand L1g, and applied these ligands in the Ni(
ii
)-catalyzed asymmetric Michael addition reaction of indoles and β,γ-unsaturated α-keto esters. Excellent yields (up to 93%) and high enantioselectivities (up to 99% ee) were obtained for a wide range of substrates under mild conditions. In addition, we discovered the presence of axial chirality in the C(aryl)-N(amide) bond in the tertiary amine-derived
N
-oxide product
via
X-ray crystallographic study. Owing to the intriguing characteristics of atropisomerism, we believe that this reaction will add an important member to the axial chiral family.
This work diversified the Py-2NO ligand library recently developed by our group and further expanded the application of chiral Py-2NO ligands in asymmetric catalysis.
N-doped ZnO/g-C
3
N
4
composites have been successfully prepared via a facile and cost-effective sol-gel method. The nanocomposites were systematically characterized by XRD, FE-SEM, HRTEM, FT-IR, ...XPS, and UV-vis DRS. The results indicated that compared with the pure N-doped ZnO, the absorption edge of binary N-doped ZnO/g-C
3
N
4
shifted to a lower energy with increasing the visible-light absorption and improving the charge separation efficiency, which would enhance its photocatalytic activity. Compared with the pure g-C
3
N
4
, ZnO, N-doped ZnO and the composite ZnO/g-C
3
N
4
, the as-prepared N-doped ZnO/g-C
3
N
4
exhibits a greatly enhanced photocatalytic degradation of methylene blue and phenol under visible-light irradiation. Meanwhile, N-doped ZnO/g-C
3
N
4
possesses a high stability. Finally, a proposed mechanism for N-doped ZnO/g-C
3
N
4
is also discussed. The improved photocatalysis can be attributed to the synergistic effect between N-doped ZnO and g-C
3
N
4
, including the energy band structure and enhanced charge separation efficiency.
Liposomes (LPs), a delivery vehicle for stabilizing drugs, the characteristics of being easy to aggregate and fuse limit its application. Polymer coating is a promising way to tackle these issues. In ...this study, the potential of carboxymethyl chitosan (CMCS) and quaternary ammonium chitosan (TMC)-coated liposomes (CMCS/TMC-LPs) for improving the oral delivery capacity of curcumin (CUR) was explored. CMCS/TMC-LPs were prepared by electrostatic adsorption in a layer-by-layer manner. CMCS/TMC-LPs were spherical and had not obvious change in particle size and morphology after storage at 4 °C for 7 and 14 days. CMCS/TMC-LPs possessed favorable gastric acid tolerance (the cumulative drug release rate <10%) due to stable structure. The hemolysis test and Cell Counting Kit-8 (CCK8) assay appeared satisfactory biocompatibility of CMCS/TMC-LPs. The pharmacokinetics exhibited that oral absolute bioavailability of CUR loaded CMCS/TMC-LPs was about 38%, which was around 6 folds and 3 folds higher than CUR loaded LPs and CUR loaded TMC-LPs, respectively. The in vivo experiments showed that CMCS/TMC-LPs could prolong the retention time of CUR in systemic circulation and generate high level of CUR in liver, spleen and lung. Thus, CMCS/TMC-LPs may be a promising carrier for improving the efficacy and safety of orally administered drugs.
Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be ...influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.
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•Colon cancer liver metastasis upregulates ALDOB, an enzyme for fructose metabolism•Metabolized fructose provides fuel for the central carbon metabolism•Targeting ALDOB or its upstream regulator GATA6 reduces liver metastasis growth•Reducing dietary fructose diminishes liver metastatic growth
Bu et al. show that, during colonization of the liver, the liver environment can cause colon cancer cells (CRC) to undergo metabolic reprogramming by upregulating aldolase B, which enhances fructose metabolism and promotes growth of CRC liver metastases. Targeting aldolase B or reducing dietary fructose reduces liver metastasis growth.
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