Ginseng-derived nanoparticles reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment.

BACKGROUND: Lines of evidence indicated that, immune checkpoints (ICs) inhibitors enhanced T cell immune response to exert anti-tumor effects. However, T cell exhaustion has been so far a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear. METHODS: The correlation between arginase-1 (ARG1) and T cells was computed based on the colorectal cancer patients in TCGA database. In vitro, we observed that GDNPs reprogrammed TAMs inhibited ARG1 release and ultimately ameliorated T cell exhaustion according to several techniques including WB, PCR, ELISA and flow cytometry. We also used an in vivo MC38 tumor-bearing model and administered GDNPs to assess their anti-tumor effects through multiple indices. The mechanism that GDNPs improved T cell exhaustion was further clarified using the bioinformatics tools and flow cytometry. RESULTS: GDNPs reprogramed TAMs via reducing ARG1 production. Moreover, normalized arginine metabolism ameliorated T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8+ T cells expansion. CONCLUSIONS: By regulating the mTOR-T-bet axis, GDNPs reprogramed macrophages to regulate ARG1 release, which further ameliorated T cell exhaustion in TME. These findings provided new insights into comprehending the mechanisms underlying the mitigation of T cell exhaustion, which may facilitate the development of innovative therapeutic strategies in the field of cancer treatment.

Effect of Shixiao San on inflammatory factors and pain in rats with endometriosis.

ETHNOPHARMACOLOGICAL RELEVANCE: In the practice of traditional Chinese medicine, endometriosis is believed to be caused by blood stasis and is characterised by dysmenorrhea, which is difficult to control. Shixiao San (SXS) has a long history of use in the treatment of gynaecological diseases. The prescriptions composed of SXS include Typhae Pollen and Faeces Trogopterori, both of which have anti-inflammatory activity. In addition, Typhae Pollen can be used to treat many kinds of blood stasis diseases. AIM OF THE STUDY: The purpose of the present study was to investigate the effect of SXS on pain relief in rats with endometriosis and to preliminarily explore its mechanism of action in alleviating pain. MATERIAL AND METHODS: Ten rats received sham operation as the Sham group, and 30 endometriosis model rats were randomly divided into three groups: the Model, Shixiao San-Low (SXS-L), and Shixiao San-High (SXS-H) groups. The rats were administered the appropriate treatment via intragastric gavage for 4 weeks. The thermal radiation pain and mechanical pain thresholds of the rats were measured every 7 days after treatment. Finally, the distribution density of nerve fibres in endometrial tissue, the inflammatory infiltration of the dorsal root ganglion (DRG), the expression of TRPV1 in the DRG, and the expression of IL-1ß, TNF-α, and IL-6 in ectopic tissue were measured. RESULTS: After SXS treatment, the growth of ectopic tissue in rats with endometriosis was significantly suppressed, their thermal radiation pain and mechanical pain thresholds increased, the density of nerve fibres and the expression of inflammatory factors in ectopic tissues reduced, and inflammatory cells infiltration in the DRG of the animals alleviated. Meanwhile, the expression of TRPV1 in the DRG was downregulated in rats with endometriosis. CONCLUSIONS: SXS could possibly inhibit the development of endometriosis and relieve pain in patients with endometriosis by reducing inflammatory responses in ectopic tissue and the DRG.

Yiguanjian decoction enhances fetal liver stem/progenitor cell-mediated repair of liver cirrhosis through regulation of macrophage activation state.

AIM: To investigate whether Yiguanjian decoction (YGJ) has an anti-liver cirrhotic effect and whether it regulates hepatic stem cell differentiation. METHODS: A rat model of liver cirrhosis was established via subcutaneous injection of carbon tetrachloride (CCl4) for 8 wk. From the beginning of the ninth week, the rats received 2-acetylaminofluorene (2-AAF) by oral gavage and a DLK-1+ fetal liver stem/progenitor cell (FLSPC) transplant or an FLSPC transplant in combination with YGJ treatment for 4 wk. In vitro, lipopolysaccharide (LPS)-activated macrophages were co-cultured with WB-F344 cells, and the differentiation of WB-F344 cells was observed in the presence and absence of YGJ treatment. RESULTS: FLSPC transplantation improved liver function and histopathology, and inhibited the activation of the non-canonical Wnt signaling pathway, while activating the canonical Wnt signaling pathway. YGJ enhanced the therapeutic effects of FLSPCs and also promoted the liver regeneration differentiation of FLSPCs into hepatocytes. In vitro, LPS-activated macrophages promoted the differentiation of WB-F344 cells into myofibroblasts, and the canonical Wnt signaling was inhibited while the non-canonical Wnt signaling was activated in WB-F344 cells. YGJ suppressed the activation of macrophages and then inhibited non-canonical Wnt signaling and promoted canonical Wnt signaling. CONCLUSION: YGJ enhances FLSPC-mediated repair of liver cirrhosis through regulation of macrophage activation state, and YGJ in combination with stem cell transplantation may be a suitable treatment for end-stage liver cirrhosis.

PPARδ activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis.

Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington's disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the U.S. Food and Drug Administration-approved drug bexarotene. We tested the therapeutic potential of bexarotene in HD and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.

Four new glycosides from the stems of Dendrobium fimbriatum Hook.

Four new glucosides, named as gigantol-5-O-ß-d-glucopyranoside (1), 9,10-dihydro-aphyllone A-5-O-ß-d-glucopyranoside (2), ficusal-4-O-ß-d-glucopyranoside (3), botrydiol-15-O-ß-d-glucopyranoside (4), together with eight known compounds (5-12) were isolated from the n-BuOH extract of the stems of Dendrobium fimbriatum Hook. Their structures were elucidated by the analyses of spectroscopic data.

Protective effects of cycloartane triterpenoides from Passiflora edulis Sims against glutamate-induced neurotoxicity in PC12 cell.

Four new cycloartane triterpenoids, 1α,3ß-dihydroxy-16-keto-24(31)-en-cycloartane (1), 31-methoxyl-passifloic acid (2), cyclopassifloside XIV (3), and cyclopassifloside XV (4), together with six known compounds (5-10) were isolated from Passiflora edulis Sims. Their structures were elucidated on the basis of extensive spectroscopic analysis. All the compounds were evaluated for protective effects against damage of PC12 cell induced by glutamate according to traditional usage of the herbal medicine, and the results indicated that cycloartane triterpenoids maybe one of the active compositions of P. edulis Sims for the treatment of neurodegenerative disease.

Astragaloside prevents BDL-induced liver fibrosis through inhibition of notch signaling activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People׳s Welfare Pharmacy in the Song Dynasty (AD1078). It consists of Radix Astragali (Astragalus membranceus (Fisch.) Bge. Root, Huangqi) and Radix Glycyrrhizae (Glycyrrhiza uralensis Fisch., root and rhizome, Gancao), and it is an effective recipe that is usually used to treat consumptive disease and chronic liver diseases. Astragaloside (AS) is a main component of Radix Astragali had an effect similar to the Huangqi decoction on hepatic fibrosis. AIM OF THE STUDY: Cholestasis is associated with a number of chronic liver diseases and Notch signaling has been demonstrated to be involved in ductular reaction. Previous studies have shown that AS can prevent the progression of cholestatic liver fibrosis, however, whether AS affects the Notch signaling pathway is unclear. MATERIALS AND METHODS: Cholestatic liver fibrosis was established by common bile duct ligation (BDL) in rats. At first weekend, the rats were randomly divided into a model group (BDL), an AS group, and a Sorafenib positive control group (SORA) and treated for 3 weeks. Bile duct proliferation and liver fibrosis were determined by tissue staining. Activation of the Notch signaling pathway was evaluated by analyzing expressions of Notch-1, -2, -3, -4, Jagged 1 (JAG1), Delta-like (DLL)-1, -3, -4, Hes1, Numb and RBP-Jκ. Activation of the Wnt signaling pathway was evaluated by analyzing expressions of Wnt-4, -5a, -5b, Frizzled (Fzd)-2, -3, -6 and ß-catenin. RESULTS: (1) Compared with the BDL group, AS significantly reduced the deposition of collagen and the Hyp content of liver tissue and inhibited the activation of HSCs. In addition, AS significantly decreased the protein and mRNA expressions of TGF-ß1 and α-SMA. In contrast, AS significantly enhanced expression of the Smad 7 protein. AS also reduced biliary epithelial cell proliferation, and reduced the mRNA and protein expressions of CK7, CK8, CK18, CK19, OV6, Sox9 and EpCAM. (2) The mRNA and protein expressions of Notch-2, -3, -4 and JAG1 were significantly reduced in the AS compared to the BDL group. In contrast, the mRNA and protein level of Numb was clearly enhanced after AS treatment. CONCLUSION: AS may prevent biliary liver fibrosis via inhibition of the Notch signaling pathway, thereby inhibiting the abnormal proliferation of biliary epithelial cells. Results indicate that AS may be a potential therapeutic drug for cholestatic liver disease.

Five new phenolic compounds from Dendrobium aphyllum.

One new phenanthrene, aphyllone A (1) and four new bibenzyl derivatives, aphyllone B (2) and aphyllals C-D (3-5), together with nine known compounds (6-14), were isolated from the stems of Dendrobium aphyllum (Roxb.) C. E. Fischer. The structures of these new compounds were elucidated by means of extensive spectroscopic analyses, and the absolute configuration of compound 1 was determined by single crystal X-ray diffraction and quantum calculations. Compounds 6, 8 and 14 inhibited NO production at the concentration of 25 µM in LPS-stimulated RAW264.7 cells with the inhibition (%) of 32.48, 35.68, and 38.50. Compound 2 possessed significant DPPH radical scavenging activity with scavenging percentage of 87.97% at the concentration of 100 µg/mL.

Cycloartane triterpenoid saponins from water soluble of Passiflora edulis Sims and their antidepressant-like effects.

ETHNOPHARMACOLOGICAL RELEVANCE: Various species of genus Passiflora have been used as traditional folk medicines owing to their sedative and anti-hypertensive properties. Passiflora edulis Sims most widely grown in the warm temperate for their fragrant fruits and their twigs and leaves are used as a folk medicine for treating both anxiety and nervousness in American countries. The present study was to evaluate the antidepressant-like effect and the active components of this plant. MATERIALS AND METHODS: The alcohol extracts of the stems (PES, 10 and 2 g/kg of the plant materials) and leaves (PEL, 10 and 2 g/kg of the plant materials) of Passiflora edulis Sims were orally administered to mice for 7 day. The animals were tested in the forced swim test (FST) and tail suspension test (TST). After behavioral assay of ethanol extract, phytochemical research of the stems and leaves (5.7 kg) of Passiflora edulis Sims were developed and further bioactive verification of monomeric compounds were conducted. RESULTS: There are mainly cycloartane triterpenoids and their saponins isolated from this plant, including two new cycloartane triterpenoid saponins named cyclopassifloside ХII (1) and ХIII (2), together with six known cycloartane triterpenoids, cyclopassifloic acids B and E, cyclopassiflosides II, VI, IX and XI. The ethanol extract of Passiflora edulis Sims together with isolated compounds cyclopassiflosides IX and XI may possess antidepressant-like effect. CONCLUSIONS: Cycloartane triterpenoid was one of the main compositions of Passiflora edulis Sims and possess antidepressant-like activity.

C-dideoxyhexosyl flavones from the stems and leaves of Passiflora edulis Sims.

The stems and leaves of Passiflora edulis Sims, are used as a folk medicine for treating both anxiety and nervousness in American countries. Phytochemical investigation of the n-butanol (n-BuOH) fraction of this plant led to the isolation of four new 2,6-dideoxyhexose-C-glycosyl flavones, including luteolin-8-C-ß-digitoxopyranosyl-4'-O-ß-d-glucopyranoside (1), apigenin-8-C-ß-digitoxopyranoside (2), apigenin-8-C-ß-boivinopyranoside (3) and luteolin-8-C-ß-boivinopyranoside (4), together with five known compounds (5-9). The structures of these compounds were elucidated by extensive spectroscopic methods. All compounds were evaluated for their neurite outgrowth enhancing activities and the results indicated that luteolin (7) enhanced NGF-induced neurite outgrowth in PC12 cells at 50.0µM.

Implantation of bFGF-treated islet progenitor cells ameliorates streptozotocin-induced diabetes in rats.

AIM: To examine whether implantation of islet preparation-derived proliferating islet cells (PIC) could ameliorate diabetes in rats. METHODS: PIC were expanded from rat islet preparation by supplementation of basic fibroblast growth factor (bFGF) and implanted into rats with streptozotocin (STZ)-induced diabetes through the portal vein. Body weight and blood glucose levels were measured. Serum insulin levels were measured by radioimmunoassay. The presence of insulin-positive cells was determined by hematoxylin and immunohistochemical staining. RESULTS: Cultured islet cells (CIC) were demonstrated to dedifferentiate in vitro, and the apoptosis ratios reached more than 50% by the 15th day post-isolation. PIC cells treated with bFGF (20 ng/mL) continued growing within 30 days after isolation, and no apoptotic cells were detected. Implantation of PIC into diabetic rats was capable of ameliorating diabetes, in terms of the restoration of euglycemia, weight gain, improved glucose response and elevated serum insulin levels for up to 130 days. Livers derived from PIC-implanted rats were examined for insulin expression and single insulin-positive cells. In addition, most islets of PIC-implanted STZ-induced diabetic rats were intact at 130 days post-transplantation and comparable to those of normal rats. CONCLUSION: Implantation of bFGF-treated proliferating islet cells is a promising cellular therapeutic approach for diabetes.