Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.

Obesity is a well-established risk factor for cancer, significantly impacting both cancer incidence and mortality. However, the intricate molecular mechanisms connecting adipose tissue to cancer cell metabolism are not fully understood. This Review explores the historical context of tumor energy metabolism research, tracing its origins to Otto Warburg's pioneering work in 1920. Warburg's discovery of the "Warburg effect", wherein cancer cells prefer anaerobic glycolysis even in the presence of oxygen, laid the foundation for understanding cancer metabolism. Building upon this foundation, the "reverse Warburg effect" emerged in 2009, elucidating the role of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and its contribution to lactate accumulation in the tumor microenvironment, subsequently serving as a metabolic substrate for cancer cells. In contrast, within high-adiposity contexts, cancer cells exhibit a unique metabolic shift termed the "inversion of the Warburg effect". This phenomenon, distinct from the stromal-dependent reverse Warburg effect, relies on increased nutrient abundance in obesity environments, leading to the generation of glucose from lactate as a metabolic substrate. This Review underscores the heightened tumor proliferation and aggressiveness associated with obesity, introducing the "inversion of the Warburg effect" as a novel mechanism rooted in the altered metabolic landscape within an obese milieu. The insights presented here open promising avenues for therapeutic exploration, offering fresh perspectives and opportunities for the development of innovative cancer treatment strategies.

Discrimination of Dendropanax morbifera via HPLC fingerprinting and SNP analysis and its impact on obesity by modulating adipogenesis- and thermogenesis-related genes.

Dendropanax morbifera (DM), a medicinal plant, is rich in polyphenols and commonly used to treat cancer, inflammation, and thrombosis. However, to date, no study has been conducted on DM regarding the enormous drift of secondary metabolites of plants in different regions of the Republic of Korea and their effects on antiobesity, to explore compounds that play an important role in two major obesity-related pathways. Here, we present an in-depth study on DM samples collected from three regions of the Republic of Korea [Jeju Island (DMJ), Bogildo (DMB), and Jangheung (DMJG)]. We used high-performance liquid chromatography (HPLC) and multivariate component analyses to analyze polyphenol contents (neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, and rutin), followed by discrimination of the samples in DMJG using single nucleotide polymorphism and chemometric analysis. In silico and in vitro evaluation of major compounds found in the plant extract on two major anti-obesity pathways (adipogenesis and thermogenesis) was carried out. Furthermore, two extraction methods (Soxhlet and ultrasound-assisted extraction) were used to understand which method is better and why. Upon quantifying plant samples in three regions with the polyphenols, DMJG had the highest content of polyphenols. The internal transcribed region (ITS) revealed a specific gel-based band for the authentication of DMJG. PCA and PLS-DA revealed the polyphenol's discriminative power of the region DMJG. The anti-obesity effects of plant extracts from the three regions were related to their polyphenol contents, with DMJG showing the highest effect followed by DMJ and DMB. Ultrasound-assisted extraction yielded a high number of polyphenols compared to that of the Soxhlet method, which was supported by scanning electron microscopy. The present work encourages studies on plants rich in secondary metabolites to efficiently use them for dietary and therapeutic purposes.

ß-Glucosidase and Its Application in Bioconversion of Ginsenosides in Panax ginseng.

Ginsenosides are a group of bioactive compounds isolated from Panax ginseng. Conventional major ginsenosides have a long history of use in traditional medicine for both illness prevention and therapy. Bioconversion processes have the potential to create new and valuable products in pharmaceutical and biological activities, making them both critical for research and highly economic to implement. This has led to an increase in the number of studies that use major ginsenosides as a precursor to generate minor ones using ß-glucosidase. Minor ginsenosides may also have useful properties but are difficult to isolate from raw ginseng because of their scarcity. Bioconversion processes have the potential to create novel minor ginsenosides from the more abundant major ginsenoside precursors in a cost-effective manner. While numerous bioconversion techniques have been developed, an increasing number of studies have reported that ß-glucosidase can effectively and specifically generate minor ginsenosides. This paper summarizes the probable bioconversion mechanisms of two protopanaxadiol (PPD) and protopanaxatriol (PPT) types. Other high-efficiency and high-value bioconversion processes using complete proteins isolated from bacterial biomass or recombinant enzymes are also discussed in this article. This paper also discusses the various conversion and analysis methods and their potential applications. Overall, this paper offers theoretical and technical foundations for future studies that will be both scientifically and economically significant.

Comparison of In Vitro Estrogenic Activity of Polygoni multiflori Radix and Cynanchi wilfordii Radix via the Enhancement of ERα/ß Expression in MCF7 Cells.

Postmenopausal women experience several symptoms, including inflammation and a sharp rise in oxidative stress caused by estrogen deprivation. Although estrogen replacement therapy (ERT) is generally regarded as an effective treatment for menopause, it has been used less frequently due to some adverse effects and high costs. Therefore, there is an immediate need to develop an effective herbal-based treatment that is affordable for low-income populations. Acordingly, this study explored the estrogen-like properties of methanol extracts from Cynanchum wilfordii (CW) and Poligonum multiflorum (PM), two important medicinal plants in Republic of Korea, Japan, and China. Due to the similar names and morphologies of these two radixes, they are frequently confused in the marketplace. Our previous colleagues discriminated between these two plants. In this study, we investigated the estrogenic activity of PM and CW using several in vitro assays with their possible mechanism of action. First, their phytochemical contents, such as gallic acid, 2,3,5,4'-tetrahydroxystilbene-2-O-glucoside (TSG) and emodin, were quantified using high-performance liquid chromatography (HPLC). Secondly, estrogen-like activity was assessed utilizing the well-known E-screen test and gene expression analysis in estrogen receptor (ER)-positive MCF7 cells. ROS inhibition and anti-inflammatory effects were analyzed using HaCaT and Raw 264.7 cells, respectively. Our findings demonstrate that PM extracts significantly increased the expression of the estrogen-dependent genes (ERα, ERß, pS2) and boosted MCF7 cell proliferation in comparison to CW extracts. Additionally, PM extract demonstrated a significant reduction in reactive oxygen species (ROS) production as well as an enhanced antioxidant profile compared to the CW extract. Further, the PM extract treatment significantly reduced the generation of nitric oxide (NO) in RAW 264.7 cells, a murine macrophage cell line, demonstrating the anti-inflammatory properties of the extract. Finally, this research offers an experimental foundation for the use of PM as a phytoestrogen to minimize menopausal symptoms.

Anti-inflammatory properties of neutral lipids, glycolipids, and phospholipids isolated from Ammodytes personatus eggs in LPS-stimulated RAW264.7 cells.

In the present study, total lipids were extracted from Ammodytes personatus eggs and separated into neutral lipids, glycolipids, and phospholipids. The anti-inflammatory activity of the neutral lipids, glycolipids, and phospholipids was investigated in macrophages, as well as the fatty acid profiles of the lipids. Palmitic acid, oleic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) were the primary fatty acids in the three fractionated lipids. Among the lipids, the phospholipids contained the highest concentration of polyunsaturated fatty acids (PUFAs), particularly DHA and EPA (31.89 and 16.93% of the total fatty acids, respectively). The anti-inflammatory effects of the three lipids isolated from A. personatus eggs were analyzed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The three lipids significantly reduced nitric oxide (NO) production and the mRNA expression of immune-associated genes in a dose-dependent manner. All lipids down-regulated the protein expression of phosphorylated NF-κB-p65 and MAPK (p38, JNK, and ERK1/2) signaling pathways, suggesting that they could inhibit cell signaling pathways by activating NF-κB and MAPK. The expression of CD40 and CD86 in LPS-stimulated RAW264.7 cells was also significantly decreased by A. personatus lipids. Consequently, the neutral lipids, glycolipids, and phospholipids from A. personatus eggs could serve as anti-inflammatory agents.

Immune-enhancing effects of anionic macromolecules extracted from Codium fragile coupled with arachidonic acid in RAW264.7 cells.

Arachidonic acid (ARA) is an integral constituent of the biological cell membrane, conferring it with fluidity and flexibility, which are necessary for the function of all cells, especially nervous system, skeletal muscle, and immune system. Codium species biosynthesize sulfated polysaccharides with very distinct structural features. Some of them have different biological activities with great potential in pharmaceutical applications. In this study, anionic macromolecules extracted from Codium fragile were investigated for their cooperative immune-enhancing activities with ARA. The cooperation between ARA and Codium resulted in increased, dose-dependent nitric oxide production and iNOS gene expression. In addition, co-treatment of ARA and Codium effectively increased pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), compared with Codium alone. We also demonstrated that the expression of COX-2 mRNA was also increased, which is responsible for the production of inflammatory mediator prostaglandins and their metabolites. Compared to the Codium group, the co-treatment of Codium with ARA enhanced the phosphorylation of nuclear factor-κB p-65, p38, and extracellular signal-related kinase 1/2, indicating that this combination stimulated immune response through nuclear factor-κB and mitogen-activated protein kinase pathways. These results indicated that the coordination of arachidonic acid with polysaccharide extracted from seaweed may be a potential source of immunomodulatory molecules.

Molecular and morphological discrimination of Chrysanthemum indicum using allele-specific PCR and T-shaped trichome.

Chrysanthemum indicum L. is a traditional oriental medicinal herb prepared as a tea from flowers that have been used in China and South Korea since ancient times. It has a long history in the treatment of hypertension, inflammation, and respiratory diseases. Among Chrysanthemum species, C. indicum has more active chemical components as well as better therapeutic effects, and C. indicum is mostly used for medicinal purposes in South Korea. However, the usage of C. indicum has become problematic over the years due to the abundance of adulterated Chrysanthemum and confusion with morphologically related species such as C. morifolium, C. boreale, and Aster spathulifolius. Thus, here we developed a method for molecular authentication using chloroplast universal region rpoC2 and morphological authentication based on T-shaped trichomes of the adaxial leaf surface. By using a species-specific primer derived from the rpoC2 region, we established a multiplex allele-specific PCR for the discrimination of C. indicum. Amplicons of 675 bp for C. indicum and 1026 bp for other Chrysanthemum species were produced using both rpoC2-specific and common primers. These primers can be used to analyze dried samples of Chrysanthemum. Morphological discrimination was performed using T-shaped trichomes present only on the adaxial leaf surface of C. indicum species, and then molecular markers were utilized to authenticate C. indicum products from adulterant samples available in the market. Our results indicate that these molecular markers in combination with morphological differentiation can serve as an effective tool for identifying C. indicum.

Dendropanax Morbifera Extract-Mediated ZnO Nanoparticles Loaded with Indole-3-Carbinol for Enhancement of Anticancer Efficacy in the A549 Human Lung Carcinoma Cell Line.

Dendropanax morbifera is a versatile plant that has been used as a herbal medicine due to its various useful medicinal effects. To protect its active component from biological stress and increase its drug efficacy as well as drug bioavailability, nanoemulsion was prepared. Dendropanax morbifera zinc oxide nanoparticles (DM-ZnO NPs) were synthesized using the plant extract via the co-precipitation method and loaded with active indole-3-carbinol for nanoemulsion formulation using the ultrasonication process. Field emission transmission electron microscope revealed the flower shape of the Dendropanax morbifera indole-3-carbinol zinc oxide nanoemulsion (DM-ZnO-I3C-NE). In contrast, DM-ZnO NPs showed a spheroid shape that coincides agreeably with field emission electron scanning microscope. The hydrodynamic sizes by dynamic light scattering are about 65 ± 3 nm and 239.6 ± 6 nm and the crystallite sizes from X-ray diffraction are 11.52 nm and 16.07 nm for DM-ZnO NPs and DM-ZnO-I3C-NE, respectively. In vitro analysis revealed the cytotoxicity of DM-ZnO-I3C-NE against a human lung cancer cell line (A549) at 12.5 µg/mL as well as reactive oxygen species (ROS) production. The DM-ZnO-I3C-NE-induced ROS generation level was higher than that of DM-ZnO NPs and free indole-3-carbinol. The synergistic effect of DM-ZnO and indole-3-carbinol indicates DM-ZnO-I3C-NE as a potential candidate for future lung cancer drug and could be scope for functional food.

Co-immunomodulatory Activities of Anionic Macromolecules Extracted from Codium fragile with Red Ginseng Extract on Peritoneal Macrophage of Immune-Suppressed Mice.

In this study we investigated the immune effects of oral administration of anionic macromolecules extracted from Codium fragile (CFAM) and red ginseng extract mixture on the peritoneal macrophage cells in immune-suppressed mice. Cyclophosphamide (CY) induces the immune-suppressed condition. CY-treated mice were orally fed with different concentrations of CFAM supplemented with red ginseng extract and the peritoneal macrophages collected. CY treatment significantly decreased the immune activities of peritoneal macrophages, compared to the normal mice. The administration of CFAM mixed with red ginseng extract significantly boosted the viability of macrophage cells and nitric oxide production of peritoneal macrophages. Further, the oral administration of CFAM mixed with red ginseng extract up-regulated the expression of iNOS, COX-2, and TLR-4 as well as cytokines such as IL-1ß, IL-6, TNF-α, and IFN-γ more than the red ginseng-treated group. This study showed that CFAM enhanced the immune activity of red ginseng extract in the peritoneal macrophage cells of immune-suppressed mice. Furthermore, CFAM might be used as a co-stimulant of red ginseng extract through the regulation of macrophage cells for the enhancement of human health and immunity.

Preparation of Polyethylene Glycol-Ginsenoside Rh1 and Rh2 Conjugates and Their Efficacy against Lung Cancer and Inflammation.

Low solubility and tumor-targeted delivery of ginsenosides to avoid off-target cytotoxicity are challenges for clinical trials. In the present study, we report on a methodology for the synthesis of polyethylene glycol (PEG)-ginsenoside conjugates through a hydrolysable ester bond using the hydrophilic polymer polyethylene glycol with the hydrophobic ginsenosides Rh1 and Rh2 to enhance water solubility and passive targeted delivery. The resulting conjugates were characterized by 1H nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectroscopy (FT-IR). 1H NMR revealed that the C-6 and C-3 sugar hydroxyl groups of Rh1 and Rh2 were esterified. The conjugates showed spherical shapes that were monitored by field-emission transmission electron microscopy (FE-TEM), and the average sizes of the particles were 62 ± 5.72 nm and 134 ± 8.75 nm for PEG-Rh1and PEG-Rh2, respectively (measured using a particle size analyzer). Owing to the hydrophilic enhancing properties of PEG, PEG-Rh1 and PEG-Rh2 solubility was greatly enhanced compared to Rh1 and Rh2 alone. The release rates of Rh1 and Rh2 were increased in lower pH conditions (pH 5.0), that for pathophysiological sites as well as for intracellular endosomes and lysosomes, compared to normal-cell pH conditions (pH 7.4). In vitro cytotoxicity assays showed that the PEG-Rh1conjugates had greater anticancer activity in a human non-small cell lung cancer cell line (A549) compared to Rh1 alone, whereas PEG-Rh2 showed lower cytotoxicity in lung cancer cells. On the other hand, both PEG-Rh1 and PEG-Rh2 showed non-cytotoxicity in a nondiseased murine macrophage cell line (RAW 264.7) compared to free Rh1 and Rh2, but PEG-Rh2 exhibited increased efficacy against inflammation by greatly inhibiting nitric oxide production. Thus, the overall conclusion of our study is that PEG conjugation promotes the properties of Rh1 for anticancer and Rh2 for inflammation treatments. Depends on the disease models, they could be potential drug candidates for further studies.

Synthesis of a Zinc Oxide Nanoflower Photocatalyst from Sea Buckthorn Fruit for Degradation of Industrial Dyes in Wastewater Treatment.

: Green synthesis of ZnO nanoparticles has attracted research attention as a sustainable method of avoiding the destructive effect of chemicals. We synthesized a flower-shaped zinc oxide (ZnO) nanoflower (NF) from sea buckthorn fruit (SBT) by co-precipitation and characterized it using X-ray powder diffraction (XRD), X-ray photo electronic microscopy (XPS), photoluminescence (PL), field emission transmission electron microscopy (FE-TEM), and Fourier-transform infrared (FT-IR) spectroscopy. The ability of the ZnO/NF to degrade cationic and anionic dyes, including malachite green (MG), Congo red (CR), methylene blue (MB), and eosin Y (EY), under ultraviolet illumination was studied. The photocatalyst degraded approximately 99% of the MG, MB, CR and EY dyes within 70, 70, 80, and 90 min of contact time, respectively, at a dye concentration of 15 mg/L, 5 mg/L, SBT-ZnO/NF degraded 100% of the MG, MB, CR and EY dyes within 23, 25, 28, and 30 min, respectively. The results indicate that SBT-ZnO/NFs as synthesized is an inexpensive, non-toxic, rapid, and reusable photocatalyst that can play an enhanced role in wastewater treatment.

Anti-Inflammatory Effects of Lipids Extracted from Arctoscopus japonicus Eggs on LPS-Stimulated RAW264.7 Cells.

Arctoscopus japonicus is a cold-water marine fish. The present study investigated the fatty acid composition of A. japonicus egg lipids and their anti-inflammatory effects on LPS-stimulated RAW246.7 macrophages. The results showed that A. japonicus egg lipids contained primarily polyunsaturated fatty acids (52.9% of the total fatty acid content; mostly eicosapentaenoic acid [EPA, 21.2 ± 0.5%] and docosahexaenoic acid [DHA, 25.9 ± 0.1%]), followed by monounsaturated fatty acids and saturated fatty acids (23.7% and 23.4%, respectively). A. japonicus egg lipids significantly decreased nitric oxide (NO) production and suppressed the expression of immune-associated genes such as iNOS, COX-2, IL-1ß, IL-6, and TNF-α LPS-stimulated RAW246.7 macrophages in dose-dependent manner. A. japonicus egg lipids also reduced the phosphorylation levels of NF-κB p-65, p38, ERK1/2, and JNK, key components of the NF-κB and MAPK pathways, suggesting that the lipid-induced anti-inflammatory activity is related to these signaling pathways. These results indicate that the lipids extracted from A. japonicus eggs have potential biofunctions and might be useful for regulating inflammation in macrophages.

Investigation of ginsenosides in different tissues after elicitor treatment in Panax ginseng.

BACKGROUND: The effect of methyl jasmonate (MJ) on ginsenoside production in different organs of ginseng (Panax ginseng Meyer) was evaluated after the whole plant was dipped in an MJ-containing solution. MJ can induce the production of antioxidant defense genes and secondary metabolites in plants. In ginseng, MJ treatment in adventitious root resulted in the increase of dammarenediol synthase expression but a decrease of cycloartenol synthase expression, thereby enhancing ginsenoside biosynthesis. Although a previous study focused on the application of MJ to affect ginsenoside production in adventitious roots, we conducted our research on entire plants by evaluating the effect of exogenous MJ on ginsenoside production with the aim of obtaining new approaches to study ginsenoside biosynthesis response to MJ in vivo. METHODS: Different parts of MJ-treated ginseng plants were analyzed for ginsenoside contents (fine root, root body, epidermis, rhizome, stem, and leaf) by high-performance liquid chromatography. RESULTS: The total ginsenoside content of the ginseng root significantly increased after 2 d of MJ treatment compared with the control not subjected to MJ. Our results revealed that MJ treatment enhances ginsenoside production not in the epidermis but in the stele of the ginseng root, implying transportation of ginsenosides from the root vasculature to the epidermis. Application of MJ enhanced protopanaxadiol (PPD)-type ginsenosides, whereas chilling treatment induced protopanaxatriol (PPT)-type ginsenosides. CONCLUSION: These findings indicate that the production of PPD-type and PPT-type ginsenosides is differently affected by abiotic and biotic stresses in the ginseng plant, and they might play different defense mechanism roles.

Ginsenoside profiles and related gene expression during foliation in Panax ginseng Meyer.

Panax ginseng is one of the most important medicinal plants in Asia. Triterpene saponins, known as ginsenosides, are the major pharmacological compounds in P. ginseng. The present study was conducted to evaluate the changes in ginsenoside composition according to the foliation stage of P. ginseng cultured in a hydroponic system. Among the three tested growth stages (closed, intermediate, and opened), the highest amount of total ginsenoside in the main and fine roots was in the intermediate stage. In the leaves, the highest amount of total ginsenoside was in the opened stage. The total ginsenoside content of the ginseng leaf was markedly increased in the transition from the closed to intermediate stage, and increased more slowly from the intermediate to opened leaf stage, suggesting active biosynthesis of ginsenosides in the leaf. Conversely, the total ginsenoside content of the main and fine roots decreased from the intermediate to opened leaf stage. This suggests movement of ginsenosides during foliation from the root to the leaf, or vice versa. The difference in the composition of ginsenosides between the leaf and root in each stage of foliation suggests that the ginsenoside profile is affected by foliation stage, and this profile differs in each organ of the plant. These results suggest that protopanaxadiol- and protopanaxatriol (PPT)-type ginsenosides are produced according to growth stage to meet different needs in the growth and defense of ginseng. The higher content of PPT-type ginsenosides in leaves could be related to the positive correlation between light and PPT-type ginsenosides.

Microbacterium soli sp. nov., an alpha-glucosidase-producing bacterium isolated from soil of a ginseng field.

Five Gram-type-positive, aerobic, rod-shaped, non-motile strains of Microbacterium (DCY 17(T), Ms1, Ms2, Ms3 and Ms4) were isolated from soil from a ginseng field in Daejeon, South Korea. On the basis of 16S rRNA gene sequence similarity, these strains were shown to be related to Microbacterium esteraromaticum DSM 8609(T) (96.1 %), M. xylanilyticum DSM 16914(T) (96.0 %), M. aquimaris JS54-2(T) (95.6 %), M. insulae DS-66(T) (95.5 %), M. ketosireducens IFO 14548(T) (95.5 %) and M. arabinogalactanolyticum DSM 8611(T) (95.4 %). Chemotaxonomic data revealed that the type strain, DCY 17(T), possesses menaquinones MK-12, MK-11 and MK-13 and the predominant fatty acids C(15 : 0) anteiso (32.5 %), C(15 : 0) iso (27.5 %), C(16 : 0 ) iso (17.0 %), C(17 : 0) anteiso (13.2 %), C(17 : 0) iso (6.1 %) and C(14 : 0) iso (2.1 %). The DNA G+C content of strain DCY 17(T) is 70.2 mol% and those of strains Ms1 to Ms4 are in the range 68.9-73.5 mol%. The physiological and biochemical tests suggested that these strains represent a novel species. Based on these data, DCY 17(T) (=KCTC 19237(T) =LMG 24010(T)) is classified as the type strain of a novel Microbacterium species, for which the name Microbacterium soli sp. nov. is proposed.