Determination of Phenolic Content, Antioxidant Activity, and Tyrosinase Inhibitory Effects of Functional Cosmetic Creams Available on the Thailand Market.

Recently, the global trend toward the use of natural extracts and antioxidant agents in the cosmetic cream industry to produce whitening effects has been increasing. This has also been a persistent trend in Thailand. In this study, samples of commercial cosmetic creams on the Thai market were assessed for a functional evaluation of their antioxidant activity, tyrosinase inhibitory effects, and phenolic contents. Samples were extracted using hot water and sonication extraction method to obtain the functional cream extracts. Total phenolic contents in all samples were within the range of 0.46-47.92 mg GAE/30 g cream. Antioxidant activities of the cream extracts were within the range of 3.61-43.98 mg Trolox equivalent/30 g cream, while tyrosinase inhibition activities were within the range of 2.58-97.94% of inhibition. With regard to the relationship between the total phenolic content and the antioxidant activity of the cosmetic creams, Pearson's correlation coefficient revealed a moderately positive relationship with an r value of 0.6108. Furthermore, the relationship between the antioxidant activity and the tyrosinase inhibitory activity of the cosmetic creams was highly positive with an r value of 0.7238. Overall, this study demonstrated that the total phenolic contents in the functional cosmetic creams could play a role in antioxidant activity and anti-tyrosinase activities. The findings indicate how the whitening and antioxidant effects of cosmetic creams could be maintained after the products have been formulated, as this concern can affect the consumer's decision when purchasing cosmetic products.

Skin Wound-Healing Potential of Polysaccharides from Medicinal Mushroom Auricularia auricula-judae (Bull.).

Auricularia auricula-judae, a nutrient-rich mushroom used in traditional medicine, is a macrofungi that exhibits various biological properties. In this study, we have reported on the mechanisms that promote the wound-healing effects of a water-soluble polysaccharide-rich extract obtained from A. auricula-judae (AAP). AAP contained high amounts of polysaccharides (349.83 ± 5.00 mg/g extract) with a molecular weight of 158 kDa. The main sugar composition of AAP includes mannose, galactose, and glucose. AAP displayed antioxidant activity in vitro and was able to abort UVB-induced intracellular ROS production in human fibroblasts in cellulo. AAP significantly promoted both fibroblast and keratinocyte proliferation, migration, and invasion, along with augmentation of the wound-healing process by increasing collagen synthesis and decreasing E-cadherin expression (All p < 0.05). Specifically, the AAP significantly accelerated the wound closure in a mice skin wound-healing model on day 9 (2.5%AAP, p = 0.031 vs. control) and day 12 (1% and 2.5%AAP with p = 0.009 and p < 0.001 vs. control, respectively). Overall, our results indicate that the wound-healing activities of AAP can be applied in an AAP-based product for wound management.

Inhibitory Effect of a Rosmarinic Acid-Enriched Fraction Prepared from Nga-Mon (Perilla frutescens) Seed Meal on Osteoclastogenesis through the RANK Signaling Pathway.

The aim of this study is to determine antioxidant and anti-inflammatory activities relating to the antiosteoporosis effects of various perilla seed meal (PSM) fractions. The remaining waste of perilla seed obtained from cold oil compression was extracted with 70% ethanol and sequentially fractionated according to solvent polarity with hexane, dichloromethane, ethyl acetate, and water. The results indicated that the seed-meal ethyl acetate fraction (SMEF) exhibited the highest antioxidant and anti-inflammatory activities, and rosmarinic acid (RA) content. The signaling pathways induced by the receptor activator of the nuclear factor kappa B (NF-κB) ligand (RANKL) that trigger reactive oxygen species (ROS) and several transcription factors, leading to the induction of osteoclastogenesis, were also investigated. The SMEF clearly showed attenuated RANKL-induced tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts and TRAP activity. A Western blot analysis showed that the SMEF significantly downregulated RANKL-induced NF-κB, AP-1 activation, and the nuclear factor of activated T-cell 1 (NFATc1) expression. SMEF also suppressed RANKL-induced osteoclast-specific marker gene-like MMP-9 using zymography. Furthermore, the SMEF showed inhibition of RANKL-induced ROS production in RAW 264.7 cells. The results suggest that the SMEF, which contained high quantities of RA, could be developed as a natural active pharmaceutical ingredient for osteoclastogenic protection and health promotion.

Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo.

Curcumin (Cur) exhibits biological activities that support its candidacy for cancer treatment. However, there are limitations to its pharmacological effects, such as poor solubility and bioavailability. Notably, the use of Cur analogs has potential for addressing these limitations. Dehydrozingerone (DZG) is a representative of the half-chemical structure of Cur, and many reports have indicated that it is anticancer in vitro. We, therefore, have hypothesized that DZG could inhibit prostate cancer progression both in vitro and in vivo. Results revealed that DZG decreased cell proliferation of rat castration-resistant prostate cancer, PLS10 cells, via induction of the cell cycle arrest in the G1 phase in vitro. In the PLS10 xenograft model, DZG significantly decreased the growth of subcutaneous tumors when compared to the control via the inhibition of cell proliferation and angiogenesis. To prove that DZG could improve the limitations of Cur, an in vivo pharmacokinetic was determined. DZG was detected in the serum at higher concentrations and remained up to 3 h after intraperitoneal injections, which was longer than Cur. DZG also showed superior in vivo tissue distribution than Cur. The results suggest that DZG could be a candidate of the Cur analog that can potentially exert anticancer capabilities in vivo and thereby improve its bioavailability.

Combined Black Rice Germ, Bran Supplement and Exercise Intervention Modulate Aging Biomarkers and Improve Physical Performance and Lower-Body Muscle Strength Parameters in Aging Population.

Aging is a time-dependent functional decline in muscle mass and strength, which is reflected in poor physical performances, hormonal imbalance, and development of chronic low-grade inflammation. This study aimed to assess the effectiveness of black rice germ, bran supplement, and exercise program either alone or in combination for 24 weeks on the aging biomarkers (C-reactive protein, Interleukin-6, Insulin-like growth factor-1, and CD4:CD8 T cell ratio) physical performance, muscle strength parameters (walking speed, sit-to-stand time, grip strength) among Thai aging population. A total of 120 healthy volunteers aged 65-74 years were assigned to the exercise group (EX), black rice germ, and bran supplement (BR) group or the combination of BR and EX group (BR + EX). Over the course of the 24-week intervention, compared with baseline data (T0), the combined BR + EX intervention significantly decreased the inflammatory biomarkers (C-reactive protein and interleukin-6 levels, both p < 0.05 vs. T0) and significantly increased the insulin-like growth factor-1 levels (p < 0.001 vs. T0). Significant improvement in physical performance and muscle strength were also observed in the combined BR + EX group (decrease in sit-to-stand time and gait speed over the 24-week intervention, both p < 0.05 vs. T0, and trend toward grip strength improvement at p = 0.088 vs. T0). Overall, our results indicated a synergistic effect towards the combined intervention with the sustainable improvement in physical performances, lower-body muscle strength, and the modulation of both inflammatory and endocrine biomarkers. This study could encourage older adults to change their lifestyles to improve healthy aging and longevity.

Dicentrine Potentiates TNF-α-Induced Apoptosis and Suppresses Invasion of A549 Lung Adenocarcinoma Cells via Modulation of NF-κB and AP-1 Activation.

Numerous studies have indicated that tumor necrosis factor-alpha (TNF-α) could induce cancer cell survival and metastasis via activation of transcriptional activity of NF-κB and AP-1. Therefore, the inhibition of TNF-α-induced NF-κB and AP-1 activity has been considered in the search for drugs that could effectively treat cancer. Dicentrine, an aporphinic alkaloid, exerts anti-inflammatory and anticancer activities. Therefore, we investigated the effects of dicentrine on TNF-α-induced tumor progression in A549 lung adenocarcinoma cells. Our results demonstrated that dicentrine effectively sensitizes TNF-α-induced apoptosis in A549 cells when compared with dicentrine alone. In addition, dicentrine increases caspase-8, -9, -3, and poly (ADP-ribose) polymerase (PARP) activities by upregulating the death-inducing signaling complex and by inhibiting the expression of antiapoptotic proteins including cIAP2, cFLIP, and Bcl-XL. Furthermore, dicentrine inhibits the TNF-α-induced A549 cells invasion and migration. This inhibition is correlated with the suppression of invasive proteins in the presence of dicentrine. Moreover, dicentrine significantly blockes TNF-α-activated TAK1, p38, JNK, and Akt, leading to reduced levels of the transcriptional activity of NF-κB and AP-1. Taken together, our results suggest that dicentrine could enhance TNF-α-induced A549 cell death by inducing apoptosis and reducing cell invasion due to, at least in part, the suppression of TAK-1, MAPK, Akt, AP-1, and NF-κB signaling pathways.

The Association between Frailty Indicators and Blood-Based Biomarkers in Early-Old Community Dwellers of Thailand.

Thailand has officially reached the status of an "aged society" and become the developing country with the 2nd largest proportion of senior citizens in Southeast Asia. A cross-sectional study of 526 early-old community dwellers was conducted for the Fried frailty phenotype assessment, This included five indicators: Weakness, slowness, physical activity, exhaustion, and weight loss. C-reactive protein (CRP), interleukin-6 (IL-6), insulin-like growth factor-1, and CD4+:CD8+ Ratio which serve as blood-based biomarkers of frailty. The prevalence of frailty and pre-frail in this population was found to be 15% and 69.6% respectively and was higher among women than men. Frail (n = 58) and non-frail (n = 60) participants were evaluated for the associations between the frail indicators and the blood-based biomarkers. Serum levels of IL-6 and CRP from frail group were significantly elevated when compared with the non-frail counterparts (p = 0.044 and 0.033, respectively), and were significantly associated with the frailty status with an Odd RatioIL-6 [OR] of 1.554-fold (95% confidence interval [CI], 1.229-1.966) and an ORCRP of 1.011-fold (95 CI, 1.006-1.016). Decreased hand-grip strength was the only frailty indicator that was significantly associated with both inflammatory biomarkers, (ORIL-6 of 1.470-fold and ORCRP of 1.008-fold). Our study is the first to assess the frailty status among the early-old population in Thailand. These findings will encourage general practitioners to combine frailty indicators and serum biomarkers as early detection tools for at-risk older adults to achieve the goal of healthy aging.

Proanthocyanidin-Rich Fractions from Red Rice Extract Enhance TNF-α-Induced Cell Death and Suppress Invasion of Human Lung Adenocarcinoma Cell A549.

Tumor necrosis factor-alpha (TNF-α) plays a key role in promoting tumor progression, such as stimulation of cell proliferation and metastasis via activation of NF-κB and AP-1. The proanthocyanidin-rich fraction obtained from red rice (PRFR) has been reported for its anti-tumor effects in cancer cells. This study investigated the molecular mechanisms associated with PRFR on cell survival and metastasis of TNF-α-induced A549 human lung adenocarcinoma. Notably, PRFR enhanced TNF-α-induced A549 cell death when compared with PRFP alone and caused a G0-G1 cell cycle arrest. Although, PRFR alone enhanced cell apoptosis, the combination treatment induced the cells that had been enhanced with PRFR and TNF-α to apoptosis that was less than PRFR alone and displayed a partial effect on caspase-8 activation and PARP cleavage. By using the autophagy inhibitor; 3-MA attenuated the effect of how PRFR enhanced TNF-α-induced cell death. This indicates that PRFR not only enhanced TNF-α-induced A549 cell death by apoptotic pathway, but also by induction autophagy. Moreover, PRFR also inhibited TNF-α-induced A549 cell invasion. This effect was associated with PRFR suppressed the TNF-α-induced level of expression for survival, proliferation, and invasive proteins. This was due to reduce of MAPKs, Akt, NF-κB, and AP-1 activation. Taken together, our results suggest that TNF-α-induced A549 cell survival and invasion are attenuated by PRFR through the suppression of the MAPKs, Akt, AP-1, and NF-κB signaling pathways.

Protective Effects of Defatted Sticky Rice Bran Extracts on the Early Stages of Hepatocarcinogenesis in Rats.

Use of natural products is one strategy to lessen cancer incidence. Rice bran, especially from colored rice, contains high antioxidant activity. Cancer chemopreventive effects of hydrophilic purple rice bran extract (PRBE) and white rice bran extract (WRBE) on carcinogen-induced preneoplastic lesion formation in livers of rats were investigated. A 15-week administration of PRBE and WRBE did not induce hepatic glutathione S-transferase placental form (GST-P) positive foci formation as the biomarker of rat hepatocarcinogenesis. PRBE and WRBE at 500 mg/kg body weight significantly decreased number and size of GST-P positive foci in diethylnitrosamine (DEN)-initiated rats. The number of proliferating nuclear antigen positive hepatocytes were also reduced in preneoplastic lesions in both PRBE and WRBE fed DEN-treated rats. Notably, the inhibitory effect on GST-P positive foci formation induced by DEN during the initiation stage was found only in rats treated by PRBE for five weeks. Furthermore, PRBE attenuated the expression of proinflammatory cytokines involving genes including TNF-α, iNOS, and NF-κB. PBRE contained a higher number of anthocyanins and other phenolic compounds and vitamin E. PRBE might protect DEN-induced hepatocarcinogenesis in rats via attenuation of cellular inflammation and cell proliferation. Anthocyanins and other phenolic compounds, as well as vitamin E, might play a role in cancer chemopreventive activity in rice bran extract.

The Proanthocyanidin-Rich Fraction Obtained from Red Rice Germ and Bran Extract Induces HepG2 Hepatocellular Carcinoma Cell Apoptosis.

This study aims to determine the anti-carcinogenic effects of the proanthocyanidin-rich fraction (PRFR) obtained from red rice germ and bran extract on HepG2 cells. The PRFR obtained from red rice germ and bran extract could reduce the cell viability of HepG2 cells as shown by the IC50 value at 20 µg/mL. Notably, PRFR concentrations at 20 and 40 µg/mL significantly increased the number of cells in the G2/M phase from 25.7% ± 1.4%in the control group to 36.2% ± 3.4% (p < 0.01) and 48.9% ± 2.6% (p < 0.0001), respectively, suggesting that the cells were arrested in this phase, which was confirmed by the reduction of survival proteins, including cyclin B1 and cdc25. Moreover, the PRFR at 20 and 40 µg/mL could induce cell death via the apoptosis cascade, indicated by the percentage of total apoptotic cells from 9.9% ± 3.1% in the control group to 41.1 ± 3.9 (p < 0.0001) and 82.2% ± 5.8% (p < 0.0001), respectively. This was clarified by increasing apoptotic proteins (such as cleaved PARP-1, cleaved caspase-8 and cleaved caspase-3) and decreasing anti-apoptotic protein survivin without p53 alterations. These results demonstrated that the PRFR obtained from red rice germ and bran extract could inhibit cell proliferation and induce cell apoptosis in HepG2 cells via survivin, which could potentially serve as a new target for cancer therapeutics making it an excellent "lead candidate" molecule for in vivo proof-of concept studies.

Interleukin-8 associated with chemosensitivity and poor chemotherapeutic response to gastric cancer.

BACKGROUND: Gastric cancer (GC) patients have been found to have developed chemotherapy resistance that has resulted in a lowering of their overall survival rates. Interleukin-6 (IL-6) and interleukin-8 (IL-8) could be responsible as the predictive biomarkers in monitoring drug resistance. We have developed a protocol to monitor drug treatment by testing ex vivo chemosensitivity and cytokine levels of primary gastric cultures obtained from endoscopic biopsies. METHODS: We studied 49 patients with distal GC who underwent primary surgical resection between June 2014 and December 2016 in the northern endemic region of Thailand. The clinical and pathological data of patients were recorded, and the cancer sub-type was classified. The correlation of cytokine IL-6 and IL-8 protein expression levels and chemotherapy sensitivity in primary gastric cultures was investigated. Endoscopic biopsies were collected before and/or after chemotherapy treatment followed by FOLFOXIV regimen (oxaliplatin + 5-FU/leucovorin). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to examine ex vivo chemosensitivity to cisplatin, oxaliplatin, 5-fluorouracil (5-FU) and irinotecan. Enzyme-linked immunosorbent assay (ELISA) was performed to investigate cytokine levels. RESULTS: Ex vivo drug treatment of 49 primary gastric cultures from naive patients revealed a significant correlation between basal levels of IL-8 and chemosensitivity to cisplatin (P=0.001) and oxaliplatin (P=0.001). IL-8 protein expression levels were significantly decreased in the early phase after cisplatin and oxaliplatin treatments leading to an increase in cell sensitivity to drug treatments. Among 49 patients, 11 patients were classified as partial or poor responders after drug interventions, in which case, second endoscopic biopsies were performed for determination of chemosensitivity and cytokine levels. The results demonstrated significant decreases in sensitivity to cisplatin (P=0.049) and oxaliplatin (P=0.014), meanwhile IL-8 protein expression levels were significantly increased by P=0.0423 in both drug treatments. There was no correlation of IL-6 and drug resistance when treatments of the primary gastric cultures involved each of the four chemotherapeutic drugs (P=0.0663). CONCLUSIONS: Upregulation of IL-8 after drug intervention might be useful as predictive biomarker in monitoring drug resistance in GC patients; however, this needs to be confirmed among a larger number of patients and with control groups that are properly age-paired. The established primary gastric culture could serve as a valuable tool for chemotherapy screening, while the repeated usage of platinum drugs may result in drug resistance via upregulation of IL-8 levels.

Cyclohexanone curcumin analogs inhibit the progression of castration-resistant prostate cancer in vitro and in vivo.

Many prostate cancer patients develop resistance to treatment called castration-resistant prostate cancer (CRPC) which is the major cause of recurrence and death. In the present study, four cyclohexanone curcumin analogs were synthesized. Additionally, their anticancer progression activity on CRPC cell lines, PC3 and PLS10 cells, was examined. We first determined their anti-metastasis properties and found that 2,6-bis-(4-hydroxy-3-methoxy-benzylidene)-cyclohexanone (2A) and 2,6-bis-(3,4-dihydroxy-benzylidene)-cyclohexanone (2F) showed higher anti-invasion properties against CRPC cells than curcumin. Analog 2A inhibited both MMP-2 and MMP-9 secretions and activities, whereas analog 2F reduced only MMP activities. These findings suggest that the compounds may inhibit CRPC cell metastasis by decreased extracellular matrix degradation. Analog 2A, the most potent analog, was then subjected to an in vivo study. Similar to curcumin, analog 2A was detectable in the serum of mice at 30 and 60 minutes after i.p. injections. Analog 2A and curcumin (30 mg/kg bodyweight) showed a similar ability to reduce tumor area in lungs of mice that were i.v. injected with PLS10 cells. Additionally, analog 2A showed superior growth inhibitory effect on PLS10 cells than that of curcumin both in vitro and in vivo. The compound inhibited PLS10 cells growth by induction of G1 phase arrest and apoptosis in vitro. Interestingly, analog 2A significantly decreased tumor growth with downregulation of cell proliferation and angiogenesis in PLS10-bearing mice. Taken together, we could summarize that analog 2A showed promising activities in inhibiting CRPC progression both in vitro and in vivo.

A Pharmacological Strategy Using Stemofoline for more Efficacious Chemotherapeutic Treatments Against Human Multidrug Resistant Leukemic Cells

Our previous study reported that stemofoline (STF) exhibited a synergistic effect with chemotherapeutic drugs in human multidrug-resistant (MDR) leukemic cells (K526/Adr) by inhibiting the function of P-glycoprotein, which is a membrane transporter that is overexpressed in several types of MDR cancers. This study further investigated the effects of a combination treatment of STF and doxorubicin (DOX) in vitro and in vivo. The combination treatment of 50 mg/kg of STF strongly enhanced the anti-tumor activity of DOX in SCID-beige mice bearing K562/Adr xenografts without additional toxicity when compared to the single treatment groups. Additionally, an examination of the proliferation markers (Ki67) and the apoptotic marker (TUNEL) in tumor tissues in each group revealed that the combination therapy significantly reduced Ki67 positive cells and increased apoptotic cells. From the in vitro experiments we also found that this combination treatment dramatically induced G1 and G2M arrest in K562/Adr when compared to a single treatment of DOX. STF treatment alone did not show any cytotoxic effect to the cells. These results suggest that the accumulation of DOX enhanced by STF was sufficient to induce cell cycle arrest in K562/Adr. These findings support our previous in vitro data and indicate the possibility of developing STF as an adjuvant therapy in cancer treatments.

O-Methylbulbocapnine and Dicentrine Suppress LPS-Induced Inflammatory Response by Blocking NF-κB and AP-1 Activation through Inhibiting MAPKs and Akt Signaling in RAW264.7 Macrophages.

The natural aporphine alkaloids including crebanine (CN), O-methylbulbocapnine (OMP), and dicentrine (DC), and protoberberine alkaloids, tetrahydropalmatine (THP) and N-methyl tetrahydropalmatine (NTHP), have been found in Stephania venosa. Previous reports demonstrated CN and THP exhibited anti-inflammatory properties. In this study, we investigated anti-inflammatory effect of CN analogs including OMP, DC, THP, and NTHP in RAW264.7 macrophages. The pre-treatment of macrophages with CN, OMP and DC suppressed lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and mediators including interleukin-6 (IL-6), tumor necrosis factor alpha, prostaglandin E2 and nitric oxide, in which the rank-order of inhibitory potency was DC>CN≥OMP. Whereas, high dose THP (30-40 µg/mL) reduced LPS-induced IL-6 production in RAW264.7 cells but NTHP did not effect. Moreover, CN, OMP and DC inhibited the LPS-induced expression of inducible nitric oxide synthase and cyclooxygenase-2. OMP and DC inhibited LPS-induced nuclear factor kappa B (NF-κB) activation by suppressing the phosphorylation of NF-κB at Ser536, but not the nucleus translocation and inhibitor of kappaB (IκB)-α degradation. In addition, OMP and DC also reduced the phosphorylation and nucleus translocation of activator protein-1 (AP-1). Furthermore, OMP and DC suppressed the LPS-activated myeloid differentiation factor 88 (MyD88), Akt and mitogen-activated protein kinases (MAPKs) signaling pathway, which were the upstream signaling regulators of AP-1 and NF-κB. Collectively, OMP and DC have an anti-inflammatory effect on RAW264.7 macrophages by the suppression of pro-inflammatory cytokines and mediators. The inhibitory property of OMP and DC is mediated by blockage the activation of MyD88, MAPKs, Akt, NF-κB and AP-1 signaling molecules.