Korean Black Goat Extract Exerts Estrogen-like Osteoprotective Effects by Stimulating Osteoblast Differentiation in MC3T3-E1 Cells and Suppressing Osteoclastogenesis in RAW 264.7 Cells.

Postmenopausal osteoporosis, characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-driven bone formation, presents substantial health implications. In this study, we investigated the role of black goat extract (BGE), derived from a domesticated native Korean goat, estrogen-like activity, and osteoprotective effects in vitro. BGE's mineral and fatty acid compositions were analyzed via the ICP-AES method and gas chromatography-mass spectrometry, respectively. In vitro experiments were conducted using MCF-7 breast cancer cells, MC3T3-E1 osteoblasts, and RAW264.7 osteoclasts. BGE exhibits a favorable amount of mineral and fatty acid content. It displayed antimenopausal activity by stimulating MCF-7 cell proliferation and augmenting estrogen-related gene expression (ERα, ERß, and pS2). Moreover, BGE positively impacted osteogenesis and mineralization in MC3T3-E1 cells through Wnt/ß-catenin pathway modulation, leading to heightened expression of Runt-related transcription factor 2, osteoprotegerin, and collagen type 1. Significantly, BGE effectively suppressed osteoclastogenesis by curtailing osteoclast formation and activity in RAW264.7 cells, concurrently downregulating pivotal signaling molecules, including receptor activator of nuclear factor κ B and tumor necrosis factor receptor-associated factor 6. This study offers a shred of preliminary evidence for the prospective use of BGE as an effective postmenopausal osteoporosis treatment.

Multiomics Analysis of the PHLDA Gene Family in Different Cancers and Their Clinical Prognostic Value.

The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. The predictive significance of PHLDA genes in cancer remains unclear. To determine the role of pleckstrin as a prognostic biomarker in human cancers, we conducted a systematic multiomics investigation. Through various survival analyses, pleckstrin expression was evaluated, and their predictive significance in human tumors was discovered using a variety of online platforms. By analyzing the protein-protein interactions, we also chose a collection of well-known functional protein partners for pleckstrin. Investigations were also carried out on the relationship between pleckstrins and other cancers regarding mutations and copy number alterations. The cumulative impact of pleckstrin and their associated genes on various cancers, Gene Ontology (GO), and pathway analyses were used for their evaluation. Thus, the expression profiles of PHLDA family members and their prognosis in various cancers may be revealed by this study. During this multiomics analysis, we found that among the PHLDA family, PHLDA1 may be a therapeutic target for several cancers, including kidney, colon, and brain cancer, while PHLDA2 can be a therapeutic target for cancers of the colon, esophagus, and pancreas. Additionally, PHLDA3 may be a useful therapeutic target for ovarian, renal, and gastric cancer.

In Silico and In Vitro Study of Isoquercitrin against Kidney Cancer and Inflammation by Triggering Potential Gene Targets.

Kidney cancer has emerged as a major medical problem in recent times. Multiple compounds are used to treat kidney cancer by triggering cancer-causing gene targets. For instance, isoquercitrin (quercetin-3-O-ß-d-glucopyranoside) is frequently present in fruits, vegetables, medicinal herbs, and foods and drinks made from plants. Our previous study predicted using protein-protein interaction (PPI) and molecular docking analysis that the isoquercitrin compound can control kidney cancer and inflammation by triggering potential gene targets of IGF1R, PIK3CA, IL6, and PTGS2. So, the present study is about further in silico and in vitro validation. We performed molecular dynamic (MD) simulation, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, cytotoxicity assay, and RT-PCR and qRT-PCR validation. According to the MD simulation (250 ns), we found that IGF1R, PIK3CA, and PTGS2, except for IL6 gene targets, show stable binding energy with a stable complex with isoquercitrin. We also performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the final targets to determine their regulatory functions and signaling pathways. Furthermore, we checked the cytotoxicity effect of isoquercitrin (IQ) and found that 5 µg/mL and 10 µg/mL doses showed higher cell viability in a normal kidney cell line (HEK 293) and also inversely showed an inhibition of cell growth at 35% and 45%, respectively, in the kidney cancer cell line (A498). Lastly, the RT-PCR and qRT-PCR findings showed a significant decrease in PTGS2, PIK3CA, and IGF1R gene expression, except for IL6 expression, following dose-dependent treatments with IQ. Thus, we can conclude that isoquercitrin inhibits the expression of PTGS2, PIK3CA, and IGF1R gene targets, which in turn controls kidney cancer and inflammation.

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.

Butyrate's (a short-chain fatty acid) microbial synthesis, absorption, and preventive roles against colorectal and lung cancer.

Butyrate, a short-chain fatty acid (SCFA) produced by bacterial fermentation of fiber in the colon, is a source of energy for colonocytes. Butyrate is essential for improving gastrointestinal (GI) health since it helps colonocyte function, reduces inflammation, preserves the gut barrier, and fosters a balanced microbiome. Human colonic butyrate producers are Gram-positive firmicutes, which are phylogenetically varied. The two most prevalent subgroups are associated with Eubacterium rectale/Roseburia spp. and Faecalibacterium prausnitzii. Now, the mechanism for the production of butyrate from microbes is a very vital topic to know. In the present study, we discuss the genes encoding the core of the butyrate synthesis pathway and also discuss the butyryl-CoA:acetate CoA-transferase, instead of butyrate kinase, which usually appears to be the enzyme that completes the process. Recently, butyrate-producing microbes have been genetically modified by researchers to increase butyrate synthesis from microbes. The activity of butyrate as a histone deacetylase inhibitor (HDACi) has led to several clinical trials to assess its effectiveness as a potential cancer treatment. Among various significant roles, butyrate is the main energy source for intestinal epithelial cells, which helps maintain colonic homeostasis. Moreover, people with non-small-cell lung cancer (NSCLC) have distinct gut microbiota from healthy adults and frequently have dysbiosis of the butyrate-producing bacteria in their guts. So, with an emphasis on colon and lung cancer, this review also discusses how the microbiome is crucial in preventing the progression of certain cancers through butyrate production. Further studies should be performed to investigate the underlying mechanisms of how these specific butyrate-producing bacteria can control both colon and lung cancer progression and prognosis.

A Network Pharmacology and Molecular-Docking-Based Approach to Identify the Probable Targets of Short-Chain Fatty-Acid-Producing Microbial Metabolites against Kidney Cancer and Inflammation.

(1) Background: A large and diverse microbial population exists in the human intestinal tract, which supports gut homeostasis and the health of the host. Short-chain fatty acid (SCFA)-secreting microbes also generate several metabolites with favorable regulatory effects on various malignancies and immunological inflammations. The involvement of intestinal SCFAs in kidney diseases, such as various kidney malignancies and inflammations, has emerged as a fascinating area of study in recent years. However, the mechanisms of SCFAs and other metabolites produced by SCFA-producing bacteria against kidney cancer and inflammation have not yet been investigated. (2) Methods: We considered 177 different SCFA-producing microbial species and 114 metabolites from the gutMgene database. Further, we used different online-based database platforms to predict 1890 gene targets associated with metabolites. Moreover, DisGeNET, OMIM, and Genecard databases were used to consider 13,104 disease-related gene targets. We used a Venn diagram and various protein-protein interactions (PPIs), KEGG pathways, and GO analyses for the functional analysis of gene targets. Moreover, the subnetwork of protein-protein interactions (through string and cytoscape platforms) was used to select the top 20% of gene targets through degree centrality, betweenness centrality, and closeness centrality. To screen the possible candidate compounds, we performed an analysis of the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of metabolites and then found the best binding affinity using molecular docking simulation. (3) Results: Finally, we found the key gene targets that interact with suitable compounds and function against kidney cancer and inflammation, such as MTOR (with glycocholic acid), PIK3CA (with 11-methoxycurvularin, glycocholic acid, and isoquercitrin), IL6 (with isoquercitrin), PTGS2 (with isoquercitrin), and IGF1R (with 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine, isoquercitrin), showed a lower binding affinity. (4) Conclusions: This study provides evidence to support the positive effects of SCFA-producing microbial metabolites that function against kidney cancer and inflammation and makes integrative research proposals that may be used to guide future studies.

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.

Ketonization of Ginsenoside C-K by Novel Recombinant 3-ß-Hydroxysteroid Dehydrogenases and Effect on Human Fibroblast Cells.

BACKGROUND AND OBJECTIVE: The ginsenoside compound K (C-K) (which is a de-glycosylated derivative of major ginsenosides) is effective in the treatment of cancer, diabetes, inflammation, allergy, angiogenesis, aging, and has neuroprotective, and hepatoprotective than other minor ginsenosides. Thus, a lot of studies have been focused on the conversion of major ginsenosides to minor ginsenosides using glycoside hydrolases but there is no study yet published for the bioconversion of minor ginsenosides into another high pharmacological active compound. Therefore, the objective of this study to identify a new gene (besides the glycoside hydrolases) for the conversion of minor ginsenosides C-K into another highly pharmacological active compound. METHODS AND RESULTS: Lactobacillus brevis which was isolated from Kimchi has showed the ginsenoside C-K altering capabilities. From this strain, a novel potent decarboxylation gene, named HSDLb1, was isolated and expressed in Escherichia coli BL21 (DE3) using the pMAL-c5X vector system. Recombinant HSDLb1 was also characterized. The HSDLb1 consists of 774 bp (258 amino acids residues) with a predicted molecular mass of 28.64 kDa. The optimum enzyme activity was recorded at pH 6.0-8.0 and temperature 30 °C. Recombinant HSDLb1 effectively transformed the ginsenoside C-K to 12-ß-hydroxydammar-3-one-20(S)-O-ß-D-glucopyranoside (3-oxo-C-K). The experimental data proved that recombinant HSDLb1 strongly ketonized the hydroxyl (-O-H) group at C-3 of C-K via the following pathway: C-K → 3-oxo-C-K. In vitro study, 3-oxo-C-K showed higher solubility than C-K, and no cytotoxicity to fibroblast cells. In addition, 3-oxo-C-K induced the inhibitory activity of ultraviolet A (UVA) against matrix metalloproteinase-1 (MMP-1) and promoted procollagen type I synthesis. Based on these expectations, we hypothesized that 3-oxo-C-K can be used in cosmetic products to block UV radiations and anti-ageing agent. Furthermore, we expect that 3-oxo-C-K will show higher efficacy than C-K for the treatment of cancer, ageing and other related diseases, for which more studies are needed.

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.

Tuft cells - the immunological interface and role in disease regulation.

Tuft cells, also known as taste chemosensory cells, accumulate during parasite colonization or infection and have powerful immunomodulatory effects on substances that could be detrimental, as well as possible anti-inflammatory or antibacterial effects. Tuft cells are the primary source of interleukin (IL)-25. They trigger extra Innate lymphoid type-2 cells (ILC2) in the intestinal lamina propria to create cytokines (type 2); for instance, IL-13, which leads to an increase in IL-25. As tuft cells can produce biological effector molecules, such as IL-25 and eicosanoids involved in allergy (for example, cysteinyl leukotrienes and prostaglandin D2) and the neurotransmitter acetylcholine. Following parasite infection, tuft cells require transient receptor potential cation channel subfamily M member 5 (TRPM5)-dependent chemosensation to produce responses. Secretory tuft cells provide a physical mucus barrier against the external environment and therefore have vital defensive roles against diseases by supporting tissue maintenance and repair. In addition to recent research on tuft cells, more studies are required to understand the distribution, cell turnover, molecular characteristics, responses in various species, involvement in immunological function across tissues, and most importantly, the mechanism involved in the control of various diseases.

A review on Impact of dietary interventions, drugs, and traditional herbal supplements on the gut microbiome.

The gut microbiome is the community of healthy, and infectious organisms in the gut and its interaction in the host gut intestine (GI) environment. The balance of microbial richness with beneficial microbes is very important to perform healthy body functions like digesting food, controlling metabolism, and precise immune function. Alternately, this microbial dysbiosis occurs due to changes in the physiochemical condition, substrate avidity, and drugs. Moreover, various categories of diet such as "plant-based", "animal-based", "western", "mediterranean", and various drugs (antibiotic and common drugs) also contribute to maintaining microbial flora inside the gut. The imbalance (dysbiosis) in the microbiota of the GI tract can cause several disorders (such as diabetes, obesity, cancer, inflammation, and so on). Recently, the major interest is to use prebiotic, probiotic, postbiotic, and herbal supplements to balance such microbial community in the GI tract. But, there has still a large gap in understanding the microbiome function, and its relation to the host diet, drugs, and herbal supplements to maintain the healthy life of the host. So, the present review is about the updates on the microbiome concerns related to diet, drug, and herbal supplements, and also gives research evidence to improve our daily habits regarding diet, drugs, and herbal supplements. Because our regular dietary plan and traditional herbal supplements can improve our health by balancing the bacteria in our gut.

Hydroponic Ginseng ROOT Mediated with CMC Polymer-Coated Zinc Oxide Nanoparticles for Cellular Apoptosis via Downregulation of BCL-2 Gene Expression in A549 Lung Cancer Cell Line.

The unique and tailorable physicochemical features of zinc oxide nanoparticles (ZnO-NPs) synthesized from green sources make them attractive for use in cancer treatment. Hydroponic-cultured ginseng-root-synthesized ZnO-NPs (HGRCm-ZnO NPs) were coated with O-carboxymethyl chitosan (CMC) polymer, which stabilized and enhanced the biological efficacy of the nanoparticles. Nanoparticles were characterized by X-ray diffraction (XRD), UV-Vis spectroscopy, transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), and energy-dispersive X-ray spectroscopy (EDS). The flower-shaped nanoparticles were crystalline in nature with a particle size of 28 nm. To evaluate if these NPs had anti-lung cancer activity, analysis was performed on a human lung carcinoma cell line (A549). HGRCm-ZnO nanoparticles showed less toxicity to normal keratinocytes (HaCaTs), at concentrations up to 20 µg/mL, than A549 cancer cells. Additionally, these NPs showed dose-dependent colony formation and cell migration inhibition ability, which makes them more promising for lung cancer treatment. Additionally, Hoechst and propidium iodide dye staining also confirmed that the NP formulation had apoptotic activity in cancer cells. Further, to evaluate the mechanism of cancer cell death via checking the gene expression, HGRCm ZnO NPs upregulated the BAX and Caspase 3 and 9 expression levels but downregulated Bcl-2 expression, indicating that the nanoformulation induced mitochondrial-mediated apoptosis. Moreover, these preliminary results suggest that HGRCm ZnO NPs can be a potential candidate for future lung cancer treatment.

A Focused Review on Molecular Signalling Mechanisms of Ginsenosides Anti-Lung Cancer and Anti-inflammatory Activities.

BACKGROUND: Ginseng (Panax ginseng Meyer) is a cultivated medicinal herb that has been widely available in the Asian region since the last century. Ginseng root is used worldwide in Oriental medicine. Currently, the global mortality and infection rates for lung cancer and inflammation are significantly increasing. Therefore, various preventative methods related to the activity of ginsenosides have been used for lung cancer as well as inflammation. METHODS: Web-based searches were performed on Web of Science, Springer, PubMed, and Scopus. A cancer statistical analysis was also conducted to show the current ratio of affected cases and death from lung cancer around the world. RESULTS: Ginsenosides regulate the enzymes that participate in tumor growth and migration, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), extracellular signalregulated kinases 1/2 (ERK1/2), the gelatinase network metalloproteinase-2 (MMP-2/9) and activator protein 1 (AP-1). In addition, ginsenosides also possess anti-inflammatory effects by inhibiting the formation of proinflammatory cytokines (tumor necrosis factor-α) (TNF-α) and interleukin-1ß (IL-1ß) and controlling the activities of inflammatory signalling pathways, such as NF-κB, Janus kinase2/signal transducer, and activator of transcription 3 (Jak2/Stat3). CONCLUSION: In several in vitro and in vivo models, P. ginseng showed potential beneficial effects in lung cancer and inflammation treatment. In this review, we provide a detailed and up-to-date summary of research evidence for antilung cancer and anti-inflammatory protective effects of ginsenosides and their potential molecular mechanisms.

Investigating the Anticancer Activity of G-Rh1 Using In Silico and In Vitro Studies (A549 Lung Cancer Cells).

Ginsenoside Rh1 (G-Rh1), a possible bioactive substance isolated from the Korean Panax ginseng Meyer, has a wide range of pharmacological effects. In this study, we have investigated the anticancer efficacy of G-Rh1 via in silico and in vitro methodologies. This study mainly focuses on the two metastatic regulators, Rho-associated protein kinase 1 (ROCK1) and RhoA, along with other standard apoptosis regulators. The ROCK1 protein is a member of the active serine/threonine kinase family that is crucial for many biological processes, including cell division, differentiation, and death, as well as many cellular processes and muscle contraction. The abnormal activation of ROCK1 kinase causes several disorders, whereas numerous studies have also shown that RhoA is expressed highly in various cancers, including colon, lung, ovarian, gastric, and liver malignancies. Hence, inhibiting both ROCK1 and RhoA will be promising in preventing metastasis. Therefore, the molecular level interaction of G-Rh1 with the ROCK1 and RhoA active site residues from the preliminary screening clearly shows its inhibitory potential. Molecular dynamics simulation and principal component analysis give essential insights for comprehending the conformational changes that result from G-Rh1 binding to ROCK1 and RhoA. Further, MTT assay was employed to examine the potential cytotoxicity in vitro against human lung cancer cells (A549) and Raw 264.7 Murine macrophage cells. Thus, G-Rh1 showed significant cytotoxicity against human lung adenocarcinoma (A549) at 100 µg/mL. In addition, we observed an elevated level of reactive oxygen species (ROS) generation, perhaps promoting cancer cell toxicity. Additionally, G-Rh1 suppressed the mRNA expression of RhoA, ROCK1, MMP1, and MMP9 in cancer cell. Accordingly, G-Rh1 upregulated the p53, Bax, Caspase 3, caspase 9 while Bcl2 is downregulated intrinsic pathway. The findings from our study propose that the anticancer activity of G-Rh1 may be related to the induction of apoptosis by the RhoA/ROCK1 signaling pathway. As a result, this study evaluated the functional drug-like compound G-Rh1 from Panax ginseng in preventing and treating lung cancer adenocarcinoma via regulating metastasis and apoptosis.

Transcriptome expression profile of compound-K-enriched red ginseng extract (DDK-401) in Korean volunteers and its apoptotic properties.

Ginseng and ginsenosides have been reported to have various pharmacological effects, but their efficacies depend on intestinal absorption. Compound K (CK) is gaining prominence for its biological and pharmaceutical properties. In this study, CK-enriched fermented red ginseng extract (DDK-401) was prepared by enzymatic reactions. To examine its pharmacokinetics, a randomized, single-dose, two-sequence, crossover study was performed with eleven healthy Korean male and female volunteers. The volunteers were assigned to take a single oral dose of one of two extracts, DDK-401 or common red ginseng extract (DDK-204), during the initial period. After a 7-day washout, they received the other extract. The pharmacokinetics of DDK-401 showed that its maximum plasma concentration (Cmax) occurred at 184.8 ± 39.64 ng/mL, Tmax was at 2.4 h, and AUC0-12h was 920.3 ± 194.70 ng h/mL, which were all better than those of DDK-204. The maximum CK absorption in the female volunteers was higher than that in the male volunteers. The differentially expressed genes from the male and female groups were subjected to a KEGG pathway analysis, which showed results in the cell death pathway, such as apoptosis and necroptosis. In cytotoxicity tests, DDK-401 and DDK-204 were not particularly toxic to normal (HaCaT) cells, but at a concentration of 250 µg/mL, DDK-401 had a much higher toxicity to human lung cancer (A549) cells than DDK-204. DDK-401 also showed a stronger antioxidant capacity than DDK-204 in both the DPPH and potassium ferricyanide reducing power assays. DDK-401 reduced the reactive oxygen species production in HaCaT cells with induced oxidative stress and led to apoptosis in the A549 cells. In the mRNA sequence analysis, a signaling pathway with selected marker genes was assessed by RT-PCR. In the HaCaT cells, DDK-401 and DDK-204 did not regulate FOXO3, TLR4, MMP-9, or p38 expression; however, in the A549 cells, DDK-401 downregulated the expressions of MMP9 and TLR4 as well as upregulated the expressions of the p38 and caspase-8 genes compared to DDK-204. These results suggest that DDK-401 could act as a molecular switch for these two cellular processes in response to cell damage signaling and that it could be a potential candidate for further evaluations in health promotion studies.

Pomegranate juice fermented by tannin acyl hydrolase and Lactobacillus vespulae DCY75 enhance estrogen receptor expression and anti-inflammatory effect.

Phenolics are phytochemicals in plants, fruits, and vegetables have potential health-promoting efficacies. However, mostly available as a complex form. So, to increase the contents and nutritional value of the phenolic compounds, fermentation is most readily used in the food industry. Especially, the hydrolyzable tannins present in the pomegranate that can be liberated into monomolecular substances, which enhances biological activity. Thus, this study aims to convert hydrolyzable tannins to ellagic acid by fermentation using Tannin acyl hydrolase (TAH) and a novel bacteria strain Lactobacillus vespulae DCY75, respectively to investigate its effect on Estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) mRNA expression along with inflammation inhibition. As a result, the fermentation enhanced the ellagic acid content up to 70% by the synergetic effect of TAH and DCY75. Furthermore, fermented pomegranate (PG-F) increased cellular proliferation as well as upregulated the gene expression of estrogen regulators such as ERα, ERß, and pS2 in breast cancer cell line (MCF-7), which commonly used to evaluate estrogenic activity. Moreover, to study the inflammation associated with low estrogen in menopause, we have analyzed the inhibition of nitric oxide (NO)/inducible nitric oxide synthase (iNOS) in RAW 264.7 cells. The PG-F juice did not exert any cytotoxicity in RAW 264.7 cells and inhibited NO production along with the downregulation of a major pro-inflammatory cytokine iNOS which indicates the anti-inflammatory potential of it. To sum it up, the fermented commercial pomegranate juice using a novel bacteria strain increased the amount of ellagic acid that the value added bioactive of pomegranate and it has significantly increased the estrogenic activity via upregulating estrogen related biomarkers expression and reduced the risk of related inflammation via NO/iNOS inhibition. This study could be a preliminary study to use fermented pomegranate as a potential health functional food after further evaluation.

Production of Minor Ginsenoside CK from Major Ginsenosides by Biotransformation and Its Advances in Targeted Delivery to Tumor Tissues Using Nanoformulations.

For over 2000 years, ginseng (roots of Panax ginseng C.A. Meyer) has been used as a traditional herbal medicine. Ginsenosides are bioactive compounds present in ginseng responsible for the pharmacological effects and curing various acute diseases as well as chronic diseases including cardiovascular disease, cancer and diabetes. Structurally, ginsenosides consist of a hydrophobic aglycone moiety fused with one to four hydrophilic glycoside moieties. Based on the position of sugar units and their abundance, ginsenosides are classified into major and minor ginsenosides. Despite the great potential of ginsenosides, major ginsenosides are poorly absorbed in the blood circulation, resulting in poor bioavailability. Interestingly, owing to their small molecular weight, minor ginsenosides exhibit good permeability across cell membranes and bioavailability. However, extremely small quantities of minor ginsenosides extracted from ginseng plants cannot fulfill the requirement of scientific and clinical studies. Therefore, the production of minor ginsenosides in mass production is a topic of interest. In addition, their poor solubility and lack of targetability to tumor tissues limits their application in cancer therapy. In this review, various methods used for the transformation of major ginsenosides to minor ginsenoside compound K (CK) are summarized. For the production of CK, various transformation methods apply to major ginsenosides. The challenges present in these transformations and future research directions for producing bulk quantities of minor ginsenosides are discussed. Furthermore, attention is also paid to the utilization of nanoformulation technology to improve the bioavailability of minor ginsenoside CK.

Cellulose Nanocrystals-Incorporated Thermosensitive Hydrogel for Controlled Release, 3D Printing, and Breast Cancer Treatment Applications.

In situ-gel-forming thermoresponsive copolymers have been widely exploited in controlled delivery applications because their critical gel temperature is similar to human body temperature. However, there are limitations to controlling the delivery of biologics from a hydrogel network because of the poor networking and reinforcement between the copolymer networks. This study developed an in situ-forming robust injectable and 3D printable hydrogel network based on cellulose nanocrystals (CNCs) incorporated amphiphilic copolymers, poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide (PCLA). In addition, the physicochemical and mechanical properties of injectable hydrogels were controlled by physically incorporating CNCs with amphiphilic PCLA copolymers. CNCs played an unprecedented role in physically reinforcing the PCLA copolymers' micelle network via intermicellar bridges. Apart from that, the free-flowing closely packed rod-like CNCs incorporated PCLA micelle networks at low temperature transformed to a stable viscoelastic hydrogel network at physiological temperature. CNC incorporated PCLA copolymer sols effectively coordinated with hydrophobic doxorubicin and water-soluble lysozyme by a combination of hydrophobic and hydrogen bonding interaction and controlled the release of biologics. As shown by the 3D printing results, the biocompatible PCLA hydrogels continuously extruded during printing had good injectability and maintained high shape fidelity after printing without any secondary cross-linking steps. The interlayer bonding between the printed layers was high and formed stable 3D structures up to 10 layers. Subcutaneous injection of free-flowing CNC incorporated PCLA copolymer sols to BALB/c mice formed a hydrogel instantly and showed controlled biodegradation of the hydrogel depot without induction of toxicity at the implantation sites or surrounding tissues. At the same time, the in vivo antitumor effect on the MDA-MB-231 tumor xenograft model demonstrated that DOX-loaded hydrogel formulation significantly inhibited the tumor growth. In summary, the CNC incorporated biodegradable hydrogels developed in this study exhibit a prolonged release with special release kinetics for hydrophobic and hydrophilic biologics.

Gene Regulations upon Hydrogel-Mediated Drug Delivery Systems in Skin Cancers-An Overview.

The incidence of skin cancer has increased dramatically in recent years, particularly in Caucasian populations. Specifically, the metastatic melanoma is one of the most aggressive cancers and is responsible for more than 80% of skin cancer deaths around the globe. Though there are many treatment techniques, and drugs have been used to cure this belligerent skin cancer, the side effects and reduced bioavailability of drug in the targeted area makes it difficult to eradicate. In addition, cellular metabolic pathways are controlled by the skin cancer driver genes, and mutations in these genes promote tumor progression. Consequently, the MAPK (RAS-RAF-MEK-ERK pathway), WNT and PI3K signaling pathways are found to be important molecular regulators in melanoma development. Even though hydrogels have turned out to be a promising drug delivery system in skin cancer treatment, the regulations at the molecular level have not been reported. Thus, we aimed to decipher the molecular pathways of hydrogel drug delivery systems for skin cancer in this review. Special attention has been paid to the hydrogel systems that deliver drugs to regulate MAPK, PI3K-AKT-mTOR, JAK-STAT and cGAS-STING pathways. These signaling pathways can be molecular drivers of skin cancers and possible potential targets for the further research on treatment of skin cancers.

Binary Effects of Gynostemma Gold Nanoparticles on Obesity and Inflammation via Downregulation of PPARγ/CEPBα and TNF-α Gene Expression.

Nanoscience is a multidisciplinary skill with elucidated nanoscale particles and their advantages in applications to various fields. Owing to their economical synthesis, biocompatible nature, and widespread biomedical and environmental applications, the green synthesis of metal nanoparticles using medicinal plants has become a potential research area in biomedical research and functional food formulations. Gynostemma pentaphyllum (GP) has been extensively used in traditional Chinese medicine to cure several diseases, including diabetes mellitus (DM). This is the first study in which we examined the efficacy of G. pentaphyllum gold nanoparticles (GP-AuNPs) against obesity and related inflammation. GP extract was used as a capping agent to reduce Au2+ to Au0 to form stable gold nanoparticles. The nanoparticles were characterized by using UV-VIS spectroscopy, and TEM images were used to analyze morphology. In contrast, the existence of the functional group was measured using FTIR, and size and shape were examined using XRD analysis. In vitro analysis on GP-AuNPs was nontoxic to RAW 264.7 cells and 3T3-L1 cells up to a specific concentration. It significantly decreased lipid accumulation in 3T3-L1 obese and reduced NO production in Raw 264.7 macrophage cells. The significant adipogenic genes PPARγ and CEPBα and a major pro-inflammatory cytokine TNF-α expression were quantified using RT-PCR. The GP-AuNPs decreased the face of these genes remarkably, revealing the antiadipogenic and anti-inflammatory activity of our synthesized GP-AuNPs. This study represents thorough research on the antiobesity effect of Gynostemma pentaphyllum gold nanoparticles synthesized using a green approach and the efficacy instead of related inflammatory responses.