Curcumol Exerts Antitumor Effect via Inhibiting EGFR-Akt-Mcl-1 Signaling.

Dysfunction of epidermal growth factor receptor (EGFR) signaling plays a critical role in the tumorigenesis of oral squamous cell carcinoma (OSCC). In the present study, the data analysis results of immunohistochemistry and the TCGA database verified that the expression of EGFR is significantly upregulated in OSCC tumor tissues, and depletion of EGFR inhibits the growth of OSCC cells in vitro and in vivo. Moreover, these results showed that the natural compound, curcumol, exhibited a profound antitumor effect on OSCC cells. Western blotting, MTS, and immunofluorescent staining assays indicated that curcumol inhibited cell proliferation and induced intrinsic apoptosis in OSCC cells via downregulating myeloid cell leukemia 1 (Mcl-1). A mechanistic study revealed that curcumol inhibited the EGFR-Akt signal pathway, which activated GSK-3[Formula: see text]-mediated Mcl-1 phosphorylation. Further research showed that curcumol-induced Mcl-1 Ser159 phosphorylation is required to disrupt the interaction between deubiquitinase JOSD1 and Mcl-1 and eventually induce Mcl-1 ubiquitination and degradation. In addition, curcumol administration can effectively inhibit CAL27 and SCC25 xenograft tumor growth and is well-tolerated in vivo. Finally, we demonstrated that Mcl-1 is upregulated and positively correlates with p-EGFR and p-Akt in OSCC tumor tissues. Collectively, the present results provide new insights into the antitumor mechanism of curcumol, identifying it as an attractive therapeutic agent that reduces Mcl-1 expression and inhibits OSCC growth. Targeting EGFR/Akt/Mcl-1 signaling could be a promising option in the clinical treatment of OSCC.

Wrist-Ankle Acupuncture as Additional Therapy for Postoperative Multimodal Analgesia in Orthopedic Surgery: Systematic Review and Meta-Analysis.

BACKGROUND: The present meta-analysis analyzed the efficacy and safety of wrist-ankle acupuncture (WAA) as an additional therapy for postoperative multimodal analgesia after orthopedic surgery. METHODS: Electronic databases, including Cochrane Library, PubMed, EMBASE, Web of Science, CNKI, SinoMed, Wanfang, and VIP, were searched to identify randomized controlled trials and cohort studies that reported details of WAA as an additional therapy for postoperative multiple analgesia in orthopedic surgery before October 1, 2021. Analyzed outcomes included time points of the visual analog scale, use of patient-controlled intravenous analgesia (PCIA), and postoperative adverse events. Subgroup analysis was performed according to time points and complication type. RESULTS: Eleven randomized controlled trials and one cohort study were included in the meta-analysis. Among a total of 845 patients, there were 422 patients in the WAA groups and 423 patients in the control groups. The WAA groups showed a better analgesic effect (standard mean difference [SMD] = -1.34; 95% confidence interval [CI]: -1.76 to -0.91; P < 0.00001; I2 = 0.94), lower use of PCIA (SMD = -1.48; 95% CI: -2.26 to -0.69; P = 0.0002; I2 = 0.94), and lower occurrence of postoperative adverse events (risk ratio = 0.38; 95% CI: 0.30 to 0.49; P < 0.00001; I2 = 0) than did the control groups. CONCLUSION: WAA as an additional therapy for postoperative multimodal analgesia in orthopedic surgery showed advantages over control treatment in terms of pain relief, use of PCIA, and occurrence of postoperative adverse events.

Effect of Curcumol on NOD-Like Receptor Thermoprotein Domain 3 Inflammasomes in Liver Fibrosis of Mice.

OBJECTIVE: To investigate the effect of curcumol on NOD-like receptor thermoprotein domain 3 (NLRP3) inflammasomes, and analyze the mechanism underlying curcumol against liver fibrosis. METHODS: Thirty Kunming mice were divided into a control group, a model group and a curcumol group according to a random number table, 10 mice in each group. Mice were intraperitoneally injected with 40% carbon tetrachloride (CCl4:peanut oil, 2:3 preparation) at 5 mL/kg for 6 weeks, twice a week, for developing a liver fibrosis model. The mice in the control group were given the same amount of peanut oil twice a week for 6 weeks. The mice in the curcumol group were given curcumol (30 mL/kg) intragastrically, and the mice in the model and control groups were given the same amount of normal saline once a day for 6 weeks. Changes in liver structure were observed by hematoxylin and eosin (HE) and Masson staining. Liver function, liver fiber indices, and the expression of interleukin (IL)-10 and tumor necrosis factor-α (TNF-α) levels were determined by automatic biochemical analyzer and enzyme linked immunosorbent assay kit. Immunoblotting and reverse transcription-quantitative PCR (RT-qPCR) were performed to detect the expression of NLRP3 inflammasome-related molecules, TGF-ß and collagen. RESULTS: HE and Masson staining results showed that the hepatocytes of the model group were arranged irregularly with pseudo-lobular structure and a large amount of collagen deposition. The mice in the curcumol group had a significant decrease in liver function and liver fibers indices compared with the model group (P<0.05); RT-qPCR and Western blotting results reveal that, in the curcumol group, the mRNA and protein expression levels of NLRP3, IL-1 ß, Caspase 1 and gasdermin D decreased significantly compared with the model group (P<0.05); immunohistochemical results showed that in the curcumol group, the protein expression levels of NLRP3 and IL-1 ß decreased significantly compared with the model group (P<0.05). CONCLUSION: A potential anti-liver fibrosis mechanism of curcumol may be associated with the inhibition of NLRP3 inflammasomes and decreasing the downstream inflammatory response.

Chemical characters and protective effect of Baqi Lingmao formula on experimental liver injury.

OBJECTIVE: To investigate the chemical characters of water-extract of Baqi Lingmao formula (BQLM formula) and its effects on anti-liver injury in model mice and live cells. METHODS: BQLM formula was composed of ten herbal medicines. We determined the contents of alkaloids, saponins, phenolic acids and flavonoid in BQLM formula by UV spectrophotometry. The active components of alkaloids and phenolic acids in BQLM formula were identified by HPLC chromatography. The anti-hepatic injury effects of BQLM formula were investigated with concanavalin A (ConA)-induced hepatitis model of mice, human liver LO2 and HepG2.2.15 cells. RESULTS: BQLM formula (2 and 10 g/kg, orally) significantly improved the damages of liver tissues and functions caused by ConA in mice, reduced the infiltration of inflammatory cells into liver and inhibited the inflammatory cytokine secretion of interferon-γ, tumor necrosis factor-α and interleukin-6. BQLM formula simultaneously decreased the levels of alanine aminotransferase and aspartate aminotransferase of liver and serum, and recovered the superoxide dismutase and catalase activities of liver to normal levels in ConA-induced hepatic-injury mice. The serum of BQLM formula group stimulated the human liver LO2 cell proliferation in vitro. Further, BQLM formula obviously promoted the proliferation of normal hepatocytes (LO2 cells) and inhibited the hepatocytes death induced by ConA. It also significantly inhibited the proliferation of HepG2.2.15 cells and decreased the secretion of HBsAg and HBeAg in vitro. CONCLUSIONS: BQLM formula has anti-inflammation and anti-hepatitis virus Beffects, and is capable of improving liver injury in vivo and in vitro.

Novel kojic acid derivatives with anti-inflammatory effects from Aspergillus versicolor.

Two novel kojic acid derivatives, kojicones A and B (1 and 2), along with the precursors kojic acid (3) and (2R,4R)-4-hydroxy-5-methoxy-2,4-dimethyl-2- [(2R)-2-methylbutyryloxy]-5-cyclohexen-1,3-dione (4), were isolated from a fungal strain Aspergillus versicolor. Their structures and absolute configurations were accurately confirmed by HRESIMS data, NMR analysis, and electronic circular dichroism (ECD) calculations. Kojicones A and B were the first examples of kojic acid adducts with cyclohexen-1,3-dione possessing unprecedented tricycle skeletons. Compounds 1-3 were found to have inhibition on the NO production of murine RAW 264.7 cells. They can also reduce the mRNA expression of four cytokines (IL-6, IL-1ß, TNF-α, and iNOS) and promote the expression of IL-4 at 20 µM. Moreover, kojic acid (3) could treat the DSS (dextran sulfate sodium)-induced colitis on mice with the effectiveness similar to that of the positive control. The results suggested that kojic acid and its derivatives could be a promising anti-inflammatory source for the medicinal and cosmetic industry.

Feature-Based Molecular Networking Analysis of the Metabolites Produced by In Vitro Solid-State Fermentation Reveals Pathways for the Bioconversion of Epigallocatechin Gallate.

Dark teas are prepared by a microbial fermentation process. Flavan-3-ol B-ring fission analogues (FBRFAs) are some of the key bioactive constituents that characterize dark teas. The precursors and the synthetic mechanism involved in the formation of FBRFAs are not known. Using a unique solid-state fermentation system with ß-cyclodextrin inclusion complexation as well as targeted chromatographic isolation, spectroscopic identification, and Feature-based Molecular Networking on the Global Natural Products Social Molecular Networking web platform, we reveal that dihydromyricetin and the FBRFAs, including teadenol A and fuzhuanin A, are derived from epigallocatechin gallate upon exposure to fungal strains isolated from Fuzhuan brick tea. In particular, the strains from subphylum Pezizomycotina were key drivers for these B-/C-ring oxidation transformations. These are the same transformations seen during the fermentation process of dark teas. These discoveries set the stage to enrich dark teas and other food products for these health-promoting constituents.

[Cloning and quantitative expression analysis of GMPP gene from Dendrobium huoshanense].

In order to understand the function of GDP-mannose pyrophosphorylase(GMPP) function and its regulation in polysaccharide biosynthesis mechanism in Dendrobium. D. huoshanense was used to clone GMPP gene. GMPP gene expression in D. huoshanense,D. officinale and D. moniliforme was also determined by qPCR. The results showed that the length of D. huoshanense GMPP gene c DNA sequence is 1 867 bp,containing 1 245 bp open reading frame(ORF),encoding 415 amino acids. Phylogenetic tree analysis showed that D. huoshanense,D. officinale and D. moniliforme are closely related with GMPP taken into consideration. Bioinformatics analysis demonstrated that GMPP sequence similarity among the three species reached as high as 99%. qPCR results indicated that GMPP genes was highly expressed in stem of D. huoshanense compared with its leaf,flower and root. According to GMPP gene expression profile in D. huoshanense,D. officinale and D. moniliforme grown in Huoshan area,it was clear that GMPP in D. huoshanense showed the highest expression level. Furthermore,our findings of GMPP gene expression profile will facilitate future researches into its polysaccharide biosynthetic mechanism.

Abiotic and biotic controls on dynamics of labile phosphorus fractions in calcareous soils under agricultural cultivation.

Soil labile inorganic and organic phosphorus (L-Pi and L-Po) extracted by NaHCO3 are potentially important sources of plant-available P. Their availability is strongly affected by soil physiochemical and biological properties. Here we conducted a field study in an arid region of northwestern China to investigate how L-Pi and L-Po dynamics are affected by changes in physiochemical and biological variables caused by agricultural cultivation of calcareous soils. Topsoils were sampled at multiple sites from natural calcareous grasslands and cultivated farmlands of different ages (32-40 vs. 90-100 years) that had been converted from natural grasslands. We measured L-Pi and L-Po concentrations and a set of key physiochemical (soil pH, concentrations of base cations (K+ + Na+ + Ca2+ + Mg2+), acid anions (Cl- + NO3- + SO42-), nitrate and ammonium nitrogen (N), organic carbon, and total P) and biological (soil microbial biomass carbon (Cmic), alkaline phosphatase activity (Aalp), and abundances of soil macroinvertebrates (Amacro) and mesoinvertebrates (Ameso)) variables. The concentration of L-Pi and L-Po was 484% and 128% higher and their proportion in the total P content was 354% and 78% higher in young farmland soils, whereas L-Pi and L-Po concentrations were 583% and 423% higher and their proportions were 353% and 240% higher in old farmland soils compared to grassland soils. Increases in L-Pi and L-Po attributable to soil P release may be driven by crucial processes of soil acidification-induced phosphate dissolution and soil biota-driven Po mineralisation. Path analyses revealed that L-Pi and L-Po dynamics were shaped by the complex interactions among five key controlling factors, soil pH, nitrate-N, Ameso, Cmic, and Aalp, involved in these crucial processes. We conclude that cultivation of calcareous soils significantly increases the availability of L-Pi and L-Po, emphasizing the importance of this land-use change as a regulator of P cycling in calcareous soils.

The identification and isolation of anti-inflammatory ingredients of ethno medicine Breynia fruticosa.

ETHNOPHARMACOLOGICAL RELEVANCE: Breynia fruticosa is a folk medicine in China, traditionally used to treat gastroenteritis, sore throat, eczema and arthritis. However, the bioactive ingredients are unknown. AIM OF THE STUDY: To identify and isolate the anti-inflammatory ingredients of B. fruticosa. MATERIALS AND METHODS: B. fruticosa extracts were fractioned by Amberchrom CG161M and Toyopearl HW40C resins. Acetic acid-induced capillary permeability mice model was used to evaluate the anti-inflammation activities of fractions. The anti-inflammatory ingredients were identified by high performance liquid chromatography/mass spectroscopy (HPLC-MS). On-line two dimensional liquid chromatography system was constructed to remove the tannins and enrich the breynins. The breynins were purified by preparative HPLC and evaluated for their anti-arthritis activities using complete Freund's adjuvant (CFA) induced arthritis rats model. RESULTS: The anti-inflammatory ingredients of B. fruticosa are sulfur containing sesquiterpenoids (breynins). The on-line two dimensional preparative liquid chromatography system can effectively remove the tannins and enrich the bioactive ingredients in large scale within 1 h. Four major breynins were purified, and their structures were elucidated by analysis of MS and NMR data. Breynins can significantly prevent the rats' arthritis deterioration, with inhibition ratio 50% at dose 0.2 mg kg-1, comparable with that of indomethacin at dose 2 mg kg-1. CONCLUSION: The breynins have strong anti-arthritis activities, which is responsible to the anti-inflammatory effects of B. fruticosa. However, breynins are also toxic components of B. fruticosa.

Implementation intention training for prospective memory in schizophrenia: A 3-month follow-up study.

The beneficial effect of implementation intentions (II) on prospective memory (PM) deficits in patients with schizophrenia has been reported. However, these studies were limited to brief interventions such that the transfer and long-term effects of II training remains unclear. This study examined whether a 10-session II programme could improve PM performance, social functioning and functional capacity in patients with schizophrenia immediately after training and at 3-month follow-up. Patients with schizophrenia (n = 42) recruited from the community were randomly assigned to II training (n = 21) or treatment as usual (TAU) (n = 21). Participants in the II group learned the verbal and imagery component of II and were encouraged to apply these strategies in their daily lives. We found that the II group performed better than the TAU group on computer-based PM tasks and a daily life PM task (telephone call at specified date and time) at post-treatment and at 3-month follow-up. The II group also exhibited better working ability than the TAU group at post-treatment. Our results suggest that the II intervention programme may have lasting beneficial effects in PM performance and significant transfer effects to functional capacity in schizophrenia patients.

Isolation and Purification of Condensed Tannin from the Leaves and Branches of Prunus cerasifera and Its Structure and Bioactivities.

Prunus cerasifera has a rich resource and a weak utilization rate and its biological functions have been investigated. We found that the contents of total phenol (TP) in leaves and branches of Prunus cerasifera were 117.8 ± 8.8 and 100.04 ± 0.9 mg/g, respectively; the contents of soluble condensed tannin (SCT) were 73.95 ± 0.9 and 78.65 ± 4.1 mg/g, respectively; the structure of SCT containing afzelechin/epiafzelechin, catechin/epicatechin, and atechin/epicatechin as the main units and the SCT from leaves and branches exhibited better anti-tyrosinase and antioxidant activities. This study could clarify Prunus cerasifera condensed tannin resource availability and lay a theoretical foundation for its development as a natural antioxidant and tyrosinase inhibitor.