Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer.

Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphorylation of downstream BAD is associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT promoting cell survival, was observed to be correlated with worse clinicopathologic indicators of outcome, including higher grade, higher proliferative index and lymph node metastasis. The structural optimization of a previously reported inhibitor of BAD-Ser99 phosphorylation was therefore achieved to generate a small molecule inhibiting the phosphorylation of BAD at Ser99 with enhanced potency and improved oral bioavailability. The molecule 2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl) phenol (NCK) displayed no toxicity at supra-therapeutic doses and was therefore assessed for utility in TNBC. NCK promoted apoptosis and G0/G1 cell cycle arrest of TNBC cell lines in vitro, concordant with gene expression analyses, and reduced in vivo xenograft growth and metastatic burden, demonstrating efficacy as a single agent. Additionally, combinatorial oncology compound library screening demonstrated that NCK synergized with tyrosine kinase inhibitors (TKIs), specifically OSI-930 or Crizotinib in reducing cell viability and promoting apoptosis of TNBC cells. The synergistic effects of NCK and TKIs were also observed in vivo with complete regression of a percentage of TNBC cell line derived xenografts and prevention of metastatic spread. In patient-derived TNBC xenograft models, NCK prolonged survival times of host animals, and in combination with TKIs generated superior survival outcomes to single agent treatment. Hence, this study provides proof of concept to further develop rational and mechanistic based therapeutic strategies to ameliorate the outcome of TNBC.

Insights from ß-Conglycinin and Glycinin into the Mechanism of Nanoliposome-Soybean Protein Isolate Interactions.

The interaction mechanism between nanoliposomes (NL) and a soybean protein isolate (SPI) was investigated via the complexation between NL and two major components of SPI, i.e., ß-conglycinin (7S) and glycinin (11S). The endogenous fluorescence emissions of 7S and 11S were statically quenched after complexation with NL, and the polarity of the SPI fluorophore increased. The interaction between NL and SPI was exothermic and spontaneous, 7S/11S secondary structures were altered, and more hydrophobic groups were exposed on protein surfaces. Moreover, the NL-SPI complex had a large zeta potential to attain system stability. Hydrophobic forces and hydrogen bonds played vital roles in the interaction between NL and 7S/11S, and a salt bridge was also involved in the NL-11S interaction. The binding characteristics between NL and 7S/11S were chiefly governed by the protein characteristics, such as amino acid composition, surface hydrophobicity, and advanced structure. These findings could deepen the understanding of the interaction mechanism between NL and SPI.

Development of a metabolomics-based data analysis approach for identifying drug metabolites based on high-resolution mass spectrometry.

A metabolomics-based approach to data analysis is required for drug metabolites to be identified quickly. This study developed such an approach based on high-resolution mass spectrometry. Our approach is a two-stage one that combines a time-course experiment with stable isotope tracing. Pioglitazone (PIO) was used to improve glycemic management for type 2 diabetes mellitus. Consequently, PIO was taken as a model drug for identifying metabolites. During Stage I of data analysis, 704 out of 26626 ions exhibited a positive relationship between ion abundance ratio and incubation time in a time-course experiment. During Stage II, 25 isotope pairs were identified among the 704 ions. Among these 25 ions, 18 exhibited a dose-response relationship. Finally, 14 of the 18 ions were verified to be PIO structure-related metabolite ions. Otherwise, orthogonal partial least squares-discriminant analysis (OPLS-DA) was adopted to mine PIO metabolite ions, and 10 PIO structure-related metabolite ions were identified. However, only four ions were identified by both our developed approach and OPLS-DA, indicating that differences in the designs of metabolomics-based approaches to data analysis can result in differences in which metabolites are identified. A total of 20 PIO structure-related metabolites were identified by our developed approach and OPLS-DA, and six metabolites were novel. The results demonstrated that our developed two-stage data analysis approach can be used to effectively mine data on PIO metabolite ions from a relatively complex matrix.

Selective Formation of Osteogenic and Vasculogenic Tissues for Cartilage Regeneration.

Tissue-engineered periosteum substitutes (TEPSs) incorporating hierarchical architecture with osteoprogenitor and vascular niches are drawing much attention as a promising tool to support functional cells in defined zones and nourish the cortical bone. Current TEPSs usually lack technologies to closely observe cell performance, especially at the cell contact interface between distinct compartments containing defined biological configurations and functions. Here, an electrodeposition strategy is reported, which enables the selective formation of TEPSs with osteoprogenitor and vascular niches in a multiphasic scaffold in combination with different human cell types for cartilage regeneration in an in vivo osteochondral defect model. Human umbilical vein endothelial cells (HUVECs), dermal fibroblasts (HDFs), and bone marrow mesenchymal stem cells (hMSCs) are used to mirror both the vascular and osteogenic niches, respectively. It is observed that the intrinsic viscoelastic nature of the porous solid matrix is essential to successfully induce angiogenesis. Coculture of hMSCs with functional cells (HUVECs/HDFs) in TEPSs also effectively promoted periosteal regeneration, including osteogenic and angiogenic processes. The osteoarthritis cartilage histopathology assessment and histologic/histochemical grading system data indicate that the TEPSs containing hMSCs/HUVECs/HDFs exhibit superior potential for cartilage regeneration.

Piceatannol Prevents Colon Cancer Progression via Dual-Targeting to M2-Polarized Tumor-Associated Macrophages and the TGF-ß1 Positive Feedback Signaling Pathway.

SCOPE: M2 phenotype tumor-associated macrophages (M2-TAMs) play a key role in distant metastasis and poor clinical outcomes. Herein, a specific molecular mechanism that contributes to malignant progression is illuminated and investigates whether piceatannol (PIC) can target the crosstalk between M2-TAMs and cancer cells for potential colorectal cancer (CRC) therapy. METHODS AND RESULTS: To mimic the tumor microenvironment (TME), direct and indirect coculture systems in vitro and in vivo mouse xenograft models are established. The results demonstrate that post-treatment with PIC in TME more effectively prevented the aggressive features and stemness of SW480 cells by restricting the polarization of M2-like macrophages and blocking the transforming growth factor ß1 (TGF-ß1) positive feedback autocrine/paracrine loop that exists between M2-like polarized macrophages and cancer cells. Furthermore, xenograft assays also observe significant repression in tumor growth and lung metastases with the administration of PIC. The key mechanism underlying the antimetastasis effects of PIC may include its directly inhibitory activity against TGF-ß receptor type-1 (TGF-ßR1) in the M2-like TAMs-created TME. CONCLUSION: These novel findings demonstrate that PIC is a potent TGF-ß1/TGF-ßR1 pathway inhibitor and TME modulator for preventing tumor progression and metastasis in CRC by reeducating TAMs.

Trefoil factor 3 promotes pancreatic carcinoma progression via WNT pathway activation mediated by enhanced WNT ligand expression.

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality with a dismal prognosis that has changed little over the past few decades. Further understanding of the molecular pathology of PDAC progression is urgently required in order to improve the prognosis of patients with PDAC. Herein, it was observed that trefoil factor 3 (TFF3) expression was elevated in PDAC, and was positively correlated with a worse overall patient survival outcome. Forced expression of TFF3 promoted oncogenic functions of PDAC cells in vitro including cell proliferation, survival, foci formation, cancer stem cell-like behavior and invasion, ex vivo colony growth in 3D-Matrigel, and xenograft growth in vivo. Depletion or pharmacological inhibition of TFF3 inhibited these same processes. RNA-Seq analysis and subsequent mechanistic analyses demonstrated that TFF3 increased the expression of various WNT ligands to mediate WNT pathway activation required for TFF3-stimulated PDAC progression. Combined pharmacological inhibition of TFF3 and WNT signaling significantly attenuated PDAC xenograft growth and potentiated the therapeutic efficacy of gemcitabine in both ex vivo and in vivo models. Hence, a mechanistic basis for combined inhibition of pathways enhancing PDAC progression is provided and suggests that inhibition of TFF3 may assist to ameliorate outcomes in PDAC.

Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis.

Cancer cells display phenotypic equilibrium between the stem-like and differentiated states during neoplastic homeostasis. The functional and mechanistic implications of this subpopulation plasticity remain largely unknown. Herein, it is demonstrated that the breast cancer stem cell (BCSC) secretome autonomously compresses the stem cell population. Co-implantation with BCSCs decreases the tumor-initiating capacity yet increases metastasis of accompanying cancer cells, wherein DKK1 is identified as a pivotal factor secreted by BCSCs for such functions. DKK1-promotes differentiation is indispensable for disseminated tumor cell metastatic outgrowth. In contrast, DKK1 inhibitors substantially relieve the metastatic burden by restraining metastatic cells in the dormant state. DKK1 increases the expression of SLC7A11 to protect metastasizing cancer cells from lipid peroxidation and ferroptosis. Combined treatment with a ferroptosis inducer and a DKK1 inhibitor exhibits synergistic effects in diminishing metastasis. Hence, this study deciphers the contribution of CSC-regulated phenotypic plasticity in metastatic colonization and provides therapeutic approaches to limit metastatic outgrowth.

Surface characteristics and emulsifying properties of whey protein/nanoliposome complexes.

The surface characteristics and emulsifying properties of whey proteins (WP) after complexation with nanoliposomes (NL) were investigated. WP surface hydrophobicity enhanced after complexation with NL, and it indicated the exposure increase of WP hydrophobic groups. WPNL interfacial tension significantly decreased compared with that of WP. The interfacial protein content of WPNL-stabilized emulsions was slightly different from that of WP-stabilized emulsions. WP emulsifying properties were significantly improved after complexation with NL. The mean sizes and polydispersity indexes of WPNL-stabilized emulsion droplets were smaller than those of WP-stabilized emulsion droplets. The absolute zeta-potential values of WPNL-stabilized emulsions were greater than those of WP-stabilized emulsions. Electrostatic repulsion played a vital role in WPNL-stabilized emulsion stability. Moreover, surface and emulsifying properties of WPNL were changed by exterior factor-induced alteration of protein advanced structures. The emulsifying properties of WP after complexation with NL were improved due to the modification of WP surface characteristics.

Correction: Hepatoprotective effect of piceatannol against carbon tetrachloride-induced liver fibrosis in mice.

Correction for 'Hepatoprotective effect of piceatannol against carbon tetrachloride-induced liver fibrosis in mice' by Wei-Lun Hung et al., Food Funct., 2021, DOI: 10.1039/D1FO02545G.

Hepatoprotective effect of piceatannol against carbon tetrachloride-induced liver fibrosis in mice.

Piceatannol (3,5,3',4'-trans-tetrahydroxystilbene) is a natural analog and a metabolite of resveratrol present in grapes and red wine. Previous studies have reported that piceatannol exerts a broad spectrum of health benefits including antioxidant, anti-inflammatory, chemopreventive, and neuroprotective effects. However, little is known about the hepatoprotective effect of piceatannol against toxin-induced liver fibrosis. Therefore, the objective of this study is to evaluate the protective effect of piceatannol in a mouse model of CCl4-induced hepatic fibrosis. Oral administration of piceatannol significantly improved the hepatic functions of CCl4-treated mice in both therapeutic and preventive models. Additionally, the immunohistochemical staining results revealed that collagen deposition in CCl4-injected mice was significantly reduced by treatment with piceatannol. Moreover, piceatannol remarkably suppressed the expressions of collagen I, α-smooth muscle protein (α-SMA), and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) induced by CCl4. The anti-fibrotic mechanism of piceatannol was associated with the regulation of the transforming growth factor-ß (TGF-ß)/Smad signaling pathway. Finally, piceatannol also profoundly alleviated CCl4-induced hepatic oxidative damage by elevating the level of glutathione and catalase activity. Altogether, our current findings suggest that piceatannol may serve as a bioactive agent that inhibits or alleviates toxic-induced fibroproliferative diseases, especially in the prevention of liver fibrosis.

The interaction mechanism between liposome and whey protein: Effect of liposomal vesicles concentration.

The interaction mechanism between liposomes (Lips) and whey protein isolates (WPI) with different mass ratios was explored in this paper. After binding with different concentration of Lips, the changes in hydrophilic and hydrophobic regions of WPI were investigated with fluorescein isothiocyanate (FITC) and pyrene fluorescence probes. The spatial structure changes of WPI were further characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and circular dichroism. The results indicated that the structure of WPI was changed due to binding with Lips in hydrophilic and hydrophobic groups. The binding process might result in the migration, recombination, and alignment of WPI and Lip groups. Moreover, the oil-water interfacial tension with WPI decreased from 9.20 mN/m to 3.29 mN/m upon increasing the Lip-to-WPI ratio. This work suggests that the physiochemical properties of Lip-WPI complexes could be manipulated by adjusting the Lip-to-WPI ratio. This study shed some light on the mechanism explanation of the WPI structural changes due to the interaction with Lips during food processing.

3'-Hydroxypterostilbene Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-Acetate (TPA)-Induced Mouse Skin Carcinogenesis.

BACKGROUND: A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear. PURPOSE: The aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism. STUDY DESIGN AND METHODS: This study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated. RESULTS: The results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes. CONCLUSION: This is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.

Pharmacological Inhibition of BAD Ser99 Phosphorylation Enhances the Efficacy of Cisplatin in Ovarian Cancer by Inhibition of Cancer Stem Cell-like Behavior.

Platinum-based chemotherapy has been the standard treatment for ovarian cancer patients for approximately four decades. However, the prognosis of patients with advanced ovarian carcinoma remains dismal, mainly attributed to both dose-limiting toxicities of cisplatin and the high rate of chemo-resistant disease recurrence. Herein, both patient-derived and experimentally generated cisplatin-sensitive and -resistant ovarian cancer cell line models were used to delineate BADSer99 phosphorylation as an actionable target in ovarian cancer. BADSer99 phosphorylation was negatively associated with cisplatin sensitivity in ovarian cancer, and the inhibition of BADSer99 phosphorylation by point mutation induced apoptosis and reduced cisplatin IC50. In addition, BAD phosphorylation was also shown to be associated with cancer stem cell-like properties. Henceforth, a novel small molecule which inhibits BAD phosphorylation specifically at Ser99 (NPB) was utilized. NPB promoted apoptosis and reduced 3D growth of bulk cancer cells and inhibited cancer stem cell-like properties in both cisplatin-sensitive and -resistant ovarian cancer cells. The combination of cisplatin with NPB exhibited synergistic effects in vitro. NPB in combination with cisplatin also achieved an improved outcome compared to either monotreatment in vivo, including suppression of the cancer stem cell population, an effect not observed with cisplatin treatment. Furthermore, NPB exhibited strong synergistic effects with the AKT inhibitor AZD5363, and significantly reduced its IC50 in cells resistant to cisplatin treatment. These findings identify BADSer99 phosphorylation as an actionable and pharmacologically relevant target to improve outcomes of cisplatin treated ovarian cancer.

3'-Hydroxypterostilbene Potently Alleviates Obesity Exacerbated Colitis in Mice.

Epidemiological surveys show that obesity and the western diet increase the risk of colitis. Studies have also confirmed that the high-fat-diet (HFD) promoted the deterioration of colitis-related indicators in mice. Compared with stilbenoids, the results showed that 3'-hydroxypterostilbene (HPSB) was found to be the most effective inhibitor for the antiadipogenesis and anti-inflammation. However, its role in ameliorating obesity-promoted colitis is still unknown. We intend to investigate the protective effect and related molecular mechanisms of HPSB on HFD promoted dextran sodium sulfate (DSS)-induced colitis in mice. The results indicate that colitis in the HFD+DSS group tends to be more apparent in the DSS-only group, while feeding 0.025% of HPSB at different stages can improve the colitis induced by HFD+DSS. HPSB significantly reduced the levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) induced by HFD+DSS in mice. Furthermore, the Western blotting revealed that the administration of HPSB significantly downregulated cyclooxygenase-2 (COX-2), plasmalemma vesicle-associated protein-1 (PV-1), and phospho-signal transducer and activator of transcription 3 (p-STAT3) expressions in HFD+DSS treated mice. Presented results reveal that HPSB is a novel functional agent capable of preventing HFD exacerbated colitis.

Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK.

Increased expression of trefoil factor 3 (TFF3) has been reported in colorectal carcinoma (CRC), being correlated with distant metastasis and poor clinical outcomes. Amongst the CRC subtypes, mesenchymal (CMS4) CRC is associated with the worst survival outcome. Herein, the functional roles of TFF3 and the pharmacological inhibition of TFF3 by a novel specific small molecule TFF3 inhibitor-2-amino-4-(4-(6-fluoro-5-methylpyridin-3-yl)phenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile (AMPC) in CMS4 CRC was explored. Forced expression of TFF3 in CMS4 CRC cells promoted cell proliferation, cell survival, foci formation, invasion, migration, cancer stem cell like behaviour and growth in 3D Matrigel. In contrast, siRNA-mediated depletion of TFF3 or AMPC inhibition of TFF3 in CMS4 CRC cells decreased oncogenic behaviour as indicated by the above cell function assays. AMPC also inhibited tumour growth in vivo. The TFF3-stimulated oncogenic behaviour of CMS4 CRC cells was dependent on TFF3 activation of the p44/42 MAPK (ERK1/2) pathway. Furthermore, the forced expression of TFF3 decreased the sensitivity of CMS4 CRC cells to 5-fluorouracil (5-FU); while depleted TFF3 expression enhanced 5-FU sensitivity in CMS4 CRC cells. 5-FU treatment induced TFF3 expression in CMS4 CRC cells. AMPC, when used in combination with 5-FU in CMS4 CRC cells exhibited a synergistic inhibitory effect. In summary, this study provides functional evidence for TFF3 as a therapeutic target in CMS4 CRC.

Adzuki Bean Water Extract Attenuates Obesity by Modulating M2/M1 Macrophage Polarization and Gut Microbiota Composition.

SCOPE: Obesity is a chronic condition resulting in excessive fat accumulation in adipose tissues. Adipose tissue is now considered as an immune organ, at the crossroads between metabolism and immunity. Thus, this study investigates the effects of adzuki beans on obesity and gut microbiota in high fat diet-induced mice. METHODS AND RESULTS: In this study, adzuki bean hot water extract (AWE) is determined to have the most significant anti-adipogenic effect; it is able to inhibit lipid accumulation in 3T3-L1 adipocytes and reduces body weight and adipose tissue weight in a dose-dependent manner. AWE treatment also decreases M1-polarized adipose tissue macrophages (ATMs) while inducing M2-polarized ATMs. The number and size of fat vacuoles in liver lesions are significantly reduced, indicating that AWE could ameliorate steatosis in high fat diet-induced mice. The results also demonstrate that AWE-treated groups inhibit adipogenesis via activating the Wnt/ß-catenin pathway and reduce peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding proteins α expression. Moreover, the studies confirm that AWE decreases obesity through modulating gut microbiota. CONCLUSION: The results demonstrate that AWE supplementation ameliorates high fat diet-induced obesity and gut microbiota composition and suggests that AWE may have the potential to be developed into a functional food to improve metabolic disorders.

Inhibition of TFF3 Enhances Sensitivity-and Overcomes Acquired Resistance-to Doxorubicin in Estrogen Receptor-Positive Mammary Carcinoma.

Dose-dependent toxicity and acquired resistance are two major challenges limiting the efficacious treatment of mammary carcinoma (MC) with doxorubicin. Herein, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity and acquired resistance of estrogen receptor positive (ER+) MC cells to doxorubicin. Doxorubicin treatment of ER+MC cells increased TFF3 expression. The depletion of TFF3 by siRNA or inhibition with a small molecule TFF3 inhibitor (AMPC) synergistically enhanced the efficacy of doxorubicin in ER+MC through the suppression of doxorubicin-induced AKT activation and enhancement of doxorubicin-induced apoptosis. Elevated expression of TFF3 and increased activation of AKT were also observed using a model of acquired doxorubicin resistance in ER+MC cells. AMPC partially re-sensitized the doxorubicin resistant cells to doxorubicin-induced apoptosis. Indeed, doxorubicin resistant ER + MC cells exhibited increased sensitivity to AMPC as a single agent compared to doxorubicin sensitive cells. In vivo, AMPC attenuated growth of doxorubicin sensitive ER+MC xenografts whereas it produced regression of xenografts generated by doxorubicin resistant ER+MC cells. Hence, TFF3 inhibition may improve the efficacy and reduce required doses of doxorubicin in ER+MC. Moreover, inhibition of TFF3 may also be an effective therapeutic strategy to eradicate doxorubicin resistant ER+MC.

CCM111 prevents hepatic fibrosis via cooperative inhibition of TGF-ß, Wnt and STAT3 signaling pathways.

CCM111 is an aqueous extract of Antrodia cinnamomea (AC) that has exhibited anti-liver fibrosis functions. However, the detailed mechanisms of AC action against liver fibrosis have not been elucidated yet. The present research showed that CCM111 significantly lowered the levels of the hepatic enzyme markers glutamate oxaloacetate transaminase (GOT) and glutamic pyruvic transaminase (GPT), prevented liver damage and collagen deposition, and downregulated TGF-ß/Smad signaling in a dose-dependent manner compared with CCl4 treatment alone. CCM111 markedly inhibited TGF-ß, Wnt and STAT3 signaling pathway-regulated downstream genes in the liver by next-generation sequencing. The antifibrotic mechanisms of CCM111 were further demonstrated in HSC-T6 cells. Our data demonstrated for the first time that CCM111 can protect against CCl4-induced liver fibrosis by the cooperative inhibition of TGF-ß-, Wnt- and STAT3-dependent proinflammatory and profibrotic mediators, suggesting that CCM111 might be a candidate for preventing and treating chronic fibrotic liver diseases.

Optimized Extraction of Phenolics from Jujube Peel and Their Anti-inflammatory Effects in LPS-Stimulated Murine Macrophages.

The extraction of phenolics from jujube peel (PJP) was optimized using response surface methodology (RSM). A Box-Behnken design was utilized to analyze the effects of NaOH concentration, temperature, and extraction time on the total phenolic content (TPC). The results showed that RSM could be an adequate approach for modeling the extraction of PJP. The optimal extraction condition for the highest TPC was obtained with 3.4 M NaOH concentration for 67 min at 50 °C. Not only PJP but also phenolics from the jujube seed (PJS) contain considerable amounts of phenolics, particularly flavonoids. Quercetin and galangin were found to be the predominant phenolics. PJP markedly down-regulated the levels iNOS and COX-2 proteins in macrophages by inhibiting the activation of NF-κB through interfering with the MAPK signaling pathways. Compared to PJS, PJP presented higher anti-inflammatory activities, reflecting increased amounts of TPC and total flavonoid content (TFC). These findings suggest that PJP could be a potential source of anti-inflammatory agents.

Prevention of Breast Cancer by Natural Phytochemicals: Focusing on Molecular Targets and Combinational Strategy.

Starting from the 21st century, breast cancer can be classified as the most common invasive malignancy in women. Among the preventive or therapeutic strategies of breast cancer, combination therapy is the most promising approach. This mode of treatment of breast cancer concurrently maximizes efficacy, overcomes multidrug resistance, and minimizes harmful side effects caused by radiotherapy and chemotherapy alone. The risk of cancer can be reduced by supplementing diets with naturally occurring products known as phytochemicals. These phytochemicals have well-defined roles in the management of every stage of breast carcinogenesis. In this review, the collective data of dietary phytochemicals used to sensitize breast cancer cells to therapeutic approaches are reported and their specific molecular targets through synergistic, additive, and potentiation effects are highlighted. The concept of combining natural agents with medicines to augment therapeutic responses creates an optimal modality, which may facilitate clinical applications of combination regimens in the future.