• Dual-purpose breeding
• Growth performance
• Middle Anatolian Merino
• Multi-locus GWAS
• Wool traits

• Animals
• Genome-Wide Association Study/methods
• Multifactorial Inheritance/genetics
• Quantitative Trait Loci
• Wool
• Sheep/genetics
• Polymorphism, Single Nucleotide
• Phenotype
• Turkey

• TAGEM/HAYSÜD/E/20/A4/P2/2141 Türkiye Cumhuriyeti Tarım ve Orman Bakanlığı
• TAGEM/HAYSÜD/E/20/A4/P2/2141 Türkiye Cumhuriyeti Tarım ve Orman Bakanlığı

• chemoresistance
• colorectal cancer
• flavonoids
• polyphenols
• signaling pathways
• synergistic mechanisms

• Circular RNA_0045474
• Extracellular matrix
• MicroRNA-485-3p
• Osteoarthritis
• Progression
• Transcription factor 4

• Osteoarthritis/genetics
• Osteoarthritis/metabolism
• Osteoarthritis/pathology
• Osteoarthritis/drug therapy
• Humans
• MicroRNAs/genetics
• MicroRNAs/metabolism
• RNA, Circular/genetics
• Animals
• Transcription Factor 4/genetics
• Transcription Factor 4/metabolism
• Chondrocytes/metabolism
• Chondrocytes/drug effects
• Mice
• Male
• Interleukin-1beta/genetics
• Interleukin-1beta/metabolism
• Disease Models, Animal
• Middle Aged
• Female
• Apoptosis/drug effects
• Gene Expression Regulation/drug effects
• Cell Line
• Mice, Inbred C57BL

• Cancer
• chemotherapeutic treatments.
• drug
• flavonoid
• resveratrol
• signaling pathways

• Resveratrol/pharmacology
• Resveratrol/therapeutic use
• Humans
• Animals
• Antineoplastic Agents, Phytogenic/therapeutic use
• Antineoplastic Agents, Phytogenic/pharmacology
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Carcinoma/drug therapy
• Carcinoma/metabolism
• Carcinoma/pathology

• WNT signaling
• cancer
• mutations
• natural compounds
• β-catenin
• β-catenin inhibitors

• Female
• Pregnancy
• Humans
• beta Catenin
• Neoplasms
• Carcinogenesis
• Cell Transformation, Neoplastic
• Signal Transduction

• Humans
• Codon, Nonsense/genetics
• Protein Biosynthesis/genetics
• Anti-Bacterial Agents/pharmacology
• Neoplasms

• The German-Israel Foundation (GIF)

• Gastrointestinal cancer
• Nanoformulation
• Resveratrol
• Therapy

Low back pain (LBP) management is an important clinical issue. Inadequate LBP control has consequences on the mental and physical health of patients. Thus, acquiring new information on LBP mechanism would increase the available therapeutic tools. Resveratrol is a natural compound with many beneficial effects. In this study, we investigated the role of resveratrol on behavioral changes, inflammation and oxidative stress induced by LBP. Ten microliters of Complete Freund’s adjuvant (CFA) was injected in the lumbar intervertebral disk of Sprague Dawley rats to induce degeneration, and resveratrol was administered daily. Behavioral analyses were performed on day zero, three, five and seven, and the animals were sacrificed to evaluate the molecular pathways involved. Resveratrol administration alleviated hyperalgesia, motor disfunction and allodynia. Resveratrol administration significantly reduced the loss of notochordal cells and degenerative changes in the intervertebral disk. From the molecular point of view, resveratrol reduced the 5th/6th lumbar (L5–6) spinal activation of the WNT pathway, reducing the expression of WNT3a and cysteine-rich domain frizzled (FZ)8 and the accumulation of cytosolic and nuclear β-catenin. Moreover, resveratrol reduced the levels of TNF-α and IL-18 that are target genes strictly downstream of the WNT/β-catenin pathway. It also showed important anti-inflammatory activities by reducing the activation of the NFkB pathway, the expression of iNOS and COX-2, and the levels of PGE2 in the lumbar spinal cord. Moreover, resveratrol reduced the oxidative stress associated with inflammation and pain, as shown by the observed reduced lipid peroxidation and increased GSH, SOD, and CAT activities. Therefore, resveratrol administration controlled the WNT/β-catenin pathway and the related inflammatory and oxidative alterations, thus alleviating the behavioral changes induced by LBP.

• biochemistry
• pain
• resveratrol

Colorectal cancer (CRC) is an emerging public health problem and the second leading cause of death worldwide, with a significant socioeconomic impact in several countries. The 5-year survival rate is only 12% due to the lack of early diagnosis and resistance to available treatments, and the canonical Wnt signaling pathway is involved in this process. This review underlines the importance of understanding the fundamental roles of this pathway in physiological and pathological contexts and analyzes the use of naturally occurring small molecules that inhibits the Wnt/β-catenin pathway in experimental models of CRC. We also discuss the progress and challenges of moving these small molecules off the laboratory bench into the clinical platform.

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

Resveratrol (RES) and Vitamin E (VE) are anti-cancer active ingredients with relatively high content in peanut seeds and sprouts. This study aimed to determine the synergistic inhibitory effect of RES and VE on colorectal cancer. Using 5-FU as a positive drug control, the effect of RES combined with VE on HCT-8 cells was determined, and cell viability was detected using the cell-counting kit 8 (CCK8) method. Cell morphology changes were observed using optical microscopy. Cell migration ability was evaluated by the scratch test, while cell colonies were determined by the cloning test formation ability. Apoptosis status was assessed by flow cytometry and nuclear staining by DAPI, and the expression level of apoptosis-related proteins was determined by western blotting. Compared with the single component group, the RES combined with VE group significantly inhibited the growth and proliferation of HCT-8 intestinal cancer cells in vitro. The RES combined with VE group had a greater impact on cell morphology changes and cell colony formation and significantly reduced cell migration ability and intestinal cancer cell apoptosis (p < 0.05). Additionally, combined treatment with RES and VE significantly upregulated the expression of pro-apoptotic proteins BAX, caspase-3, caspase-8, and caspase-9, and downregulated the expression of anti-apoptotic protein BCL-2, compared to the single component treatment. RES combined with VE is effective in promoting intestinal cancer cell apoptosis. This study demonstrated the significant positive synergy of RES and VE on HCT-8 cells, providing a new perspective for more effective use of RES.

• BAX and BCL-2
• HCT-8
• apoptosis
• caspase
• resveatrol
• vitamim E

• molecular biology
• cell biology
• biochemistry

• Humans
• Neoplasm Proteins/genetics
• Neoplasm Proteins/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/therapy
• Wnt Proteins/genetics
• Wnt Proteins/metabolism
• Wnt Signaling Pathway
• beta Catenin/genetics
• beta Catenin/metabolism

• National Natural Science Foundation of China (National Science Foundation of China)
• State Key Laboratory of Oral Diseases SKLOD202007

Angiogenesis belongs to the most clinical characteristics of colorectal cancer (CRC) and is strongly linked to the activation of Wnt/β-catenin signaling. The most prominent factors stimulating constitutive activation of this pathway, and in consequence angiogenesis, are genetic alterations (mainly mutations) concerning APC and the β-catenin encoding gene (CTNNB1), detected in a large majority of CRC patients. Wnt/β-catenin signaling is involved in the basic types of vascularization (sprouting and nonsprouting angiogenesis), vasculogenic mimicry as well as the formation of mosaic vessels. The number of known Wnt/β-catenin signaling components and other pathways interacting with Wnt signaling, regulating angiogenesis, and enabling CRC progression continuously increases. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.

Aberrant activation of the Wnt/Fzd/β-catenin signaling pathway is one of the major molecular mechanisms of colorectal cancer (CRC) development and progression. On the other hand, one of the most common clinical CRC characteristics include high levels of angiogenesis, which is a key event in cancer cell dissemination and distant metastasis. The canonical Wnt/β-catenin downstream signaling regulates the most important pro-angiogenic molecules including vascular endothelial growth factor (VEGF) family members, matrix metalloproteinases (MMPs), and chemokines. Furthermore, mutations of the β-catenin gene associated with nuclear localization of the protein have been mainly detected in microsatellite unstable CRC. Elevated nuclear β-catenin increases the expression of many genes involved in tumor angiogenesis. Factors regulating angiogenesis with the participation of Wnt/β-catenin signaling include different groups of biologically active molecules including Wnt pathway components (e.g., Wnt2, DKK, BCL9 proteins), and non-Wnt pathway factors (e.g., chemoattractant cytokines, enzymatic proteins, and bioactive compounds of plants). Several lines of evidence argue for the use of angiogenesis inhibition in the treatment of CRC. In the context of this paper, components of the Wnt pathway are among the most promising targets for CRC therapy. This review summarizes the current knowledge about the role of the Wnt/Fzd/β-catenin signaling pathway in the process of CRC angiogenesis, aiming to improve the understanding of the mechanisms of metastasis as well as improvements in the management of this cancer.

• Wnt/beta-catenin signaling
• angiogenesis
• anti-angiogenic therapy
• colorectal cancer

• Cancer
• Cancer stem cells
• In vitro and in vivo studies
• Resistance
• Resveratrol
• Signal transduction
• Therapeutic targeting

Gastrointestinal (GI) cancer is one of the leading causes of cancer-related deaths worldwide. According to the Global Cancer Statistics, colorectal cancer is the second leading cause of cancer-related mortality, closely followed by gastric cancer (GC). Environmental, dietary, and lifestyle factors including cigarette smoking, alcohol intake, and genetics are the most important risk factors for GI cancer. Furthermore, infections caused by Helicobacter pylori are a major cause of GC initiation. Despite improvements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the length or quality of life of patients with advanced GI cancer is still poor because of delayed diagnosis, recurrence and side effect. Resveratrol (3, 4, 5-trihydroxy-trans-stilbene; Res), a natural polyphenolic compound, reportedly has various pharmacologic functions including anti-oxidant, anti-inflammatory, anti-cancer, and cardioprotective functions. Many studies have demonstrated that Res also exerts a chemopreventive effect on GI cancer. Research investigating the anti-cancer mechanism of Res for the prevention and treatment of GI cancer has implicated multiple pathways including oxidative stress, cell proliferation, and apoptosis. Therefore, this paper provides a review of the function and molecular mechanisms of Res in the prevention and treatment of GI cancer.

• Gastrointestinal cancer
• Resveratrol
• Function
• Molecular mechanisms
• Prevention
• Treatment

• Wnt signaling
• cancer
• drug discover
• natural products
• regeneration

• Biological Products/therapeutic use
• Drug Discovery/methods
• Humans
• Wnt Signaling Pathway/physiology

• Box–Behnken design
• Chitosan
• pectin
• quasi emulsion solvent diffusion method
• release kinetics
• ulcerative colitis

Given that colon cancer is the third most common cancer in incidence and cause of death in the United States, and current treatment modalities are insufficient, there is a need to develop novel agents. Towards this, here we focus on γ-Mangostin, a bioactive compound present in the Mangosteen (Garcinia mangostana) fruit. γ-Mangostin suppressed proliferation and colony formation, and induced cell cycle arrest and apoptosis of colon cancer cell lines. Further, γ-Mangostin inhibited colonosphere formation. Molecular docking and CETSA (Cellular thermal shift assay) binding assays demonstrated that γ-Mangostin interacts with transcription factor TCF4 (T-Cell Factor 4) at the β-catenin binding domain with the binding energy of -5.5 Kcal/mol. Moreover, γ-Mangostin treatment decreased TCF4 expression and reduced TCF reporter activity. The compound also suppressed the expression of Wnt signaling target proteins cyclin D1 and c-Myc, and stem cell markers such as LGR5, DCLK1 and CD44. To determine the effect of γ-Mangostin on tumor growth in vivo, we administered nude mice harboring HCT116 tumor xenografts with 5 mg/Kg of γ-Mangostin intraperitoneally for 21 days. γ-Mangostin treatment significantly suppressed tumor growth, with notably lowered tumor volume and weight. In addition, western blot analysis revealed a significant decrease in the expression of TCF4 and its downstream targets such as cyclin D1 and c-Myc. Together, these data suggest that γ-Mangostin inhibits colon cancer growth through targeting TCF4. γ-Mangostin may be a potential therapeutic agent for colon cancer.

• Wnt signaling
• beta-catenin
• natural product
• preventive agent
• tumor xenograft

• CSCs
• SIRT
• curcumin
• gene methylation
• miRs
• natural products
• resveratrol

Genomic and proteomic studies have helped improve our understanding of the underlying mechanism(s) of cancer development and progression. Mutations, overexpressed oncogenes, inactivated/downregulated tumor suppressors, loss of apoptosis, and dysregulated signal transduction cascades are some of the well-studied areas of research. Resveratrol has gained considerable attention in the last two decades because of its pleiotropic anticancer activities. In this review, we have summarized the regulation of WNT, SHH (sonic hedgehog)/GLI (glioma-associated oncogene homolog), TGFβ1 (transforming growth factor beta 1)/SMAD, NOTCH, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), STAT (signal transducer and activator of transcription), and microRNAs by resveratrol in different cancers. The importance of these signaling pathways in cancer progression, along with their modulation by resveratrol, is discussed. Further, we also evaluate the mechanisms and implications of the downregulation of oncogenic miRNAs and the upregulation of tumor suppressor miRNAs by resveratrol, both of which also define its ability to inhibit tumor growth and metastasis. It is envisioned that designing effective clinical trials will be helpful for the identification of resveratrol responders and non-responders and the elucidation of how this phytochemical can be combined with current therapeutic options to improve their clinical efficacy and reduce off-target effects.

• cell signaling
• miRNAs
• resveratrol

• Cancer
• Capsaicin
• Cucurbitacin B
• Curcumin
• Deguelin
• Diindolylmethane (DIM)
• Isothiocyanate
• Natural compounds
• Piperine

The theory that several carcinogenetic processes are initiated and sustained by cancer stem cells (CSCs) has been validated, and specific methods to identify the CSCs in the entire population of cancer cells have also proven to be effective. This review aims to provide an overview of recently acquired scientific knowledge regarding phytochemicals and herbal extracts, which have been shown to be able to target and kill CSCs. Many genes and proteins that sustain the CSCs’ self-renewal capacity and drug resistance have been described and applications of phytochemicals able to interfere with these signaling systems have been shown to be operatively efficient both in vitro and in vivo. Identification of specific surface antigens, mammosphere formation assays, serial colony-forming unit assays, xenograft transplantation and label-retention assays coupled with Aldehyde dehydrogenase 1 (ALDH1) activity evaluation are the most frequently used techniques for measuring phytochemical efficiency in killing CSCs. Moreover, it has been demonstrated that EGCG, curcumin, piperine, sulforaphane, β-carotene, genistein and the whole extract of some plants are able to kill CSCs. Most of these phytochemicals act by interfering with the canonical Wnt (β-catenin/T cell factor-lymphoid enhancer factor (TCF-LEF)) pathway implicated in the pathogenesis of several cancers. Therefore, the use of phytochemicals may be a true therapeutic strategy for eradicating cancer through the elimination of CSCs.

• cancer stem cells
• chemoprevention
• herbal extracts
• metastases
• molecular mechanisms
• phytochemicals
• self-renewal
• therapeutic agents

• Aldehyde Dehydrogenase 1 Family
• Animals
• Apoptosis/drug effects
• Cell Proliferation/drug effects
• Humans
• Isoenzymes/metabolism
• Neoplastic Stem Cells/cytology
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/metabolism
• Phytochemicals/toxicity
• Retinal Dehydrogenase/metabolism
• Wnt Proteins/metabolism
• Wnt Signaling Pathway/drug effects
• beta Catenin/metabolism