Synthesis of bioactive evodiamine and rutaecarpine analogues under ball milling conditions.

Mechanochemical reactions achieved by processes such as milling and grinding are promising alternatives to traditional solution-based chemistry. This approach not only eliminates the need for large amounts of solvents, thereby reducing waste generation, but also finds applications in chemical and materials synthesis. The focus of this study is on the synthesis of quinazolinone derivatives by ball milling, in particular evodiamine and rutaecarpine analogues. These compounds are of interest due to their diverse bioactivities, including potential anticancer properties. The study examines the reactions carried out under ball milling conditions, emphasizing their efficiency in terms of shorter reaction times and reduced environmental impact compared to conventional methods. The ball milling reaction of evodiamine and rutaecarpine analogues resulted in yields of 63-78% and 22-61%, respectively. In addition, these compounds were tested for their cytotoxic activity, and evodiamine exhibited an IC50 of 0.75 ± 0.04 µg mL-1 against the Ca9-22 cell line. At its core, this research represents a new means to synthesise these compounds, providing a more environmentally friendly and sustainable alternative to traditional approaches.

Natural products modulate phthalate-associated miRNAs and targets.

Phthalates are widespread and commonly used plasticizers that lead to adverse health effects. Several natural products provide a protective effect against phthalates. Moreover, microRNAs (miRNAs) are regulated by natural products and phthalates. Therefore, miRNAs' impacts and potential targets may underlie the mechanism of phthalates. However, the relationship between phthalate-modulated miRNAs and phthalate protectors derived from natural products is poorly understood and requires further supporting information. In this paper, we review the adverse effects and potential targets of phthalates on reproductive systems as well as cancer and non-cancer responses. Information on natural products that attenuate the adverse effects of phthalates is retrieved through a search of Google Scholar and the miRDB database. Moreover, information on miRNAs that are upregulated or downregulated in response to phthalates is collected, along with their potential targets. The interplay between phthalate-modulated miRNAs and natural products is established. Overall, this review proposes a straightforward pathway showing how phthalates modulate different miRNAs and targets and cause adverse effects, which are partly attenuated by several natural products, thereby providing a direction for investigating the natural product-miRNA-target axis against phthalate-induced effects.

Protein phosphatase 2A modulation and connection with miRNAs and natural products.

Protein phosphatase 2A (PP2A), a heterotrimeric holoenzyme (scaffolding, catalytic, and regulatory subunits), regulates dephosphorylation for more than half of serine/threonine phosphosites and exhibits diverse cellular functions. Although several studies on natural products and miRNAs have emphasized their impacts on PP2A regulation, their connections lack systemic organization. Moreover, only part of the PP2A family has been investigated. This review focuses on the PP2A-modulating effects of natural products and miRNAs' interactions with potential PP2A targets in cancer and non-cancer cells. PP2A-modulating natural products and miRNAs were retrieved through a literature search. Utilizing the miRDB database, potential PP2A targets of these PP2A-modulating miRNAs for the whole set (17 members) of the PP2A family were retrieved. Finally, PP2A-modulating natural products and miRNAs were linked via a literature search. This review provides systemic directions for assessing natural products and miRNAs relating to the PP2A-modulating functions in cancer and disease treatments.

Demethoxymurrapanine, an indole-naphthoquinone alkaloid, inhibits the proliferation of oral cancer cells without major side effects on normal cells.

Antioral cancer drugs need a greater antiproliferative impact on cancer than on normal cells. Demethoxymurrapanine (DEMU) inhibits proliferation in several cancer cells, but an in-depth investigation was necessary. This study evaluated the proliferation-modulating effects of DEMU, focusing on oral cancer and normal cells. DEMU (0, 2, 3, and 4 µg/mL) at 48 h treatments inhibited the proliferation of oral cancer cells (the cell viability (%) for Ca9-22 cells was 100.0 ± 2.2, 75.4 ± 5.6, 26.0 ± 3.8, and 15.4 ± 1.4, and for CAL 27 cells was 100.0 ± 9.4, 77.2 ± 5.9, 57.4 ± 10.7, and 27.1 ± 1.1) more strongly than that of normal cells (the cell viability (%) for S-G cells was 100.0 ± 6.6, 91.0 ± 4.6, 95.0 ± 2.6, and 95.8 ± 5.5), although this was blocked by the antioxidant N-acetylcysteine. The presence of oxidative stress was evidenced by the increase of reactive oxygen species and mitochondrial superoxide and the downregulation of the cellular antioxidant glutathione in oral cancer cells, but these changes were minor in normal cells. DEMU also caused greater induction of the subG1 phase, extrinsic and intrinsic apoptosis (annexin V and caspases 3, 8, and 9), and DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in oral cancer than in normal cells. N-acetylcysteine attenuated all these DEMU-induced changes. Together, these data demonstrate the preferential antiproliferative function of DEMU in oral cancer cells, with the preferential induction of oxidative stress, apoptosis, and DNA damage in these cancer cells, and low cytotoxicity toward normal cells.

Ferroptosis-Regulated Natural Products and miRNAs and Their Potential Targeting to Ferroptosis and Exosome Biogenesis.

Ferroptosis, which comprises iron-dependent cell death, is crucial in cancer and non-cancer treatments. Exosomes, the extracellular vesicles, may deliver biomolecules to regulate disease progression. The interplay between ferroptosis and exosomes may modulate cancer development but is rarely investigated in natural product treatments and their modulating miRNAs. This review focuses on the ferroptosis-modulating effects of natural products and miRNAs concerning their participation in ferroptosis and exosome biogenesis (secretion and assembly)-related targets in cancer and non-cancer cells. Natural products and miRNAs with ferroptosis-modulating effects were retrieved and organized. Next, a literature search established the connection of a panel of ferroptosis-modulating genes to these ferroptosis-associated natural products. Moreover, ferroptosis-associated miRNAs were inputted into the miRNA database (miRDB) to bioinformatically search the potential targets for the modulation of ferroptosis and exosome biogenesis. Finally, the literature search provided a connection between ferroptosis-modulating miRNAs and natural products. Consequently, the connections from ferroptosis-miRNA-exosome biogenesis to natural product-based anticancer treatments are well-organized. This review sheds light on the research directions for integrating miRNAs and exosome biogenesis into the ferroptosis-modulating therapeutic effects of natural products on cancer and non-cancer diseases.

Connection between Radiation-Regulating Functions of Natural Products and miRNAs Targeting Radiomodulation and Exosome Biogenesis.

Exosomes are cell-derived membranous structures primarily involved in the delivery of the payload to the recipient cells, and they play central roles in carcinogenesis and metastasis. Radiotherapy is a common cancer treatment that occasionally generates exosomal miRNA-associated modulation to regulate the therapeutic anticancer function and side effects. Combining radiotherapy and natural products may modulate the radioprotective and radiosensitizing responses of non-cancer and cancer cells, but there is a knowledge gap regarding the connection of this combined treatment with exosomal miRNAs and their downstream targets for radiation and exosome biogenesis. This review focuses on radioprotective natural products in terms of their impacts on exosomal miRNAs to target radiation-modulating and exosome biogenesis (secretion and assembly) genes. Several natural products have individually demonstrated radioprotective and miRNA-modulating effects. However, the impact of natural-product-modulated miRNAs on radiation response and exosome biogenesis remains unclear. In this review, by searching through PubMed/Google Scholar, available reports on potential functions that show radioprotection for non-cancer tissues and radiosensitization for cancer among these natural-product-modulated miRNAs were assessed. Next, by accessing the miRNA database (miRDB), the predicted targets of the radiation- and exosome biogenesis-modulating genes from the Gene Ontology database (MGI) were retrieved bioinformatically based on these miRNAs. Moreover, the target-centric analysis showed that several natural products share the same miRNAs and targets to regulate radiation response and exosome biogenesis. As a result, the miRNA-radiomodulation (radioprotection and radiosensitization)-exosome biogenesis axis in regard to natural-product-mediated radiotherapeutic effects is well organized. This review focuses on natural products and their regulating effects on miRNAs to assess the potential impacts of radiomodulation and exosome biogenesis for both the radiosensitization of cancer cells and the radioprotection of non-cancer cells.

Cyclodepsipeptides: Isolation from Endophytic Fungi of Sarcophyton ehrenbergi and Verification of Their Larvicidal Activity via In-Vitro and In-Silico Studies.

Culex pipiens mosquitoes are vectors to many viruses and can transmit diseases such as filariasis and avian malaria. The present study evaluated the larvicidal activity of marine-derived endophytic fungi Aspergillus nomius and Aspergillus flavus from the soft coral Sarcophyton ehrenbergi along with two known cyclodepsipeptide compounds, scopularide A (1) and B (2), isolated from A. flavus extract, against third-instar larvae of C. pipiens, using distilled water as a negative control and toosenedanin as a positive control. The structures of the isolated compounds were confirmed by various spectroscopic analyses. The lethal concentrations (LC50 and LC90) were calculated by probit analysis. Scopularide A was the most potent after 96 h treatment, with LC50 and LC90 values of 58.96 and 994.31 ppm, respectively, and with 82.66% mortality at a concentration of 300 ppm. To unravel the biochemical mechanism of the tested extracts and compounds, their effects against protease, chitinase, phenoloxidases and lipase enzymes from the whole-body tissue of C. pipiens were evaluated after 72 h treatment at LC50 dose. Superior activity was observed for A. flavus extract against all tested enzymes. A molecular docking study was conducted for scopularide A and B on the four tested enzymes, to further verify the observed activity. Results revealed good binding affinities for both compounds as compared to the docked ligands, mainly via a number of hydrogen bonds. This was the first study to report the isolation of endophytic fungi A. flavus and A. nomius from the marine soft coral S. ehrenbergi. The endophytic fungal extract of A. flavus was found to be a promising source for a natural larvicidal agent against C. pipiens populations.

Protective Effects of the Chalcone-Based Derivative AN07 on Inflammation-Associated Myotube Atrophy Induced by Lipopolysaccharide.

Inflammation is a major cause of skeletal muscle atrophy in various diseases. 2-Hydroxy-4'-methoxychalcone (AN07) is a chalcone-based peroxisome-proliferator-activated receptor gamma (PPARγ) agonist with various effects, such as antiatherosclerosis, anti-inflammation, antioxidative stress, and neuroprotection. In this study, we examined the effects of AN07 on protein homeostasis pathway and mitochondrial function in inflammation-associated myotube atrophy induced by lipopolysaccharides (LPS). We found that AN07 significantly attenuated NF-κB activation, inflammatory factors (TNF-α, IL-1ß, COX-2, and PGE2), Nox4 expression, and reactive oxygen species levels in LPS-treated C2C12 myotubes. Moreover, AN07 increased SOD2 expression and improved mitochondrial function, including mitochondrial membrane potential and mitochondrial oxygen consumption rate. We also demonstrated that AN07 attenuated LPS-induced reduction of myotube diameter, MyHC expression, and IGF-1/IGF-1R/p-Akt-mediated protein synthesis signaling. Additionally, AN07 downregulated LPS-induced autophagy-lysosomal protein degradation molecules (LC3-II/LC3-I and degraded p62) and ubiquitin-proteasome protein degradation molecules (n-FoxO1a/MuRF1/atrogin-1). However, the regulatory effects of AN07 on protein synthesis and degradation signaling were inhibited by the IGF-1R inhibitor AG1024 and the PI3K inhibitor wortmannin. In addition, the PPARγ antagonist GW9662 attenuated the effects of AN07 against LPS-induced inflammation, oxidation, and protein catabolism. In conclusion, our findings suggest that AN07 possesses protective effects on inflammation-induced myotube atrophy and mitochondrial dysfunction.

Bioactive polyketides from the pathogenic fungus of Epicoccum sorghinum.

MAIN CONCLUSION: We discovered and identified a series of characteristic substances, including one new polyketide, epicorepoxydon B, of the important pathogenic fungus, Epicoccum sorghinum, of sorghum. The fungal extract and some isolated polyketides are sensitive to a malignant triple-negative breast cancer cell line, MDA-MB-231. Sorghum (Kaoliang) grain is an important crop with high economic value and several applications. In Taiwan, sorghum has been used in the wine industry, and "Kinmen Kaoliang Liquor" is a well-known Asian brand. Fungal contamination is one of the major threats affecting the production of sorghum grain resulting in economic losses as well as human and animal health problems. Several fungal species can infect sorghum grain and generate some toxic secondary metabolites. Epicoccum sorghinum is one of the major fungal contaminants of sorghum grains and a potent producer of mycotoxins such as tenuazonic acid (TeA). However, except for TeA, few studies focused on chemical compounds produced by this fungus. To explore the potential biological and toxic effects of E. sorghinum, a chemical investigation was carried out on the ethyl acetate extract of the fungus because it showed cytotoxic activity against a triple-negative breast cancer cell line, MDA-MB-231 (54.82% inhibition at 20 µg/mL). One new polyketide, epicorepoxydon B (1), along with six known compounds including 4,5-dihydroxy-6-(6'-methylsalicyloxy)-2-hydroxymethyl-2-cyclohexenl-one (2), epicorepoxydon A (3), 3-hydroxybenzyl alcohol (4), 6-methylsalicylic acid (5), gentisyl alcohol (6), and 6-(hydroxymethyl)benzene-1,2,4-triol (7) were obtained, and their structures were established by the interpretation of their MS and NMR spectroscopic data. The cytotoxic activity of all isolated polyketides 1-7 was evaluated, and compounds 2, 6, and 7 exhibited potent activities against A549, HepG2, and MDA-MB-231 human cancer cell lines with IC50 value ranging from 1.86 to 18.31 µM. The structure-activity relationship of the isolated compounds was proposed.

2-Iodo-4'-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway.

Methylglyoxal (MG) acts as a reactive precursor of advanced glycation end products (AGEs). This compound is often connected with pathologies such as diabetes, neurodegenerative processes and diseases of aging. 2-iodo-4'-methoxychalcone (CHA79), a synthetic halogen-containing chalcone derivative, has been reported its anti-diabetic activity. This study aims to investigate the potential protective capability of CHA79 against MG-mediated neurotoxicity in SH-SY5Y cells. Results indicated CHA79 increased viability of cells and attenuated the rate of apoptosis in MG-exposed SH-SY5Y. CHA79 up-regulated expression of anti-apoptotic protein (Bcl-2) and down-regulated apoptotic proteins (Bax, cytochrome c, caspase-3, caspase-9). Moreover, CHA79 significantly up-regulated expression of neurotrophic factors, including glucagon-like peptide-1 receptor (GLP-1R), brain derived neurotrophic factor (BDNF), p75NTR, p-TrkB, p-Akt, p-GK-3ß and p-CREB. CHA79 attenuated MG-induced ROS production and enhanced the antioxidant defense including nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, SOD and GSH. Furthermore, CHA79 attenuated MG-induced reduction of glyoxalase-1 (GLO-1), a vital enzyme on removing AGE precursors. In conclusion, CHA79 is the first novel synthetic chalcone possessing the GLP-1R and GLO-1 activating properties. CHA 79 also exhibits neuroprotective effects against MG toxicity by enhancing neurotrophic signal, antioxidant defense and anti-apoptosis pathway.

2-Bromo-4'-methoxychalcone and 2-Iodo-4'-methoxychalcone Prevent Progression of Hyperglycemia and Obesity via 5'-Adenosine-Monophosphate-Activated Protein Kinase in Diet-Induced Obese Mice.

Obesity and diabetes are global health-threatening issues. Interestingly, the mechanism of these pathologies is quite different among individuals. The discovery and development of new categories of medicines from diverse sources are urgently needed for preventing and treating diabetes and other metabolic disorders. Previously, we reported that chalcones are important for preventing biological disorders, such as diabetes. In this study, we demonstrate that the synthetic halogen-containing chalcone derivatives 2-bromo-4'-methoxychalcone (compound 5) and 2-iodo-4'-methoxychalcone (compound 6) can promote glucose consumption and inhibit cellular lipid accumulation via 5'-adenosine-monophosphate-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase 1 (ACC) phosphorylation in 3T3-L1 adipocytes and C2C12 skeletal myotubes. In addition, the two compounds significantly prevented body weight gain and impaired glucose tolerance, hyperinsulinemia, and insulin resistance, which collectively help to delay the progression of hyperglycemia in high-fat-diet-induced obese C57BL/6 mice. These findings indicate that 2-bromo-4'-methoxychalcone and 2-iodo-4'-methoxychalcone could act as AMPK activators, and may serve as lead compounds for a new class of medicines that target obesity and diabetes.

6-Paradol and 6-Shogaol, the Pungent Compounds of Ginger, Promote Glucose Utilization in Adipocytes and Myotubes, and 6-Paradol Reduces Blood Glucose in High-Fat Diet-Fed Mice.

The anti-diabetic activity of ginger powder (Zingiber officinale) has been recently promoted, with the recommendation to be included as one of the dietary supplements for diabetic patients. However, previous studies presented different results, which may be caused by degradation and metabolic changes of ginger components, gingerols, shogaols and paradols. Therefore, we prepared 10 ginger active components, namely 6-, 8-, 10-paradols, 6-, 8-, 10-shogaols, 6-, 8-, 10-gingerols and zingerone, and evaluated their anti-hyperglycemic activity. Among the tested compounds, 6-paradol and 6-shogaol showed potent activity in stimulating glucose utilization by 3T3-L1 adipocytes and C2C12 myotubes. The effects were attributed to the increase in 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation in 3T3-L1 adipocytes. 6-Paradol, the major metabolite of 6-shogaol, was utilized in an in vivo assay and significantly reduced blood glucose, cholesterol and body weight in high-fat diet-fed mice.

Pandalisines A and B, novel indolizidine alkaloids from the leaves of Pandanus utilis.

Two novel alkaloids named pandalisines A (1) and B (2), constituting a new class of C8-substituted indolizidine moiety, were isolated from the leaves of Pandanus utilis. The structures of these new compounds were established by their mass and spectroscopic data. The absolute configuration was determined by the comparison of experimental CD and calculated ECD spectra. A plausible biosynthetic pathway for compounds 1 and 2 is advanced. The cytotoxic activities of the isolated alkaloids against A-549, Hep-G2, and MDA-MB-231 cancer cell lines were evaluated. The result showed that 1 and 2 are the first non-cytotoxic indolizidine alkaloids.

Marine anticancer drugs in modulating miRNAs and antioxidant signaling.

Several marine drugs exert anticancer effects by inducing oxidative stress, which becomes overloaded and kills cancer cells when redox homeostasis is imbalanced. The downregulation of antioxidant signaling induces oxidative stress, while its upregulation attenuates oxidative stress. Marine drugs have miRNA-modulating effects against cancer cells. However, the potential antioxidant targets of such drugs have been rarely explored. This review aims to categorize the marine-drug-modulated miRNAs that downregulate their antioxidant targets, causing oxidative stress in anticancer treatments. We also categorize the downregulation of oxidative-stress-inducing miRNAs in antioxidant protection among non-cancer cells. We summarize the putative antioxidant targets of miRNA-modulating marine drugs by introducing a bioinformatics tool (miRDB). Finally, the marine drugs affecting antioxidant targets are surveyed. In this way, the connections between marine drugs and their modulating miRNA and antioxidant targets are innovatively categorized to provide a precise network for exploring their potential anticancer functions and protective effects on non-cancer cells.

Quality and production enhancement of fish mint, Houttuynia cordata Thunb., cultivated in a hydroponic planting system with designed plant growth-promoting additives.

Fish mint, Houttuynia cordata Thunb. (HCT) is an edible vegetable that has also been used in traditional folk medicines. As both a medicinal herb and a dietary source, HCT has been clinically proven to be a pivotal ingredient in formulas administered to alleviate COVID-19 symptoms. With the increasing market demand for imported materials, ensuring the quality consistency of HCT becomes a significant concern. In this study, the growing time for hydroponically-cultivated HCT with seaweed extract and amino acids added (HCTW) reduced by half compared to conventional soil-cultivated HCT (HCTS). Key quantified components in HCTW, flavonoid glycosides and caffeoylquinic acid derivatives, exhibited a 143% increase over HCTS. These crucial constituents were responsible for possessing antioxidant activity (IC50 < 25 µg/mL) and anti-nitrite oxide production (IC50 < 20 µg/mL). An economically-designed hydroponic system with appropriate additives is proposed to replace HCTS with improvements of growth time, overall production yields, and bioactive qualities.

Connection of Cancer Exosomal LncRNAs, Sponging miRNAs, and Exosomal Processing and Their Potential Modulation by Natural Products.

Cancerous exosomes contain diverse biomolecules that regulate cancer progression. Modulating exosome biogenesis with clinical drugs has become an effective strategy for cancer therapy. Suppressing exosomal processing (assembly and secretion) may block exosomal function to reduce the proliferation of cancer cells. However, the information on natural products that modulate cancer exosomes lacks systemic organization, particularly for exosomal long noncoding RNAs (lncRNAs). There is a gap in the connection between exosomal lncRNAs and exosomal processing. This review introduces the database (LncTarD) to explore the potential of exosomal lncRNAs and their sponging miRNAs. The names of sponging miRNAs were transferred to the database (miRDB) for the target prediction of exosomal processing genes. Moreover, the impacts of lncRNAs, sponging miRNAs, and exosomal processing on the tumor microenvironment (TME) and natural-product-modulating anticancer effects were then retrieved and organized. This review sheds light on the functions of exosomal lncRNAs, sponging miRNAs, and exosomal processing in anticancer processes. It also provides future directions for the application of natural products when regulating cancerous exosomal lncRNAs.

Development on potential skin anti-aging agents of Cosmos caudatus Kunth via inhibition of collagenase, MMP-1 and MMP-3 activities.

BACKGROUND: Skin aging is associated with degradation of collagen by matrix metalloproteinases (MMPs), which leads to loss of skin elasticity and formation of wrinkles. Cosmos caudatus Kunth (CC) has been traditionally claimed as an anti-aging agent in Malaysia. Despite its well-known antioxidant activity, the anti-aging properties of CC was not validated. PURPOSE: This study aimed to investigate the anti-aging potential of CC extracts and fractions, particularly their inhibition of collagenase, MMP-1 and MMP-3 activities in human dermal fibroblasts CCD-966SK, followed by isolation, identification and analysis of their bioactive constituents. STUDY DESIGN AND METHODS: DPPH assay was firstly used to evaluate the antioxidant activity throughout the bioactivity-guided fractionation. Cell viability was determined using MTS assay. Collagenase activity was examined, while MMP-1 and MMP-3 expression were measured using qRT-PCR and western blotting. Then, chemical identification of pure compounds isolated from CC fractions was done by using ESIMS, 1H and 13C NMR spectroscopies. HPLC analyses were carried out for bioactive fractions to quantify the major components. RESULTS: Throughout the antioxidant activity-guided fractionation, fractions CC-E2 and CC-E3 with antioxidant activity and no toxicity towards CCD-966SK cells were obtained from CC 75% ethanol partitioned layer (CC-E). Both fractions inhibited collagenase activity, MMP-1 and MMP-3 mRNA and protein expression, as well as NF-κB activation induced by TNF-α in CCD-966SK cells. 14 compounds, which mainly consists of flavonoids and their glycosides, were isolated. Quercitrin (14.79% w/w) and quercetin (11.20% w/w) were major compounds in CC-E2 and CC-E3, respectively, as quantified by HPLC. Interestingly, both fractions also inhibited the MMP-3 protein expression synergistically, compared with treatment alone. CONCLUSION: The quantified CC fractions rich in flavonoid glycosides exhibited skin anti-aging effects via the inhibition of collagenase, MMP-1 and MMP-3 activities, probably through NF-κB pathway. This is the first study reported on MMP-1 and MMP-3 inhibitory activity of CC with its chemical profile, which revealed its potential to be developed as anti-aging products in the future.

Guilu Erxian Jiao enhances protein synthesis, glucose homeostasis, mitochondrial biogenesis and slow-twitch fibers in the skeletal muscle.

Guilu Erxian Jiao (GEJ) is a commonly used nutritional supplement due to its rich content of amino acids. It is also a traditional herbal medicine for improving degenerative joint. This study aimed to investigate the effect and mechanism of GEJ water extract (GEJ-WE) on skeletal muscle in C2C12 myotubes and C57BL/6J mice. Analysis of GEJ-WE were performed by high-performance liquid chromatography fingerprinting with chemical standards. Protein expression, mRNA level, glycogen content, mitochondria activity and ATP level were evaluated by western blots, real-time PCR, PAS staining, MTT and ATP bioluminescence assay, respectively. Skeletal muscle strength was evaluated by grip strength. Skeletal muscle volume, mass and fiber types were evaluated by micro computed tomography, histological analysis and immunofluorescence staining, respectively. Motor function was evaluated by rotarod performance and locomotor activity. In C2C12 myotubes, GEJ-WE significantly enhanced myogenic differentiation and myotube growth, protein synthesis signaling IGF-1/IGF-1R/IRS-1/Akt, Glut4 translocation, glycogen content, mitochondrial biogenesis signaling PGC-1α/NRF1/TFAM, mitochondrial activity and ATP production. However, IGF-1R antagonist AG1024 and PI3K inhibitor wortmannin reduced GEJ-WE-induced protein expression of MyHC, p-Akt, p-mTOR and p-GSK-3ß, Glut4 translocation and glycogen content. In C57BL/6J mice, GEJ-WE not only upregulated protein synthesis and mitochondrial biogenesis signaling, but it also increased muscle volume, relative muscle weight, cross-sectional area of myofibers, glycogen content and transition of fast-to-slow type fibers of skeletal muscles. Moreover, GEJ-WE enhanced grip strength and motor activity of mice. In conclusion, the upregulation of protein synthesis, myogenic differentiation, glucose homeostasis, mitochondrial biogenesis and slow-twitch fibers contributes to the mechanisms of GEJ-WE on the enhancement of skeletal muscle mass and motor function.

Synthesis of chalcone derivatives as potential anti-diabetic agents.

Chalcones bearing electron donating or electron withdrawing substitutions were prepared and their glucose uptake activity was evaluated. Chalcone derivatives were synthesized in one step protocol with high purity and yield. Chalcones with chloro, bromo, iodo and hydroxy substitutions at position 2 on A-ring exhibited the highest activity with glucose medium concentration (210 to 236 mg/dl) compared to pioglitazone and rosiglitazone (230 and 263 mg/dl, respectively). Also chalcones with iodo substitution at position 3 on A-ring were comparably active (≤238 mg/dl). The structure-activity relationship of the tested chalcones was studied and the findings were supported statistically.

The effectiveness of Fuzi in combination with routine heart failure treatment on chronic heart failure patients.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, Aconiti Lateralis Radix Praeparata, is widely used in Traditional Chinese Medicine (TCM) for the treatment of acute heart failure (HF) for 2000 years. However, the clinical evidence of Fuzi in the treatment of chronic HF is limited, especially when used in combination with Western medications. MATERIALS AND METHODS: This population-based propensity score (PS)-matched cohort study aimed to evaluate the effectiveness of Fuzi on the chronic HF. From 4753 chronic HF patients who had used TCM herbal medicine, we performed 1:1 PS matching and selected target patients with (n = 921) and without (n = 921) Fuzi use for further analysis. The primary outcomes were all-cause mortality and composite cardiovascular (CV) outcomes. Hazard ratio (HR) was calculated by Cox proportional hazard regression and the competing risk analysis. The dose-response relationship and the association between the initiation of TCM herbal medicine and the primary outcomes were evaluated by restricted cubic spline (RCS) functions. RESULTS: There was no difference in all-cause mortality (HR, 0.99; 95% confidence interval [CI], 0.76-1.27) and composite CV outcomes (HR, 0.96; 95% CI, 0.84-1.11) between the Fuzi user and non-user groups. For CV safety issue, the result showed that Fuzi use was not associated with a higher risk of cardiac arrhythmias (HR, 1.03; 95% CI, 0.83-1.29). The dose-response relationship showed that Fuzi cumulative dose (≥150g) was associated with lower composite CV risk (HR, 0.76; 95% CI, 0.59-0.99). In addition, the RCS model showed that late initiation (≥2.5 years) of TCM herbal drugs in chronic HF patients had a higher risk of all-cause mortality (HR, 1.81; 95%CI, 1.07-3.08). CONCLUSIONS: This study is the first real-world evidence to demonstrate the effect of Fuzi combined with routine HF treatment. Importantly, the result indicated that long-term Fuzi use had a significant benefit in preventing cardiovascular events. The late initiation of TCM herbal drugs was associated with a higher risk of all-cause mortality. Further clinical trials are needed to support or undermine the assumption of using Fuzi and current Western medications to treat chronic HF.