Hypoxia-responsive Immunostimulatory Nanomedicines Synergize with Checkpoint Blockade Immunotherapy for Potentiating Cancer Immunotherapy.

Inducing cell death while simultaneously enhancing antitumor immune responses is a promising therapeutic approach for multiple cancers. Celastrol (Cel) and 7-ethyl-10-hydroxycamptothecin (SN38) have contrasting physicochemical properties, but strong synergy in immunogenic cell death induction and anticancer activity. Herein, a hypoxia-sensitive nanosystem (CS@TAP) was designed to demonstrate effective immunotherapy for colorectal cancer by systemic delivery of an immunostimulatory chemotherapy combination. Furthermore, the combination of CS@TAP with anti-PD-L1 mAb (αPD-L1) exhibited a significant therapeutic benefit of delaying tumor growth and increased local doses of immunogenic signaling and T-cell infiltration, ultimately extending survival. We conclude that CS@TAP is an effective inducer of immunogenic cell death (ICD) in cancer immunotherapy. Therefore, this study provides an encouraging strategy to synergistically induce immunogenic cell death to enhance tumor cytotoxic T lymphocytes (CTLs) infiltration for anticancer immunotherapy.

Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared. METHODS: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17. RESULTS: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

Falcarindiol and dichloromethane fraction are bioactive components in Oplopanax elatus: Colorectal cancer chemoprevention via induction of apoptosis and G2/M cell cycle arrest mediated by cyclin A upregulation.

Oplopanax elatus (Nakai) Nakai has a long history of use as an ethnomedicine by the people living in eastern Asia. However, its bioactive constituents and cancer chemopreventive mechanisms are largely unknown. The aim of this study was to prepare O. elatus extracts, fractions, and single compounds and to investigate the herb's antiproliferative effects on colon cancer cells and the involved mechanisms of action. Two polyyne compounds were isolated from O. elatus, falcarindiol and oplopandiol. Based on our HPLC analysis, falcarindiol and oplopandiol are major constituents in the dichloromethane (CH2Cl2) fraction. For the HCT-116 cell line, the dichloromethane fraction showed significant effects. Furthermore, the IC50 for falcarindiol and oplopandiol was 1.7 µM and 15.5 µM, respectively. In the mechanistic study, after treatment with 5 µg/ml for 48 h, dichloromethane fraction induced cancer cell apoptosis by 36.5% (p < 0.01% vs. control of 3.9%). Under the same treatment condition, dichloromethane fraction caused cell cycle arrest at the G2/M phase by 32.6% (p < 0.01% vs. control of 23.4%), supported by upregulation of key cell cycle regulator cyclin A to 21.6% (p < 0.01% vs. control of 8.6%). Similar trends were observed by using cell line HT-29. Data from this study filled the gap between phytochemical components and the cancer chemoprevention of O. elatus. The dichloromethane fraction is a bioactive fraction, and falcarindiol is identified as an active constituent. The mechanisms involved in cancer chemoprevention by O. elatus were apoptosis induction and G2/M cell cycle arrest mediated by a key cell cycle regulator cyclin A.

Evidence for the existence of CD34+ angiogenic stem cells in human first-trimester decidua and their therapeutic for ischaemic heart disease.

Stem cell transplantation is nearly available for clinical application in the treatment of ischaemic heart disease (IHD), where it may be joined traditional methods (intervention and surgery). The angiogenic ability of seed cells is essential for this applicability. The aim of this study was to reveal the presence of CD34+ angiogenic stem cells in human decidua at the first trimester and to use their strong angiogenic capacity in the treatment of IHD. In vitro, human decidual CD34+ (dCD34+ ) cells from the first trimester have strong proliferation and clonality abilities. After ruling out the possibility that they were vascular endothelial cells and mesenchymal stem cells (MSCs), dCD34+ cells were found to be able to form tube structures after differentiation. Their angiogenic capacity was obviously superior to that of bone marrow mesenchymal stem cells (BMSCs). At the same time, these cells had immunogenicity similar to that of BMSCs. Following induction of myocardial infarction (MI) in adult rats, infarct size decreased and cardiac function was significantly enhanced after dCD34+ cell transplantation. The survival rate of cells increased, and more neovasculature was found following dCD34+ cell transplantation. Therefore, this study confirms the existence of CD34+ stem cells with strong angiogenic ability in human decidua from the first trimester, which can provide a new option for cell-based therapies for ischaemic diseases, especially IHD.

Human intestinal microbiota derived metabolism signature from a North American native botanical Oplopanax horridus with UPLC/Q-TOF-MS analysis.

Oplopanax horridus, widely distributed in North America, is an herbal medicine traditionally used by Pacific indigenous peoples for various medical conditions. After oral ingestion, constituents in O. horridus extract (OhE) could be converted to their metabolites by the enteric microbiome before absorption. In this study, in order to mimic gut environment, the OhE was biotransformed using the enteric microbiome of healthy human subjects. For accurate and reliable data collection with optimized approaches in sample preparation and analytical conditions, ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry were used to characterize parent constituents and their metabolites. In the extract, 20 parent compounds were identified including polyynes, sesquiterpenes, monoterpeondids, phenylpropanoids and phenolic acids. After the biotransformation, a total of 78 metabolites were identified, of which 37 belonged to polyynes metabolites. The common biotransformation pathways are hydroxylation, acetylization, methylation and demethylation. Based on the pathway distributions, the metabolism signature of OhE has been explored. The metabolism pathways of OhE compounds are dependent on their structural classifications and hydrophilic/hydrophobic properties. In summary, with comprehensive analysis, we systematically investigated human microbiome-derived OhE metabolites. The enteric microbial metabolism signature provides novel information for future effective use of O. horridus.

Effect of liquiritin on neuroendocrine-immune network in menopausal rat model.

PURPOSE: The aim of the study was to investigate the effect of liquiritin on neuroendocrine-immune network in menopausal rat model. METHODS: Liquiritin groups were respectively given liquiritin suspension at the dose of 80, 40, and 20 mg/kg, once a day for continuous 30 days after the removal of bilateral ovaries to induce the menopausal rat model. Behavioral experiments were conducted and the organs were weighed for the viscera index. The content of estradiol (E2 ) and follicle-stimulating hormone (FSH) in the serum and 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in hypothalamus were assayed by enzyme linked immunosorbent assay kits. Morphological changes of uterus and adrenal gland were observed by hematoxylin-eosin (HE) staining and estrogen receptor (ER) expression of uterus and spleen were determined by immunohistochemical staining. RESULTS: For the nervous system, liquiritin relieved menopausal depression and up-regulated the levels of 5-HT and NE in hypothalamus; for the endocrine system, it raised the concentrations of E2 and FSH in serum, relieved the histological changes of uterus and adrenal gland and increased the expression of ER in uterus; for the immune system, it increased the thymus index and the expression of ER in spleen. CONCLUSIONS: Liquiritin improved menopausal syndrome in multiple ways by affecting the neuro-endocrine-immune network.

Sirtuin3 protects aged human mesenchymal stem cells against oxidative stress and enhances efficacy of cell therapy for ischaemic heart diseases.

Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. However, the possible mechanisms underlying its influence are unknown. We hypothesized that SIRT3 increases the antioxidant capacity of aged cells and improves the efficacy of human mesenchymal stem cell (hMSC) therapy for ischaemic heart diseases in aged patients. In vitro, the antioxidant capacity of old hMSCs (O-hMSCs) was increased after SIRT3 overexpression using a gene transfection technique, while the antioxidant capacity of young hMSCs (Y-hMSCs) was decreased by SIRT3 silencing. The levels of forkhead box O3a (FoxO3a) in the nucleus, and antioxidant enzymes Mn-superoxide dismutase (MnSOD) and catalase (CAT) increased in SIRT3-overexpressed O-hMSCs while they decreased in SIRT3-silenced Y-hMSCs after oxidative stress. Following myocardial infarction in adult rats in vivo, infarct size decreased and cardiac function was significantly enhanced after cell transplantation with SIRT3 overexpressed O-hMSCs. The number of apoptotic cells decreased and the survival rate of transplanted cells increased following SIRT3 overexpression in O-hMSCs. SIRT3 protects aged hMSCs against oxidative stress by positively regulating antioxidant enzymes (MnSOD and CAT) via increasing the expression of FoxO3a in the nucleus. The efficacy of aged hMSC transplantation therapy for ischaemic heart diseases can be improved by SIRT3 overexpression.

Gastroprotective Effect of Alkaloids from Cortex Phellodendri on Gastric Ulcers in Rats through Neurohumoral Regulation.

The present study aimed to investigate the gastroprotective activity of the total alkaloids from the bark of Phellodendron amurense and identify their possible mechanism. Total alkaloids were obtained through an alcohol extraction method and were analyzed using LC-MS/MS. Chronic gastric ulcers were induced by acetic acid (0.14 mol/L) filter paper on the gastric serosa. The antiulcer effect of total alkaloids was evaluated using the ulcer area, the ulcer inhibition ratio, and epidermal growth factor. The gastroprotective mechanism of total alkaloids was revealed using the levels of serotonin and noradrenaline. The results showed that oral administration of total alkaloids (30 mg/kg/day) obviously decreased the ulcer area (7.67 ± 2.06 mm2; p < 0.01) compared with the model group (15.15 ± 2.34 mm2). The ulcer inhibition ratio of the total alkaloids group (50 %) was higher than the omeprazole-treated group (46 %), which showed that the antiulcer effect of the total alkaloids may be superior to omeprazole. Besides, the total alkaloids significantly increased the epidermal growth factor level and accelerated the healing of ulcers. Histological examination of gastric tissues also supported the same conclusion. In addition, the total alkaloids significantly elevated the levels of serotonin and noradrenaline (both p < 0.01 compared to the model group). Our data indicates that total alkaloids of Cortex Phellodendri exerts a beneficial gastroprotective effect and the involved mechanism is likely neurohumoral regulation. Thus, Cortex Phellodendri may develop into a promising clinical medicinal agent for improving the quality of ulcer healing.

Relationship between the UPLC-Q-TOF-MS fingerprinted constituents from Daphne genkwa and their anti-inflammatory, anti-oxidant activities.

Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to apply the ultra-high performance liquid chromatography system to establish a quality control method for D. genkwa. Data revealed that there were 15 common peaks in 10 batches of D. genkwa Sieb. Et Zucc. (Thymelaeaceae) from different provinces of China. On this basis, the fingerprint chromatogram was established to provide references for quality control. Afterwards, the chemical constitutions of these common peaks were analyzed using the UPLC-Q-TOF-MS system and nine of them were identified. In addition, LPS-stimulated RAW264.7 murine macrophages and DPPH assay were used to study the anti-inflammatory and anti-oxidation effects of D. genkwa. Then the fingerprint-efficacy relationships between UPLC fingerprints and pharmacodynamic data were studied with canonical correlation analysis. Analysis results indicated that the anti-inflammatory and anti-oxidation effects differed among the 10 D. genkwa samples owing to their inherent differences of chemical compositions. Taken together, this research established a fingerprint-efficacy relationship model of D. genkwa plant by combining the UPLC analytic technique and pharmacological research, which provided references for the detection of the principal components of traditional Chinese medicine on bioactivity.

Baicalin Alleviates Nitroglycerin-induced Migraine in Rats via the Trigeminovascular System.

Migraine is a common neurological disorder with a serious impact on quality of life. The aim of this study was to explore the effect of baicalin on nitroglycerin-induced migraine rats. We carried out a behavioral research within 2 h post-nitroglycerin injection, and blood samples were drawn for measurements of nitric oxide (NO), calcitonin gene-related peptide, and endothelin (ET) levels. Immunohistochemistry was adopted to detect the activation of C-fos immunoreactive neurons in periaqueductal gray. The number, area size, and integrated optical density of C-fos positive cells were measured using Image-Pro Plus. As a result, baicalin administration (0.22 mm/kg) alleviated pain responses of migraine rats. It profoundly decreased NO and calcitonin gene-related peptide levels, increased ET levels, and rebuilt the NO/ET balance in migraine rats. Besides, baicalin pretreatment significantly reduced the number, the stained area size, and integrated optical density value of C-fos positive cells. In brief, this paper supports the possibility of baicalin as a potential migraine pharmacotherapy. Copyright © 2017 John Wiley & Sons, Ltd.

The In vitro/vivo Evaluation of Prepared Gastric Floating Tablets of Berberine Hydrochloride.

Currently available antiulcer drugs suffered from serious side effects which limited their uses and prompted the need for a safe and efficient new antiulcer agent. The objective of this project work was to retain the drug in the stomach for better antiulcer activity and less side effects. Hence, the aim of our present work was to prepare a gastric floating tablet of Berberine hydrochloride (Ber) with suitable in vitro/vivo properties. In this study, different Ber gastric floating tablets were prepared by simple direct compression using various amounts of HPMCK15M and Carbopol 971PNF combined with other tablet excipients. The properties of the tablets including hardness, buoyancy, swelling ability, in vitro drug release, and in vivo pharmacokinetic study were evaluated. The obtained results disclosed that hardness, floating, swelling, and in vitro drug release of the Ber tablets depended mainly on the ratio of polymer combinations. Moreover, among six formulations, F3 exhibited desirable floating, swelling, and extended drug release. In addition, in vivo pharmacokinetic study suggested that prepared gastric floating tablets had significantly sustained-releasing effects compared with market tablets. Therefore, the developed gastric floating tablets of Ber could be an alternative dosage form for treatment of gastrointestinal disease.

Method to evaluate the quality of herbal medicines based on the dynamic changes of chemical compounds and pharmacological activity.

Quality control has been one of the key scientific issues in the modernization of traditional Chinese medicine. This study explored a novel method for quality evaluation of herbal medicines. High-performance liquid chromatography fingerprints and the osteoblast proliferation activity of 18 batches of Achyranthes bidentata, which were prepared with salt, were determined to establish a chromatographic database and an activity database. Correlation analyses of these databases were performed using partial least squares to obtain regression coefficients (positive and negative correlation coefficients). Then, the sums of the products of the positive and negative correlation peak areas and the corresponding coefficients, respectively, were calculated for each sample. The absolute value of the ratios of the sums of the positive and negative products were calculated, our studies showed that this ratio was significantly correlated with the proliferation activity, particularly when the activity was in the best and worst ranges. Therefore, we developed a parameter that was used to evaluate the quality of samples osteoblast proliferation activity. The quality of another ten batches of samples was assessed to verify this method. The results indicated that this method can be used for quality evaluation of herbal medicines according to the dynamic changes in the chemical compounds and activity.

Antitumor Activity of Total Flavonoids from Daphne genkwa in Colorectal Cancer.

Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to investigate the anticancer effects of total flavonoids in D. genkwa (TFDG) in vitro and in vivo. HT-29 and SW-480 human colorectal cancer cells were cultured to investigate the anticancer activity of TFDG. In addition, the Apc(Min/+) mouse model was applied in the in vivo experiment. Results of the cell experiment revealed that TFDG possessed significant inhibitory effects on HT-29 and SW-480 human colorectal cancer cells (both p < 0.01). Furthermore, our in vivo data showed that after treatment with TFDG, there was a significant increase in life span (both p < 0.01) and tumor numbers were reduced in the colon (both p < 0.01), which was supported by the data of tumor distribution, body weight changes and organ index. Our results also indicated that expressions of interleukin (IL)-1α, IL-1ß, IL-6, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in gut tissue were downregulated by treatments of TFDG, and immunity cytokine secretions in the serum were regulated after oral administration of TFDG. Taken together, these findings suggested that TFDG has a potential clinical utility in colorectal cancer therapeutics, and TFDG's action is likely linked to its ability to regulate immune function and inhibit the production of inflammatory cytokines.

Metabonomic Profiling Reveals Cancer Chemopreventive Effects of American Ginseng on Colon Carcinogenesis in Apc(Min/+) Mice.

American ginseng (Panax quinquefolius L.) is one of the most commonly used herbal medicines in the West. It has been reported to possess significant antitumor effects that inhibit the process of carcinogenesis. However, the mechanisms underlying its anticancer effects remain largely unresolved. In this study, we investigated the cancer chemopreventive effects of American ginseng on the progression of high fat (HF) diet-enhanced colorectal carcinogenesis with a genetically engineered Apc(Min/+) mouse model. The metabolic alterations in sera of experimental mice perturbed by HF diet intervention as well as the American ginseng treatment were measured by gas chromatography time-of-flight mass spectrometry (GC-TOFMS) and liquid chromatography time-of-flight mass spectrometry (LC-TOFMS) analysis. American ginseng treatment significantly extended the life span of the Apc(Min/+) mouse. Significant alterations of metabolites involving amino acids, organic acids, fatty acids, and carbohydrates were observed in Apc(Min/+) mouse in sera, which were attenuated by American ginseng treatment and concurrent with the histopathological improvement with significantly reduced tumor initiation, progression and gut inflammation. These metabolic changes suggest that the preventive effect of American ginseng is associated with attenuation of impaired amino acid, carbohydrates, and lipid metabolism. It also appears that American ginseng induced significant metabolic alterations independent of the Apc(Min/+) induced metabolic changes. The significantly altered metabolites induced by American ginseng intervention include arachidonic acid, linolelaidic acid, glutamate, docosahexaenoate, tryptophan, and fructose, all of which are associated with inflammation and oxidation. This suggests that American ginseng exerts the chemopreventive effects by anti-inflammatory and antioxidant mechanisms.

TRAIL pathway is associated with inhibition of colon cancer by protopanaxadiol.

Among important components of American ginseng, protopanaxadiol (PPD) showed more active anticancer potential than other triterpenoid saponins. In this study, we determined the in vivo effects of PPD in a mouse cancer model first. Then, using human colorectal cancer cell lines, we observed significant cancer cell growth inhibition by promoting G1 cell cycle redistribution and apoptosis. Subsequently, we characterized the downstream genes targeted by PPD in HCT-116 cancer cells. Using Affymetrix high density GeneChips, we obtained the gene expression profile of the cells. Microarray data indicated that the expression levels of 76 genes were changed over two-fold after PPD, of which 52 were upregulated while the remaining 24 were downregulated. Ingenuity pathway analysis of top functions affected was carried out. Data suggested that by regulating the interactions between p53 and DR4/DR5, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway played a key role in the action of PPD, a promising colon cancer inhibitory compound.

Antioxidative Activity of Flavonoids from Abrus cantoniensis against Ethanol-Induced Gastric Ulcer in Mice.

The present study investigated the flavonoids from Abrus cantoniensis against ethanol-induced gastric ulcers in mice. The flavonoids from A. cantoniensis were extracted with ethanol and purified by macroporous resin and polyamide. The 2,2-diphenyl-1-picrylhydrazyl assay was used to measure the antioxidative activities in vitro. The ethanol-induced ulcer mouse model was used to evaluate the gastroprotective activities of the flavonoids from A. cantoniensis. In addition, a method was established to ensure accuracy for animal ulcer evaluation. The flavonoids from A. cantoniensis showed a strong free radical scavenging capacity with an IC50 of 43.83 µg/mL in the 2,2-diphenyl-1-picrylhydrazyl assay. At doses between 28.16-112.67 mg/kg, the flavonoids conspicuously reduced the ulcer index in ethanol-induced mice (p<0.001). Significant differences were found in the levels of superoxide dismutase, catalase, glutathione, and myeloperoxidase in the stomach tissues between the flavonoids from the A. cantoniensis groups and the ethanol control group. The gastroprotective effect of the flavonoids from A. cantoniensis could be due to its antioxidative activity of the defensive mechanism. The data revealed that the flavonoids from A. cantoniensis could be a potential therapeutic agent for gastric ulcer prevention and treatment.

Phytochemistry of Red Ginseng, a Steam-Processed Panax ginseng.

Asian ginseng, the root of Panax ginseng C.A. Meyer, occupies a prominent position in the list of best-selling natural products in the world. There are two major types of ginseng roots: white ginseng and red ginseng, each with numerous preparations. White ginseng is prepared by air-drying fresh Asian ginseng roots after harvest. Red ginseng is prepared by steaming roots in controlled conditions using fresh or raw Asian ginseng. Red ginseng is commonly used in Asian countries due to its unique chemical profile, different therapeutic efficacy, and increased stability. Compared with the widespread research on white ginseng, the study of red ginseng is relatively limited. In this paper, after a botanical feature description, the structures of different types of constituents in red ginseng are systematically described, including naturally occurring compounds and those resulting from the steam processing. In red ginseng phytochemical studies, the number of published reports on ginsenosides is significantly higher than that for other constituents. Up to now, 57 ginsenosides have been isolated and characterized in red ginseng. The structural transformation pathways during steaming have been summarized. In comparison with white ginseng, red ginseng also contains other constituents, including polyacetylenes, Maillard reaction products, other types of glycosides, lignans, amino acids, fatty acids, and polysaccharides, which have also been presented. Appropriate analytical methods are necessary for differentiating between unprocessed white ginseng and processed red ginseng. Specific marker compounds and chemical profiles have been used to discriminate red ginseng from white ginseng and adulterated commercial products. Additionally, a brief phytochemical profile comparison has been made between white ginseng and black ginseng, and the latter is another type of processed ginseng prepared from white or red ginseng by steaming several times. In conclusion, to ensure the safe and effective use of red ginseng, phytochemical and analytical studies of its constituents are necessary and even crucial.

Light-Quality-Adapted Carotenoid Photoprotection in the Photosystem of Roseiflexus castenholzii.

The photosystem of filamentous anoxygenic phototroph Roseiflexus (Rfl.) castenholzii comprises a light-harvesting (LH) complex encircling a reaction center (RC), which intensely absorbs blue-green light by carotenoid (Car) and near-infrared light by bacteriochlorophyll (BChl). To explore the influence of light quality (color) on the photosynthetic activity, we compared the pigment compositions and triplet excitation dynamics of the LH-RCs from Rfl. castenholzii was adapted to blue-green light (bg-LH-RC) and to near-infrared light (nir-LH-RC). Both LH-RCs bind γ-carotene derivatives; however, compared to that of nir-LH-RC (12%), bg-LH-RC contains substantially higher keto-γ-carotene content (43%) and shows considerably faster BChl-to-Car triplet excitation transfer (10.9 ns vs 15.0 ns). For bg-LH-RC, but not nir-LH-RC, selective photoexcitation of Car and the 800 nm-absorbing BChl led to Car-to-Car triplet transfer and BChl-Car singlet fission reactions, respectively. The unique excitation dynamics of bg-LH-RC enhances its photoprotection, which is crucial for the survival of aquatic anoxygenic phototrophs from photooxidative stress.

Ruthenium-dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation.

BACKGROUND: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies. METHODS: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties. RESULTS: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1ß, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation. CONCLUSIONS: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

Effects of Curcuminoids and Surfactant-Formulated Curcumin on Chemo-Resistant Colorectal Cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States, and chronic gut inflammation is a risk factor for CRC initiation and development. Curcuma longa L., or turmeric, has become one of the most studied herbal medicines in recent years due to its anticancer potentials. It is generally accepted that the major component in turmeric is curcuminoids, and the active constituent in curcuminoids is curcumin. However, unprocessed curcumin is characterized by poor water solubility, which means low bioavailability in humans. To increase the bioavailability of curcumin, in this study, we utilized a novel surfactant-formulated curcumin (CuminUP60[Formula: see text]) and evaluated its CRC chemopreventive activities. Compared with the chemo-sensitive CRC cell line HCT-116, the management of the CRC SW-480 cell line is a challenge, since the latter is chemo-resistant. In other words, these cancer cells resist the effects of the chemotherapy. Using the newly formulated CuminUP60[Formula: see text] water solution, this study demonstrated its strong antiproliferative effects on the SW-480 cells in a dose- and time-dependent manner. This new formulation induced early apoptosis and arrested the cell cycle in the G2/M phase via the upregulation of cyclin B1. We also observed that this new formulation possessed inhibitory effects on Th17 cell differentiation, which regulates the body's immune response against gut malignancies. In summary, our results exhibited a potential clinical utility of the surfactant-formulated curcumin in chemo-resistant colorectal cancer management.