Long-term di-(2-ethylhexyl) phthalate exposure reduces sorafenib treatment efficacy by enhancing mesenchymal transition in hepatocellular carcinoma.

Di(2-ethylhexyl) phthalate (DEHP) is a worldwide common plasticizer. Nevertheless, DEHP is easily leached out to the environment due to the lack of covalent bonds with plastic. High dose of DEHP exposure is often observed in hemodialysis patients because of the continual usage of plastic medical devices. Although the liver is the major organ that catabolizes DEHP, the impact of long-term DEHP exposure on the sensitivity of liver cancer to chemotherapy remains unclear. In this study, we established long-term DEHP-exposed hepatocellular carcinoma (HCC) cells and two NOD/SCID mice models to investigate the effects and the underlying mechanisms of long-term DEHP exposure on chemosensitivity of HCC. The results showed long-term DEHP exposure potentially increased epithelial-mesenchymal transition (EMT) in HCC cells. Next generation sequencing showed that long-term DEHP exposure increased cell adhesion/migratory related genes expression and blunted sorafenib treatment induced genes alterations. Long-term exposure to DEHP reduced the sensitivity of HCC cells to sorafenib-induced anti-migratory effect by enhancing the EMT transcription factors (slug, twist, and ZEB1) and mesenchymal protein (vimentin) expression. In NOD/SCID mice model, we showed that long-term DEHP-exposed HCC cells exhibited higher growth rate. Regarding the anti-HCC effects of sorafenib, subcutaneous HuH7 tumor grew slowly in sorafenib-treated mice. Nonetheless, the anti-tumor growth effect of sorafenib was not observed in long-term DEHP-exposed mice. Higher mesenchymal markers and proliferating cell nuclear antigen (PCNA) expression were found in sorafenib-treated long-term DEHP-exposed mice. In conclusion, long-term DEHP exposure promoted migratory activity in HCC cells and decreased sorafenib sensitivity in tumor-bearing mice.

Inhibition of Polyinosinic-Polycytidylic Acid-Induced Acute Pulmonary Inflammation and NF-κB Activation in Mice by a Banana Plant Extract.

NF-κB activation is pivotal for the excess inflammation causing the critical condition and mortality of respiratory viral infection patients. This study was aimed to evaluate the effect of a banana plant extract (BPE) on suppressing NF-κB activity and acute lung inflammatory responses in mice induced by a synthetic double-stranded RNA viral mimetic, polyinosinic-polycytidylic acid (poly (I:C)). The inflammatory responses were analyzed by immunohistochemistry and HE stains and ELISA. The NF-κB activities were detected by immunohistochemistry in vivo and immunofluorescence and Western blot in vitro. Results showed that BPE significantly decreased influx of immune cells (neutrophils, lymphocytes, and total WBC), markedly suppressed the elevation of pro-inflammatory cytokines and chemokines (IL-6, RANTES, IFN-γ, MCP-1, keratinocyte-derived chemokine, and IL-17), and restored the diminished anti-inflammatory IL-10 in the bronchoalveolar lavage fluid (BALF) of poly (I:C)-stimulated mice. Accordingly, HE staining revealed that BPE treatment alleviated poly (I:C)-induced inflammatory cell infiltration and histopathologic changes in mice lungs. Moreover, immunohistochemical analysis showed that BPE reduced the pulmonary IL-6, CD11b (macrophage marker), and nuclear NF-κB p65 staining intensities, whilst restored that of IL-10 in poly (I:C)-stimulated mice. In vitro, BPE antagonized poly(I:C)-induced elevation of IL-6, nitric oxide, reactive oxygen species, NF-κB p65 signaling, and transient activation of p38 MAPK in human lung epithelial-like A549 cells. Taken together, BPE ameliorated viral mimic poly(I:C)-induced acute pulmonary inflammation in mice, evidenced by reduced inflammatory cell infiltration and regulation of both pro- and anti-inflammatory cytokines. The mechanism of action might closely associate with NF-κB signaling inhibition.

[Clinical efficacy of fire needling combined with cupping therapy on herpes zoster of acute stage and the effect on Th17/Treg cellular immune balance].

OBJECTIVE: To compare the clinical efficacy between the combined therapy of fire needling and cupping, and western medication on herpes zoster of acute stage, as well as the effects on Th17 and Treg cells and inflammatory factors, i.e. IL-10 and IL-17 in the peripheral blood. METHODS: Eighty patients with herpes zoster of acute stage were randomly divided into a combined therapy (fire needling plus cupping) group and a western medication group, 40 cases in each one. In the combined therapy group, the pricking and scattering techniques with fire needle were used at ashi points and Jiaji (EX-B 2) corresponding to the affected spinal segments; afterwards, cupping therapy was delivered. The combined treatment was given once daily. In the western medication group, valaciclovir hydrochloride tablet and vitamin B1 tablet were administered orally. The duration of treatment in each group was 10 days. Before each treatment from day 1 to day 10 and on day 11 , the score of symptoms and physical signs was observed in the two groups separately. Before each treatment from day 1 to day 10 and on day 11, 30, 60, the score of visual analogue scale (VAS) and skin lesion indexes were observed in the two groups. On day 60, the incidence of postherpetic neuralgia was recorded in the two groups. The levels of Th17 and Treg cells, Th17/Treg ratio in the peripheral blood, as well as serum levels of IL-10 and IL-17 were detected before and after treatment in the two groups. The clinical efficacy was compared between the two groups. RESULTS: From day 6 to day 10 during treatment and on day 11, the scores of symptoms and physical signs in the combined therapy group were lower than those of the western medication group (P<0.05, P<0.01). On day 3, day 6 to day 10 during treatment and day 11, day 30, VAS scores in the combined therapy group were lower than those of the western medication group (P<0.05, P<0.01). On day 60, the incidence of postherpetic neuralgia in the combined therapy group was lower compared with that in the western medication group (P<0.05). The blister arresting time and scabbing time in the combined therapy group were shorter than those of the western medication group (P<0.05). After treatment, the level of Th17, and Th17/Treg ratio in the peripheral blood, as well as the serum levels of IL-10 and IL-17 were all lower in comparison with those in the western medication group (P<0.05). The curative and remarkably effective rate was 82.5% (33/40) in the combined therapy group, higher than 62.5% (25/40) in the western medication group (P<0.05). CONCLUSION: The early application of fire needling combined with cupping therapy can effectively treat herpes zoster of acute stage, relieve pain, and reduce the incidence of postherpetic neuralgia, which may be related to reducing the levels of Th17 and Treg cells, and Th17/Treg ratio in the peripheral blood, as well as the serum levels of IL-10 and IL-17 so that the cellular immune balance is modulated.

Rice GA3ox1 modulates pollen starch granule accumulation and pollen wall development.

The rice GA biosynthetic gene OsGA3ox1 has been proposed to regulate pollen development through the gametophytic manner, but cellular characterization of its mutant pollen is lacking. In this study, three heterozygotic biallelic variants, "-3/-19", "-3/-2" and "-3/-10", each containing one null and one 3bp-deletion allele, were obtained by the CRISPR/Cas9 technique for the functional study of OsGA3ox1. The three homozygotes, "-19/-19", "-2/-2" and "-10/-10", derived from heterozygotic variants, did not affect the development of most vegetative and floral organs but showed a significant reduction in seed-setting rate and in pollen viability. Anatomic characterizations of these mutated osga3ox1 pollens revealed defects in starch granule accumulation and pollen wall development. Additional molecular characterization suggests that abnormal pollen development in the osga3ox1 mutants might be linked to the regulation of transcription factors OsGAMYB, OsTDR and OsbHLH142 during late pollen development. In brief, the rice GA3ox1 is a crucial gene that modulates pollen starch granule accumulation and pollen wall development at the gametophytic phase.

ß-HB treatment reverses sorafenib resistance by shifting glycolysis-lactate metabolism in HCC.

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor. Although sorafenib and regorafenib have been approved for first-line and second-line treatment, respectively, of patients with advanced HCC, long-term treatment often results in acquired resistance. Given that glycolysis-mediated lactate production can contribute to drug resistance and impair HCC treatment efficacy, we investigated the effects of ketone body treatment on the metabolic shift in sorafenib-resistant HCC cells. We discovered differential expression of 3-hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) and the ketone body D-ß-hydroxybutyrate (ß-HB) in four sorafenib-resistant HCC cell lines. In sorafenib-resistant HCC cells, lower HMGCS2 and ß-HB levels were correlated with more glycolytic alterations and higher lactate production. ß-HB treatment enhanced pyruvate dehydrogenase (PDH) expression and decreased lactate dehydrogenase (LDHA) expression and lactate production in sorafenib-resistant HCC cells. Additionally, ß-HB combined with sorafenib or regorafenib promoted the antiproliferative and antimigratory abilities of sorafenib-resistant HCC cells by inhibiting the B-raf/mitogen-activated protein kinase pathway and mesenchymal N-cadherin-vimentin axis. Although the in vivo ß-HB administration did not affect tumor growth, the expression of proliferative and glycolytic proteins was inhibited in subcutaneous sorafenib-resistant tumors. In conclusion, exogenous ß-HB treatment can reduce lactate production and reverse sorafenib resistance by inducing a glycolytic shift; it can also synergize with regorafenib for treating sorafenib-resistant HCC.

Survival benefit of sentinel lymph node biopsy in Asian melanoma patients.

Sentinel lymph node biopsy (SLNB) provides important prognostic information for early-stage melanomas. However, statistics regarding the survival comparison between SLNB and nodal observation in Asia, where acral lentiginous melanoma (ALM) predominates, are limited. This study aimed to identify if SLNB offered survival benefits over nodal observation in early-stage melanomas in Taiwan. The retrospective study included 227 patients who met the SLNB criteria according to the National Comprehensive Cancer Network guidelines and were treated at National Taiwan University Hospital from June 1997 to June 2021. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression models. Of the study population, ALM accounted for 73.1%; 161 patients (70.9%) underwent SLNB and 66 patients (29.1%) were under nodal observation. Multivariate analysis showed significantly improved melanoma-specific survival (hazard ratio [HR], 0.6; p = .02) in the SLNB group. Among those who underwent completion lymph node dissection (CLND), the non-sentinel node positivity rate was 44.4%. Immediate CLND resulted in significantly longer melanoma-specific survival and distant-metastasis-free survival (DMFS) compared to nodal observation. (HR, 0.2; p = .01 for melanoma-specific survival. HR, 0.3; p = .046 for DMFS). In conclusion, SLNB may provide survival benefits of cutaneous melanoma over nodal observation in the Taiwanese population.

Acupuncture effect on dumping syndrome in esophagus cancer patients with feeding jejunostomy: A study protocol for a single blind randomized control trial.

INTRODUCTION: Esophagus cancer patients are at risk for malnourishment. Feeding jejunostomy is used in advanced esophagus cancer patients in order to support and supplement the patients' nutrition needs. In dumping syndrome, the food is rapidly introduced into the intestine at a rate that is faster than normal, it is associated with both digestive system and vasoactive symptoms. Dumping syndrome has an association with both esophagus cancer patients and feeding jejunostomy. In the mid and long term, dumping syndrome is an important issue that contributes to the risk of malnourishment in advanced esophagus cancer patients. In recent studies, acupuncture was effective in regulating digestive symptoms. Acupuncture is considered to be a safe intervention, that was previously shown to be effective in treating digestive-related symptoms. METHODS: Sixty advanced esophageal cancer patients post-feeding jejunostomy will be divided into 2 equal groups, an intervention group (n = 30) and a control group (n = 30). Patients in the intervention group will receive acupuncture using the following acupoints: ST36 (Zusanli), ST37 (Shangjuxu), ST39 (Xiajuxu), PC6 (Neiguan), LI4 (Hegu), and Liv 3 (Taichung). Patients in the control group will receive shallow acupuncture on 12 non-acupoints (sham points), 1 cm from the above mention points. Patients and assessors will be blind to trial allocation. Both groups will receive acupuncture twice a week for 6 weeks. The main outcome measurements are: body weight, BMI, Sigstad's score, and the Arts' dumping questionnaire. DISCUSSION: There are no previous studies that have examined the use of acupuncture on patients with dumping syndrome. This single-blind randomized control trial will investigate the effect of acupuncture on dumping syndrome in advanced esophagus cancer patients with feeding jejunostomy. The results will determine if verum acupuncture can affect dumping syndrome and prevent weight loss.

Dietary administration of a postbiotic, heat-killed Pediococcus pentosaceus PP4012 enhances growth performance, immune response and modulates intestinal microbiota of white shrimp, Penaeus vannamei.

The efficacy of postbiotics on the immune-related gene expression and gut microbiota of white shrimp, Penaeus vannamei remains unexplored. A commercial heat-killed postbiotic Pediococcus pentosaceus PP4012 was used to evaluate the growth performance, intestinal morphology, immunological status, and microbial community of white shrimp after dietary administration in this study. White shrimp (0.040 ± 0.003 g) were divided into three treatments; a control, inanimate P. pentosaceus (105 CFU g feed-1) at low concentration (IPL) and inanimate P. pentosaceus (106 CFU g feed-1) at high concentrations (IPH). The diets of IPL and IPH significantly increased final weight, specific growth rate and production compared to the control group. Shrimp fed with IPL and IPH significantly utilized feed more efficiently than those fed the control diet. The IPH treatment significantly lowered the cumulative mortality rate compared to the control and IPL diet following Vibrio parahaemolyticus infection. No significant difference was observed for Vibrio-like and lactic acid bacteria in intestine of shrimp fed with the control diet and the experimental diets. Adding inanimate P. pentosaceus significantly improved immune responses such as lysozyme and phagocytic activity compared to the control group. However, the total hemocyte count, phenoloxidase activity, respiratory burst, and superoxide dismutase activity were not significantly different among treatments. The immune-related genes alf, pen3a, and pen4 expression were significantly higher in shrimp fed IPL diet compared with control and IPH. Taxonomic identification of bacterial genera in all dietary groups belonged to two predominant phyla, Proteobacteria and Bacteroidota. An abundance of Photobacterium, Motilimonas, Litorilituus, and Firmicutes bacterium ZOR0006 were identified in the intestine of shrimp fed postbiotic diets. Unique microbes such as Cohaesibacter was discovered in the shrimp fed IPL while Candidatus Campbellbacteria, uncultured Verrucomicrobium DEV114 and Paenalcaligenes were discovered in the intestines of shrimp fed IPH diet. Collectively, these data suggest that including heat-killed P. pentosaceus, particularly IPH, can enhance growth performance, promote microbial diversity, elevate immune responses, and increase shrimp's resistance to V. parahaemolyticus.

Anti-inflammaging effects of vitamin D in human gingival fibroblasts with advanced glycation end product stimulation.

Background/purpose: :Both periodontal disease and diabetes mellitus (DM) are long-term inflammatory disorders that are highly prevalent and have a significant health impact. Inflammaging, a state of pre-aging and hyperinflammatory state has been acknowledged for its role in DM patients to have heightened risk of periodontitis. Numerous evidences revealed that inflammaging contributed by cell senescence, acceleration of inflammation and oxidative stress participates in the destruction of periodontium in DM. Abilities of vitamin D in suppressing inflammation and oxidative stress have been revealed in a range of tissues, however in DM's gingival cells, the effect remain undefined. Materials and methods: : Under the stimulation of advanced glycation end-products (AGEs), we assessed the cell proliferation in human gingival fibroblast (HGF), IL-6 and IL-8 secretions, cellular senescence expression and generation of reactive oxygen species (ROS) with or without vitamin D intervention. Following that, we examined the expression of Nrf2 and HO-1 to see if vitamin D was able to modulate the anti-oxidant signaling. A knockdown experiment was then conducted to proof the participation of Nrf2 on the secretion of pro-inflammatory IL-6 and IL-8. Results: : Following the treatment of vitamin D, AGEs-elicited IL-6 and IL-8 production and cell senescence were dose-dependently repressed. Moreover, vitamin D attenuated AGEs-induced ROS in a dose-dependent pattern. Results from qRT-PCR demonstrated vitamin D reversed the suppression of Nrf2 and HO-1 induced by AGEs. Our findings revealed that the anti-inflammatory and anti-oxidant effect in vitamin D was mediated via the upregulation of Nrf2 expression. Conclusion: : These data showed that high levels of AGEs in the gingiva lead to inflammaging reflected by increased pro-inflammatory cytokines, cell senescence expression and oxidative stress. Vitamin D supplementation can reduce oxidative stress and inflammation via the upregulation of Nrf2 signaling and hence, may be a potential approach for treatment of diabetes-associated periodontitis.

Bromelain inhibits the inflammation and senescence effect in diabetic periodontitis: A preliminary in vitro study.

Background/purpose: Diabetes mellitus (DM) is a chronic metabolic disorder that affects millions of people worldwide. A growing evidence suggests that hyperglycemia in DM causes a pre-aging and pro-inflammatory condition known as inflammaging, which increases periodontitis susceptibility. Bromelain has been demonstrated to have anti-inflammatory and anti-aging properties in variety of tissues, but its effects on diabetic periodontitis remain unclear. Thus, the aim of this study is to investigate the its Bromelain's impact in diabetic periodontitis in terms of inflammation and senescence activity. Materials and methods: We assessed the wound healing capacity, production of pro-inflammatory cytokines Interleukin (IL)-6 and IL-8 and senescence marker p16 in human gingival fibroblasts (HGFs) in response to Advanced glycation end-products (AGEs) stimulant, with or without Bromelain treatment. The expression of p65, p-ERK, and p-p38 were also examined to elucidate whether Bromelain's anti-inflammaging activity is mediated through NF-κB and MAPK/ERK signaling pathway. Results: Bromelain concentrations ranging from 2.5 to 20 g/mL had no adverse effect on HGF cell proliferation. Bromelain improved wound healing in HGFs with AGEs stimulation. In addition, Bromelain suppressed the production of pro-inflammatory cytokines IL-6 and IL-8 in HGFs elicited by AGEs. Meanwhile, Bromelain treatment also inhibited the senescence activity and expression of p16 in AGEs-stimulated HGFs. Western blot analysis indicated that the upregulation of p-ERK, p-p38 and p65 induced by AGEs were inhibited by Bromelain in HGFs. Conclusion: These data suggest that excessive AGEs in the gingiva may lead to the accumulation of pro-inflammatory cytokines and marked senescence activity. Bromelain application may be helpful in enhancing wound healing by suppressing inflammaging via downregulation of NF-κB and MAPK/ERK signaling pathways in DM individuals with periodontal disease.

Ameliorative effect of buckwheat polysaccharides on colitis via regulation of the gut microbiota.

Plant polysaccharides act as prebiotics by modulating gut microbiota. However, the functional characteristics of buckwheat Fagopyrum tataricum polysaccharides (FTP) and F. esculentum polysaccharides (FEP) on colitis prevention are not valid. This study evaluated the ameliorative effects of FTP and FEP against TNBS-induced colitis via gut microbiota modulation in rats. The characterizations of FTP and FEP were analyzed, including FTIR, TGA, DSC, and monosaccharide composition. In addition, the pathological features of colon length and symptoms in TNBS-induced colitis were improved via the intragastric preadministration of FTP and FEP. The results showed that prefeeding with FTP and FEP decreased inflammatory cytokines (IL-6, IL-1ß, and TNF-α), ß-glucuronidase, and mucinase, as well as increasing superoxide dismutase, catalase, and glutathione peroxidase levels, in TNBS-induced rats. A decrease in inflammatory signaling-associated proteins (NF-κB, MAPK, COX-2, and iNOS) improved the treatment of TNBS-induced colitis by buckwheat polysaccharides. Moreover, prefeeding with buckwheat polysaccharides increased the Firmicutes/Bacteroidetes ratio and short-chain fatty acid (SCFA) production and decreased the abundance of inflammation-related bacteria (Oscillospiraceae and Oscillibacter). In conclusion, FTP and FEP strongly improved TNBS-induced colitis through antioxidant, anti-inflammatory, and microbiota modulation properties, especially in the high-dose FEP group. Buckwheat polysaccharides have the potential for utilization in functional ingredients or food development.

Inflammatory Milieu Induces Mitochondrial Alterations and Neuronal Activations in Hypothalamic POMC Neurons in a Time-Dependent Manner.

Inflammation has been associated with numerous neurological disorders. Inflammatory environments trigger a series of cellular and physiological alterations in the brain. However, how inflammatory milieu affects neuronal physiology and how neuronal alterations progress in the inflammatory environments are not fully understood. In this study, we examined the effects of pro-inflammatory milieu on mitochondrial functions and neuronal activities in the hypothalamic POMC neurons. Treating mHypoA-POMC/GFP1 with the conditioned medium collected from LPS activated macrophage were employed to mimic the inflammatory milieu during hypothalamic inflammation. After a 24-h treatment, intracellular ROS/RNS levels were elevated, and the antioxidant enzymes were reduced. Mitochondrial respiration and mitochondrial functions, including basal respiratory rate, spared respiration capacity, and maximal respiration, were all significantly compromised by inflammatory milieu. Moreover, pro-inflammatory cytokines altered mitochondrial dynamics in a time-dependent manner, resulting in the elongation of mitochondria in POMC neurons after a 24-h treatment. Additionally, the increase of C-Fos and Pomc genes expression indicated that the neurons were activated upon the stimulation of inflammatory environment. This neuronal activation of were confirmed on the LPS-challenged mice. Collectively, a short-term to midterm exposure to inflammatory milieu stimulated metabolic switch and neuronal activation, whereas chronic exposure triggered the elevation of oxidative stress, the decrease of the mitochondrial respiration, and the alterations of mitochondrial dynamics.

Analysis and identification of phenolic compounds with antiproliferative activity from Chinese olive (Canarium album L.) fruit extract by HPLC-DAD-SPE-TT-NMR.

Chinese olives (Canarium album L.) are rich in phenolic compounds, exhibiting a broad spectrum of potential clinical applications. This study is the first report on the isolation and elucidation of bioactive compounds with high antiproliferative activity from the ethyl acetate fraction of a Chinese olive fruit methanolic extract (CO-EtOAc). We used the WST-1 assay to determine which subfractions of CO-EtOAc had significant antiproliferative activity using the murine colon cancer cell line CT26. Subsequently, the functional compounds were characterized by the hyphenated technique and high-performance liquid chromatography-diode array detector-solid phase extraction-transfer tube-nuclear magnetic resonance (HPLC-DAD-SPE-TT-NMR). Thirteen phenolic constituents were identified from the antiproliferation-enhancing subfractions of CO-EtOAc, including two new compounds, 2,4-didehydrochebulic acid 1,7-dimethyl ester (5) and 1-hydroxybrevifolin (7), which were further purified and found to exhibit marked antiproliferative activity. Chebulic acid dimethyl ester (2), which was isolated from C. album for the first time, also possessed antiproliferative activity.

HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells.

Primary liver cancer is the fifth leading death of cancers in men, and hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancer cases. Sorafenib is a first-line drug for advanced-stage HCC patients. Sorafenib is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis. Despite sorafenib treatment extending survival, some patients experience side effects, and sorafenib resistance does occur. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, ß-hydroxybutyrate (ß-HB) and acetoacetate (AcAc). ß-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment was found to have therapeutic effects against many cancers by causing metabolic alternations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment remains unclear. In this study, we showed that HMGCS2 downregulation enhanced the proliferative ability and attenuated the cytotoxic effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-P38, and p-AKT. In contrast, HMGCS2 overexpression decreased cell proliferation and enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown HMGCS2 exhibited the potential migratory ability, as well as decreasing zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether ketone treatment influences sorafenib sensitivity. We showed that ß-HB pretreatment decreased cell proliferation and enhanced antiproliferative effect of sorafenib in both Huh7 and HepG2 cells. In conclusion, this study defined the impacts of HMGCS2 expression and ketone body treatment on influencing the sorafenib sensitivity of liver cancer cells.

Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis.

5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 µmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.

Molecular Action Mechanism of Coixol from Soft-Shelled Adlay on Tyrosinase: The Future of Cosmetics.

Coix lacryma-jobi var. ma-yuen L. Gramineae is widely cultivated in Taiwan. Literature regarding the molecular action mechanism of coixol on tyrosinase and the application of coicis seed extracts to the processing of facial masks is still lacking. Solvent extractability analysis revealed that most of the polyphenolics in coicis seeds were water soluble (3.17 ± 0.12 to 3.63 ± 0.07 µg/mLGAE). In contrast, the methanolic extract contained the most flavonoids (0.06 ± 0.00~0.26 ± 0.03 µg/mL QE) and coixol (11.43 ± 0.13~12.83 ± 0.14 µg/mL), showing potent antioxidant capability. Additionally, the contents of coixenolide (176.77 ± 5.91 to 238.60 ± 0.21 µg/g), phytosterol (52.45 ± 2.05 to 58.23 ± 1.14 mg/g), and polysaccharides (3.42 ± 0.10 to 4.41 ± 0.10 mg/g) were rather high. The aqueous extract (10 µg/mL) and the ethanolic extract (1 mg/mL) showed no cytotoxicity to B16F10 melanocytes. More attractively, the ethanolic extract at 1 mg/mL caused 48.4% inhibition of tyrosinase activity in B16F10 melanocytes, and 50.7% on human tyrosinase (hTyr) fragment 369-377. Conclusively, the coicis seed extracts containing abundant nutraceuticals with promising anti-hTyr activity and moisturizing capability can serve as good ingredients for facial mask processing.

[Ten-year Trend Analysis of Eutrophication Status and the Related Causes in Lake Hongze].

In order to propose pertinent suggestions regarding eutrophication control for Lake Hongze, we used monthly monitoring data from 2011 to 2020 to elucidate the spatiotemporal changing characteristics of eutrophic status and the relevant driving factors. As the main river entering Lake Hongze, River Huaihe experienced an increase in permanganate index and a decrease in TN in the last 10 years. Meanwhile, Secchi depth, TP, and permanganate index increased, whereas TN and Chl-a concentration decreased significantly in Lake Hongze. As a result, the eutrophic status TLI index of Lake Hongze declined over the past 10 years. The change trend of TLI in Lake Hongze differed spatially. As the main water passage of River Huaihe, the algal biomass was lower in the eastern region than that in the other two lake regions, regardless of the relatively high nutrient concentration, due to the short water retention time. Furthermore, the water quality of River Huaihe improved; thus, the TLI index decreased significantly in the eastern lake region. The northern region had a high coverage of aquatic vegetation, which not only reduced the concentration of water nutrients but also provided a habitat for zooplankton and fish, effectively inhibiting algal growth. Thus, the TLI index was lowest among the three lake areas and showed a downward trend over the last 10 years. In the western region, the algal biomass was the highest due to the intensification of phosphorus release from sediment in summer. Thus, the TLI index was the highest and had not improved in the past 10 years. There were also significant seasonal differences in the TLI of Lake Hongze, which was highest in summer, due to the relatively high algal biomass. Moreover, the algal biomass in summer was mainly affected by the concentration of nitrate. According to the spatiotemporal distribution characteristics of eutrophic status and the impacting factors in Lake Hongze, corresponding measures for eutrophication control should be taken for different seasons and lake areas.

Calycosin suppresses colorectal cancer progression by targeting ERß, upregulating PTEN, and inhibiting PI3K/Akt signal pathway.

High intake of phytoestrogen has been reported to be associated with the prevention of colorectal cancer (CRC). Calycosin belongs to the phytoestrogen that has been shown to suppress CRC cells in our previous study. However, its anticancer activity and molecular mechanisms have not been elucidated. In this study, we analyzed the effect of calycosin on the viability and apoptosis of human CRC HCT116 and SW480 cells via MTT assay, flow cytometry assay, and caspase-3/7 activity assay. The protein expressions of estrogen receptor ß (ERß), PTEN, and PI3K/Akt signal pathways were determined by Western blot analysis. And then, the alterations of biological behavior in CRC cells transfected with ERß siRNA were analyzed. Mouse xenograft models were further performed to detect the antitumor effect in vivo. The results show that calycosin reduces CRC cell viability, induces cell apoptosis, and suppresses xenograft tumor growth. The protein expressions of ERß and PTEN are significantly upregulated following calycosin treatment, whereas p-AKT/AKT ratio and Bcl-2 level are downregulated. Suppressing ERß with siRNA partially attenuates the reduction in viability and apoptosis induced by calycosin. Our results indicate that calycosin shows inhibitory effects on CRC cells, which might be obtained by targeting ERß, upregulating PTEN, and inhibiting the PI3K/Akt signal pathway.

Improvement on blood pressure and skin using roselle drink: A clinical trial.

Roselle (Hibiscus sabdariffa L.) is an increasingly attractive plant for its health and pharmaceutical, beverage, and cosmetic applications. The purpose of this study was to investigate the clinical effects of roselle drink on antioxidant activity, blood pressure, and skin condition. Roselle drink used in this study contained rich phenolics (1.96 g of gallic acid equivalent/100 ml) and anthocyanins (1.65 g of cyanidin-3-glucoside equivalent/100 ml). In a randomized, cross-over, double-blind, placebo-controlled clinical study, 39 healthy adults received drank 200 ml of roselle drink or placebo-control drink for 6 months. A significant reduction in the blood pressure was observed in the roselle drink treated group when compared with preintervention values. After 6 months of treatment with roselle drink, serum phenolics contents, the levels of Trolox equivalent antioxidant capacity (TEAC), glutathione, superoxide dismutase (SOD), glucose-6-phosphate dehydrogenase (G-6-PDH), glutathione peroxidase (GSH-Px), and glutathione reductase (GSH-Rd) were significantly increased in healthy subjects. However, a significant increment in skin redness and skin moisture was observed in the facial skin of roselle drink-treated participants. Oral administration of roselle drink for 6 months significantly lowered the blood pressure, improved antioxidation level, and positively regulated skin redness as well as moisture. Phenolics and anthocyanins in roselle could be the major potential contributors to such health effects. PRACTICAL APPLICATIONS: Roselle is a typical plant. Continuous administration of roselle drink clearly improved antioxidation levels, reduced blood pressure and positively regulated skin redness and moisture. Phenloics and anthocyanins in roselle could be the major potentila contributors of such health benefits.

N-Acetyldopamine Dimer Attenuates DSS-Induced Ulcerative Colitis by Suppressing NF-κB and MAPK Pathways.

Ulcerative Colitis (UC) is a major form of chronic inflammatory bowel disease of the colonic mucosa and exhibits progressive morbidity. There is still a substantial need of small molecules with greater efficacy and safety for UC treatment. Here, we report a N-acetyldopamine dimer (NADD) elucidated (2R,3S)-2-(3',4'-dihydroxyphenyl)-3-acetylamino-7-(N-acetyl-2″-aminoethyl)-1,4-benzodioxane, which is derived from traditional Chinese medicine Isaria cicadae, exhibits significant therapeutic efficacy against dextran sulfate sodium (DSS)-induced UC. Functionally, NADD treatment effectively relieves UC symptoms, including weight loss, colon length shortening, colonic tissue damage and expression of pro-inflammatory factors in pre-clinical models. Mechanistically, NADD treatment significantly inhibits the expression of genes in inflammation related NF-κB and MAPK signaling pathways by transcriptome analysis and western blot, which indicates that NADD inhibits the inflammation in UC might through these two pathways. Overall, this study identifies an effective small molecule for UC therapy.