Isoalantolactone exerts anti-melanoma effects via inhibiting PI3K/AKT/mTOR and STAT3 signaling in cell and mouse models.

BACKGROUND AND AIM: Although the anti-cancer activity of isoalantolactone (IATL) has been extensively studied, the anti-melanoma effects of IATL are still unknown. Here, we have investigated the anti-melanoma effects and mechanism of action of IATL. MTT and crystal violet staining assays were performed to detect the inhibitory effect of IATL on melanoma cell viability. Apoptosis and cell cycle arrest induced by IATL were examined using flow cytometry. The molecular mechanism of IATL was explored by Western blotting, confocal microscope analysis, molecular docking, and cellular thermal shift assay (CETSA). A B16F10 allograft mouse model was constructed to determine the anti-melanoma effects of IATL in vivo. The results showed that IATL exerted anti-melanoma effects in vitro and in vivo. IATL induced cytoprotective autophagy in melanoma cells by inhibiting the PI3K/AKT/mTOR signaling. Moreover, IATL inhibited STAT3 activation both in melanoma cells and allograft tumors not only by binding to the SH2 domain of STAT3 but also by suppressing the activity of its upstream kinase Src. These findings demonstrate that IATL exerts anti-melanoma effects via inhibiting the STAT3 and PI3K/AKT/mTOR signaling pathways, and provides a pharmacological basis for developing IATL as a novel phytotherapeutic agent for treating melanoma clinically.

The Effects of Cranberry Consumption on Glycemic and Lipid Profiles in Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This study aims to update the evidence and clarify whether cranberry possesses lipid-lowering and hypoglycemic properties in humans. PubMed, Web of Science, and Scopus were searched to identify relevant articles published up to December 2023. In total, 3145 publications were reviewed and 16 of them were included for qualitative synthesis and meta-analysis. Stata 15.0 and Review Manager 5.4 were applied for statistical analyses. The results revealed a significant decrease in the total cholesterol to high-density lipoprotein cholesterol ratio (TC/HDL-C) (MD = -0.24; 95% CI: -0.45, -0.04; peffect = 0.02) and homeostasis model assessment of insulin resistance (HOMA-IR) (MD = -0.59; 95% CI: -1.05, -0.14; peffect = 0.01) with cranberry consumption. However, it did not influence total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and fasting insulin. In subgroup analysis, cranberry consumption in dried form (capsules, powder, and tablets) was found to significantly decrease the fasting insulin level (three studies, one hundred sixty-five participants, MD = -2.16; 95% CI: -4.24, -0.07; peffect = 0.04), while intervention duration, health conditions, and dosage of polyphenols and anthocyanins had no impact on blood lipid and glycemic parameters. In summary, cranberry might have potential benefits in regulating lipid and glucose profiles.

Unlocking hormesis and toxic effects induced by cadmium in Polygonatum cyrtonema Hua based on morphology, physiology and metabolomics.

Traditional Chinese medicine materials (TCMMs) are widely planted and used, while cadmium (Cd) is a widespread pollutant that poses a potential risk to plant growth and human health. However, studies on the influences of Cd on TCMMs have been limited. Our study aims to reveal the antioxidation-related detoxification mechanism of Polygonatum cyrtonema Hua under Cd stress based on physiology and metabolomics. The results showed that Cd0.5 (total Cd: 0.91 mg/kg; effective Cd: 0.45 mg/kg) induced hormesis on the biomass of roots, tubers and aboveground parts with increases of 22.88%, 27.12% and 17.02%, respectively, and significantly increased the flavonoids content by 57.45%. Additionally, the metabolism of caffeine, glutamine, arginine and purine was upregulated to induce hormesis in Cd0.5, which enhanced the synthesis of resistant substances such as spermidine, choline, IAA and saponins. Under Cd2 stress, choline and IAA decreased, and fatty acid metabolites (such as peanut acid and linoleic acid) and 8-hydroxyguanosine increased in response to oxidative damage, resulting in a significant biomass decrease. Our findings further reveal the metabolic process of detoxification by antioxidants and excessive Cd damage in TCMMs, deepen the understanding of detoxification mechanisms related to antioxidation, and enrich the relevant theories of hormesis induced by Cd.

Safe utilization evaluation of two typical traditional Chinese medicinal materials in Cd-contaminated soil based on the analysis of Cd transfer and AHP model.

Due to the increasing scarcity of wild resources, most traditional Chinese medicinal materials (TCMMs) in the market are produced via artificial cultivation. The widespread pollution of cadmium (Cd) in soil limits the safe cultivation and use of TCMMs. This study investigated Cd accumulation, distribution, and the medicinal component content under simulated field conditions to clarify the differences in the Cd absorption, transfer and detoxification mechanisms of Polygonatum cyrtonema Hua and Bletilla striata, and provide the preliminary safe utilization conditions of TCMMs based on the analytic hierarchy process (AHP). The results showed that the Cd content of P. cyrtonema Hua was lower than the safety threshold under a high soil Cd concentration of 0.91 mg/kg (Cd-L), while B. striata was safe only at a low Cd concentration of 0.25 mg/kg (CK). Cd at 0.91 mg/kg induced hormesis affecting the net increase in biomass and medicinal component content for both TCMMs, while P. cyrtonema Hua showed better potential for safe utilization. Additionally, P. cyrtonema Hua had stronger resistance to Cd stress, exhibiting superior characteristics for synergistic absorption of Cd with mineral elements, transfer to nonmedical part and safer fixation forms in subcellular components. In contrast, B. striata showed insufficient Cd tolerance, and Cd was easily accumulated in organelles to inhibit plant growth. Our findings may attract more attention to the safe cultivation of TCMMs and provide insight into guidance for the safe utilization of slightly Cd-contaminated soil.

Selenium improves the medicinal safety and quality of Bletilla striata by promoting the fixation of cadmium in root: Pot and field experiments.

Soil cadmium (Cd) pollution poses a considerable threat to the safe production of traditional Chinese medicine (TCM) in China. The tubers of Bletilla striata, a precious TCM, are widely used to treat various ailments. However, the medicinal safety and quality of tubers are significantly affected by high Cd accumulation. While selenium (Se) is known to reduce Cd concentration in traditional crops, its impact on Cd content in medicinal parts and overall quality remains underexplored. To bridge the gap, a pot experiment and field validation were conducted to determine the effectiveness of foliar Se application. The results revealed that Se effectively counteracted Cd damage. Compared to Cd treatment alone, Se at 1.5 mg L-1 significantly decreased Cd content by 46.33 %, increased the biomass by 21.48 %, and raised the total phenolic, flavonoid, saponin, and polysaccharide contents by 46.31 %, 30.46 %, 27.08 %, and 29.01 %, respectively, in tubers. Furthermore, this study explored the mechanism of Se action. Se facilitated Cd accumulation in root cell walls and soluble fractions, enhanced the synthesis of phytochelatins (PC), and stored them in the form of PC-Cd complexes. These findings have profound implications for the cultivation of TCM, ensuring its safety, and promoting sustainable agricultural practices.

A traditional prescription comprising Astragali Radix and Schisandra chinensis Fructus induces apoptosis and protective autophagy in hepatocellular carcinoma cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) poses a growing challenge to global health efforts. The 5-year survival rate of HCC patients is still dismal. A traditional prescription Qi-Wei-Wan (QWW) comprising Astragali Radix and Schisandra chinensis Fructus has traditionally been used for HCC treatment according to traditional Chinese medicine theory, but the pharmacological basis is not clear. AIM OF THE STUDY: This study aims to investigate the anti-HCC effects of an ethanolic extract of QWW (hereafter, QWWE) and the mechanism of action. MATERIALS AND METHODS: An UPLC-Q-TOF-MS/MS method was developed to control the quality of QWWE. Two human HCC cell lines (HCCLM3 and HepG2) and a HCCLM3 xenograft mouse model were employed to investigate the anti-HCC effects of QWWE. The anti-proliferative effect of QWWE in vitro was determined by MTT, colony formation and EdU staining assays. Apoptosis and protein levels were examined by flow cytometry and Western blotting, respectively. Nuclear presence of signal transducer and activator of transcription 3 (STAT3) was examined by immunostaining. Transient transfection of pEGFP-LC3 and STAT3C plasmids was performed to assess autophagy and determine the involvement of STAT3 signaling in QWWE's anti-HCC effects, respectively. RESULTS: We found that QWWE inhibited the proliferation of and triggered apoptosis in HCC cells. Mechanistically, QWWE inhibited the activation of SRC and STAT3 at Tyr416 and Tyr705, respectively; inhibited the nuclear translocation of STAT3; lowered Bcl-2 protein levels, while increased Bax protein levels in HCC cells. Over-activating STAT3 attenuated the cytotoxic and apoptotic effects of QWWE in HCC cells. Moreover, QWWE induced autophagy in HCC cells by inhibiting mTOR signaling. Blocking autophagy with autophagy inhibitors (3-methyladenine and chloroquine) enhanced the cytotoxicity, apoptotic effect and the inhibitory effect on STAT3 activation of QWWE. Intragastric administration of QWWE at 10 mg/kg and 20 mg/kg potently repressed tumor growth and inhibited STAT3 and mTOR signaling in tumor tissues, but did not significantly affect mouse body weight. CONCLUSION: QWWE exhibited potent anti-HCC effects. Inhibiting the STAT3 signaling pathway is involved in QWWE-mediated apoptosis, while blocking mTOR signaling contributes to QWWE-mediated autophagy induction. Blockade of autophagy enhanced the anti-HCC effects of QWWE, indicating that the combination of an autophagy inhibitor and QWWE might be a promising therapeutic strategy for HCC management. Our findings provide pharmacological justifications for the traditional use of QWW in treating HCC.

Two-phase effects of environmentally relevant lanthanum on life-history traits of Daphnia magna and transgenerational bioenergetic profiles: Implications for nutritional and environmental consequences.

The versatile applicability of rare earth elements (REEs) especially lanthanum (La) in diverse fields, has led to large-scale mineral exploitation globally, inevitably resulting in substantial release of La into environment. As emerging anthropogenic environmental contaminant, La-induced toxicological effects and potential ecotoxicological implications in relation to realistic levels of La in aquatic ecosystems are becoming major concerns. To address these issues, Daphnia magna was selected as a prototype, and toxicity tests were conducted to explore the effects of La exposure on life-history characteristics and fecundity fitness, as showcased by quantitative variations from the individual level to population scale. In parallel, to further denote transgenerational caloric impacts of parental La exposure, bioenergetic profiles on newborn neonates were concurrently determined by measuring macromolecule forms in terms of proteins, glycogens and lipids to quantify nutritional alterations at progeny level. The results revealed that low-dose La exposure slightly stimulated the demographic potential and nutritional responses, exhibiting dose-dependent hormesis-like effects and promising non-toxicological potential to Daphnia, whereas high-dose La exposure of greater than 59.2 µg La L - 1, conspicuously imposed detrimental effects on quantity and quality of offspring, i.e. not only reducing body size, lifespan expectancy and reproductive output in a concentration-dependent way and resulting in lower population fitness by a dynamic life-table analysis, but eventually leading to the decrease of nutritional qualities and caloric contents on neonates. Taken together, these two-phase findings regarding the dose-related shift from hormesis to inhibition not only provided valuable insights into the complicated biological outcomes of La effects on environmentally-relevant organisms, but experimentally highlighted the significant implications of considering environmental and nutritional consequences in ecologically assessing the La-triggered risk at environmentally realistic occurrences, particularly on gradient scenarios crossing upstream and downstream of highly complex mining watersheds.

Isoliquiritigenin inhibits pancreatic cancer progression through blockade of p38 MAPK-regulated autophagy.

BACKGROUND: Pancreatic cancer has been characterized by poor prognosis, early metastasis and dissatisfactory treatment outcome. The high basal level of autophagy in tumor cells leads to chemoresistance and tumor progression. Thus, it is imminent to explore novel effective chemotherapeutic adjuvants to increase patients' survival rate. Isoliquiritigenin (ISL) is a bioactive flavonoid obtained from the Traditional Chinese herbal medicine Glycyrrhiza glabra, and it possesses a broad range of pharmacological effects. In this study, the anti-cancer effect of ISL in pancreatic cancer treatment and the underlying mechanism are investigated. METHODS: MTT assay, colony formation and EdU analysis were performed to explore the growth inhibition of ISL on pancreatic cancer cells. Apoptosis were analyzed using TUNEL and flow cytometry. The formations of autophagosomes were analyzed by immunofluorescence microscopy and transmission electron microscopy. RFP-GFP-LC3B probe was applied to detect the autophagy flux. To assess the structural interaction of ISL with p38 protein, molecular docking assays were performed. The molecular mechanism was elucidated by using western immunoblotting. Subsequently, the inhibition of ISL on tumor growth was determined in vivo using pancreatic tumor mice model. RESULTS: ISL inhibited pancreatic cancer cell growth and induced apoptosis, both in vitro and in vivo. ISL caused accumulation of autophagosome through blockade of late stage autophagic flux. Moreover, autophagy inducer rapamycin enhanced ISL-evoked cell growth inhibition and promoted apoptosis, while inhibition of autophagosome formation by siAtg5 attenuated ISL-induced apoptosis. It is remarkable that ISL synergistically sensitized the cytotoxic effect of gemcitabine and 5-fluorouracil on pancreatic cancer cells as both drugs induced autophagy. Molecular docking analysis has indicated that ISL acted by direct targeting of p38 MAPK, which was confirmed by ISL-induced phosphorylation of p38. The autophagy flux induced by p38 inhibitor SB203580 was blocked by ISL, with further increasing toxicity of ISL in pancreatic cancer cells. CONCLUSION: The results have revealed that ISL inhibited pancreatic cancer progression by blockade of autophagy through p38 MAPK signaling.

Differential responses of polysaccharides and antioxidant enzymes in alleviating cadmium toxicity of tuber traditional Chinese medicinal materials.

Polygonatum cyrtonema Hua (PC) and Bletilla striata (BS) are widely used and planted as tuber traditional Chinese medicinal materials (TCMMs). Cadmium (Cd) is one of the major causes of soil pollution and challenge to the quality and safety of TCMMs. Understanding the absorption and distribution of Cd is important for addressing the risks posed by its residues. As a result, the higher Cd translocation factor (TF) results in the lower Cd bioconcentration factor (BCF) in the PC tuber than that of BS attributed to a lower Cd concentration in the PC tuber, which guaranteed its safe utilization and edible safety under 1 mg·kg-1 Cd soil. Cd stress overall activated peroxidase (POD), catalase (CAT), and water-extractable polysaccharides in PC (PCP1) to exhibit better antioxidation, while the superoxide dismutase (SOD) in BS increased by approximately 206-277% to alleviate more severe oxidative damage. Particularly, Cd induced an increase in PCP1 higher than that of water-extractable polysaccharides of BS (BSP1) by approximately 335% to 1351%. PC exhibited effective strategies for alleviating Cd toxicity, including transferring Cd to nonmedicinal parts, increasing polysaccharides, and synergistically activating the enzymatic antioxidant system. This study expands the application for the safe utilization of low-Cd contaminated soil and provides novel insights for tuber TCMMs to alleviate Cd toxicity.

Selenium alleviates toxicity in Amaranthus hypochondriacus by modulating the synthesis of thiol compounds and the subcellular distribution of cadmium.

As a beneficial element, Selenium (Se) reduces toxic cadmium (Cd) absorption in many crops, but the effects of Se on Cd hyperaccumulator plants are unclear. This study examined the effects of Se on Amaranthus hypochondriacus (K472). The results showed that Se increased antioxidant enzyme activities, reduced Cd concentrations and toxicity, restored cell viability, and enhanced photosynthesis; these effects increased the biomass of roots, stems, and leaves by 59.87%, 53.85%, 44.19%, respectively, and these values exceeded the biomass of roots and stems in untreated control plants by 56.69% and 15.37%, respectively. Moreover, Se promoted PC synthesis, stably chelated Cd in the form of PC3 and PC4 and transported PC-Cd to vacuoles. Furthermore, Se protected organelles and reduced Cd migration by increasing Cd levels in cell walls and vacuoles. Interestingly, although the Cd content in K472 was decreased, Se maintained the total extracted Cd concentrations and its remediation efficiency by improving biomass and increased tolerance to Cd by approximately 5 times. The experimental results provide novel insights and methods for mitigating toxicity, promoting growth, and broadening the engineering application scope of K472; these results also provide a theoretical basis for further application of Se in soil with high Cd concentrations.

Antioxidant system response, mineral element uptake and safe utilization of Polygonatum sibiricum in cadmium-contaminated soil.

Chinese herbal medicine is widely cultivated in Southwest China, where the soil cadmium (Cd) contamination of farmland is more serious than that in China as a whole. In this study, Polygonatum sibiricum was exposed to Cd at concentrations of e-1, e0, e2, and e4 mg/kg for 30, 60, and 90 days, and the physiological stress responses, Cd and mineral element uptake, antioxidant enzyme activities, and content changes of pharmaceutical ingredients (polysaccharides) were analyzed to decipher the feasibility of safe utilization in Cd-contaminated soil. The results show that the activity of antioxidant enzymes (SOD and CAT) in the aboveground part was always higher than that in the underground part. The underground part of Polygonatum sibiricum mobilizes nonenzymatic systems to facilitate the synthesis of polysaccharides (PCP1, PCP2) with antioxidant properties to cope with Cd stress. Mineral elements (P, K, Ca, Mg, Fe, Cu, and Zn) significantly (p < 0.05) changed after 90 d of cultivation. In particular, the changes in the iron and zinc content were significantly correlated (p < 0.05) with the activities of SOD and POD. Soil Cd at e0 mg/kg can guarantee the safe production and utilization of Polygonatum sibiricum, and the stimulation of Cd promotes polysaccharide synthesis and biomass growth.

Integrating Network Analysis and Metabolomics to Reveal Mechanism of Huaganjian Decoction in Treatment of Cholestatic Hepatic Injury.

Huaganjian decoction (HGJD) was first recorded in the classic "Jing Yue Quan Shu" during the Ming dynasty, and it has been extensively applied in clinical practice to treat liver diseases for over 300 years in China. However, its bioactive constituents and relevant pharmacological mechanism are still unclear. In this study, a strategy integrating network analysis and metabolomics was applied to reveal mechanism of HGJD in treating cholestatic hepatic injury (CHI). Firstly, we observed the therapeutic effect of HGJD against CHI with an alpha-naphthylisothiocyanate (ANIT) induced CHI rat model. Then, we utilized UPLC-Q-Exactive MS/MS method to analyze the serum migrant compounds of HGJD in CHI rats. Based on these compounds, network analysis was conducted to screen for potential active components, and key signaling pathways interrelated to therapeutic effect of HGJD. Meanwhile, serum metabolomics was utilized to investigate the underlying metabolic mechanism of HGJD against CHI. Finally, the predicted key pathway was verified by western blot and biochemical analysis using rat liver tissue from in vivo efficacy experiment. Our results showed that HGJD significantly alleviated ANIT induced CHI. Totally, 31 compounds originated from HGJD have been identified in the serum sample. PI3K/Akt/Nrf2 signaling pathway related to GSH synthesis was demonstrated as one of the major pathways interrelated to therapeutic effect of HGJD against CHI. This research supplied a helpful strategy to determine the potential bioactive compounds and mechanism of traditional Chinese medicine.

Inhibitory mechanisms of Acacia mearnsii extracts on the growth of Microcystis aeruginosa.

Our previous work revealed that Acacia mearnsii extract can inhibit the growth of Microcystis aeruginosa, the common species forming toxic cyanobacterial blooms in eutrophic freshwater. In the present study, we demonstrated that this plant extract can significantly increase cell membrane permeability and Ca²âº/Mg²âº-ATPase activity on the membrane. Long-term exposure to concentrations of 20 ppm A. mearnsii extract led to algal cell membrane leakage or even lysis. Comparison of expression of three photosynthesis-related genes (rbcL, psaB and psbD) in M. aeruginosa with and without plant extract treatment revealed that their expression was remarkably reduced in the presence of the extract. Down-regulation of photosynthesis-related genes could indicate the inhibition of the photosynthetic process. Thus, our results suggested that both photosynthetic systems and membranes of M. aeruginosa are potentially damaged by A. mearnsii extract.

Effect of black wattle (Acacia mearnsii) extract on blue-green algal bloom control and plankton structure optimization: a field mesocosm experiment.

A field mesocosm experiment was conducted at the Three Gorges Reservoir to investigate the utility of black wattle extract in controlling blue algal blooms. The mesocosm experiment was divided into two parts: (1) a short-term test to evaluate how black wattle extract inhibits algal blooms in an emergency and (2) a long-term test to evaluate how black wattle extract maintains water quality and prevents algal blooms over a 1-year period. In the short-term test, the results showed that 3 to 4 mg L(-1) black wattle extract could reduce algal biomass in 1 week, whereas serious algal blooms occurred in the untreated control mesocosm. More importantly, the long-term test suggested that black wattle extract played a significant role in plankton structure optimization at lower concentrations of 1 to 2 mg L(-1). In this test, phytoplankton diversity increased, with the dominant species shifting from cyanobacteria to diatoms and other algae. Meanwhile, as water quality improved through the presence of plant extract treatment, the numbers of smaller zooplankton decreased and larger species increased. Therefore, this investigation founded a novel nature plant agent that not only has good effects on algal bloom control, but also restores the aquatic ecosystem.