Gonadotropin-releasing hormone agonist induces downregulation of tensin 1 in women with endometriosis.

INTRODUCTION: Many cell migration-related molecules are associated with endometriosis. Tensin 1 (TNS1), which has been implicated in cell migration, may play a role in endometriosis. The study goal was to evaluate the TNS1 expression in endometrial tissue and serum from women with endometriosis treated with gonadotropin-releasing hormone agonist (GnRHa). MATERIAL AND METHODS: Tissue and serum samples were collected from women with endometriosis who were treated (n = 29) with GnRHa or untreated (n = 30). TNS1 mRNA was examined using quantitative PCR. TNS1 protein levels in tissue and serum samples were investigated using Western blot, immunohistochemistry and ELISA. Eleven women with endometriosis participated in a follow-up investigation of serum TNS1 before and after GnRHa treatment. RESULTS: TNS1 mRNA (P = 0.006) and protein (P = 0.001) were significantly downregulated in endometriotic tissue from women with endometriosis who received GnRHa. Immunolocalization of TNS1 showed strong expression in the epithelial and stromal cells of endometriotic tissue from women untreated with GnRHa, whereas endometriotic tissue from GnRHa-treated women showed low TNS1 expression. Follow-up monitoring of serum TNS1 concentration in 11 women showed an average decrease in concentration of 53%, from 294.9 ± 66.69 to 140.3 ± 55.21 pg/mL, following GnRHa treatment (P = 0.003). CONCLUSIONS: GnRHa induces downregulation of TNS1 in tissue and serum in women with endometriosis. These results emphasize the importance TNS1 as a potential therapeutic molecular target for the treatment of endometriosis with GnRHa.

Decreased Level of Neurotrophic Factor Neuritin 1 in Women with Ovarian Endometriosis after Receiving Gonadotropin-Releasing Hormone Agonist Treatment.

This study aimed to investigate the effect of gonadotropin-releasing hormone agonist (GnRHa) treatment on the expression of neuritin 1 (NRN1) in women with ovarian endometriosis. We collected tissues and serum from women with endometriosis treated with (n = 45) or without (n = 37) GnRHa. NRN1 mRNA and protein levels were measured using qPCR and Western blot. Immunolocalization of NRN1 in endometriotic tissues was examined using immunohistochemistry. In addition, a follow-up study was carried out to monitor the serum level of NRN1 in patients before and after GnRHa treatment. Both mRNA (p = 0.046) and protein (p = 0.0155) levels of NRN1 were significantly lower in endometriotic tissues from patients receiving GnRHa treatment compared to the untreated group. Both epithelial and stromal cells of endometriotic tissues from untreated women with endometriosis exhibited stronger staining of NRN1 but not in those who were treated with GnRHa. The follow-up study showed that the serum level of the NRN1 concentration decreased significantly from 1149 ± 192.3 to 379.2 ± 80.16 pg/mL after GnRHa treatment (p = 0.0098). The expression of NRN1 was significantly lower in women with ovarian endometriosis treated with GnRHa. These results suggest that NRN1 may be a biomarker response to the effect of GnRHa treatment for patients with ovarian endometriosis.

Mesenchymal stem cells promote formation of colorectal tumors in mice.

BACKGROUND & AIMS: Tumor-initiating cells are a subset of tumor cells with the ability to form new tumors; however, they account for less than 0.001% of the cells in colorectal or other types of tumors. Mesenchymal stem cells (MSCs) integrate into the colorectal tumor stroma; we investigated their involvement in tumor initiation. METHODS: Human colorectal cancer cells, MSCs, and a mixture of both cell types were injected subcutaneously into immunodeficient mice. We compared the ability of each injection to form tumors and investigated the signaling pathway involved in tumor initiation. RESULTS: A small number (≤ 10) of unsorted, CD133⁻, CD166⁻, epithelial cell adhesion molecule⁻(EpCAM⁻), or CD133⁻/CD166⁻/EpCAM⁻ colorectal cancer cells, when mixed with otherwise nontumorigenic MSCs, formed tumors in mice. Secretion of interleukin (IL)-6 by MSCs increased the expression of CD133 and activation of Janus kinase 2-signal transducer and activator of transcription 3 (STAT3) in the cancer cells, and promoted sphere and tumor formation. An antibody against IL-6 or lentiviral-mediated transduction of an interfering RNA against IL-6 in MSCs or STAT3 in cancer cells prevented the ability of MSCs to promote sphere formation and tumor initiation. CONCLUSIONS: IL-6, secreted by MSCs, signals through STAT3 to increase the numbers of colorectal tumor-initiating cells and promote tumor formation. Reagents developed to disrupt this process might be developed to treat patients with colorectal cancer.

Phytochemical-rich vegetable and fruit juice alleviates oral mucositis during concurrent chemoradiotherapy in patients with locally advanced head and neck cancer.

Background: Concurrent chemoradiotherapy (CCRT)-induced oral mucositis (OM) causes oral pain, malnutrition, and impaired quality of life in patients with head and neck cancer (HNC). Phytochemicals play a potential role in eliminating cancer therapy toxicity. Objective: To evaluate the effect of phytochemical-rich vegetable and fruit juice (VFJ) consumption in preventing CCRT-induced OM among patients with locally advanced HNC. Methods: Forty-nine patients with HNC undergoing CCRT were enrolled. All patients received nutritional counseling before CCRT and weekly follow-up. The VFJ group (25 patients) received 600 mL/day VFJ, 5 days/week for two weeks preceding CCRT and during CCRT, and the control group (24 patients) did not. The contents of total polyphenols and carotenoids in the VFJ were determined. Changes in anthropometric, dietary, and laboratory profiles were compared. Assessment of OM was based on the World Health Organization (WHO) scoring system. Results: Total polyphenols content was 64.6 mg gallic acid equivalents per 100 mL of the VFJ, and the main carotenoids were ß-carotene and lycopene. The mean daily consumption of the VFJ was 538 mL for VFJ group. Changes in body weight, albumin, and energy intake were not significantly different between the two groups. The incidence of ulcerative OM was significantly lower in VFJ (64.0%) than in control (95.8%) subjects at week 6 of CCRT. Multiple logistic regressions revealed that VFJ consumption correlated significantly with lower risks of ulcerative OM. Conclusion: Consumption of VFJ rich in phytochemicals including total polyphenols and carotenoids effectively alleviates the severity of CCRT-induced OM among patients with locally advanced HNC. Section: Preventive Medicine; Dietary Therapy/Nutrition Supplements. Taxonomy: (classification by EVISE)Preventive medicine, dietary therapy, nutrition supplements.

Application of masticatory control in dental treatment for elderly individuals.

Taiwan transitioned to an aged society in 2018. Appropriate dental treatment is important for elderly individuals. Previously, reconstruction of the dentition was thought to help regain chewing function. However, concerns of the elderly population, such as decline in learning ability and saliva secretion, complicate dental reconstruction. Overlooking the special needs of elderly individuals may lead to impaired chewing function, resulting in nutritional imbalances and increased burden on the digestive tract, causing more health disorders. For the elderly population, treatment must be aimed at restoring as much chewing function as possible with minimal changes. Additionally, regular oral hygiene care, proper design of fixed partial dentures, and implant placement greatly reduce the difficulty in adapting to a new prosthesis. These measures allow us to provide better quality of life for elderly individuals.

Diallyl disulfide and diallyl trisulfide suppress oxidized LDL-induced vascular cell adhesion molecule and E-selectin expression through protein kinase A- and B-dependent signaling pathways.

Uptake of oxidized LDL (ox-LDL) by vascular endothelial cells is a critical step in the initiation and development of atherosclerosis. Adhesion molecules are upregulated by ox-LDL and numerous inflammatory cytokines and play a pivotal role in atherogenesis. In this study, we examined whether diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), 3 major organosulfur compounds of garlic oil, reduce adhesion molecule expression induced by ox-LDL and, if so, through what mechanism. Human umbilical vein endothelial cells were preincubated with 1 mmol/L DAS, 200 mumol/L DADS, or 100 mumol/L DATS for 16 h and then with 40 mg/L ox-LDL for an additional 24 h. ox-LDL induction of cellular and cell surface expression of E-selectin and vascular cell adhesion molecule (VCAM)-1 was suppressed by garlic allyl sulfides in the order DATS > DADS > DAS. The adhesion of HL-60 cells to endothelial cells was inhibited 27 and 33% and the production of cellular peroxides was inhibited 43 and 50% by DADS and DATS, respectively (P < 0.05). ox-LDL alone dephosphorylated protein kinase B (PKB) and cAMP responsive element binding protein (CREB); such deactivation was reversed by DADS and DATS. Electrophoretic mobility shift assay showed that the activation of CREB binding to DNA was consistent with changes in CREB phosphorylation. The protein kinase A (PKA) inhibitor H89 reversed the suppression of VCAM-1 by DADS and DATS, but the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin had no effect. In contrast, wortmannin abolished DADS- and DATS-induced suppression of ox-LDL-induced E-selectin expression. These results suggest that the suppression of ox-LDL-induced E-selectin and VCAM-1 expression by DADS and DATS and, thus, monocyte adhesion to endothelial cells is likely dependent on the PI3K/PKB or PKA/CREB signaling pathway in an adhesion molecule-specific manner. To our knowledge, this is the first report that garlic modulates ox-LDL-mediated leukocyte adhesion to human endothelial cells through the PKB and PKA pathways.

Effects of apomorphine on the expression of learned helplessness behavior.

Dopaminergic system and its D1 as well as D2 receptors are involved in the modulation of emotional behavior. This experiment investigated the role of dopaminergic activity in the inescapable stress-induced learned helplessness, a widely used depression animal model, by using the pharmacological manipulation through the apomorphine (APO), an agonist for D1 and D2 receptors, and sulpiride (SUL), a selective D2 antagonist. Male Sprague Dawley rats were used and tested in a shuttle box. In the day-1 session, the rats received a 10-trial (1 min/trial) inescapable stressor: a 3 sec conditioned stimulus (CS; 75 db sound and 250 lux red light) followed by a 10 sec unconditioned stimulus (UCS; electrical foot shock, 0.5 mA). In the day-2 session, a 15-trial active avoidance test, 3 sec CS followed by UCS, was performed 30 min after the administration of APO (0, 0.05, 0.5, 1, and 5 mg/kg, i.p.). The number of failures was counted and the UCS was stopped when the rats did not escape after 15 sec UCS. The results showed that APO at the dosage of 0.5 mg/kg had a tendency to enhance the avoidance behavior. In contrast, the treatment of higher dose of APO, 1 and 5 mg/kg, reduced the number of escape but increased the number of failure. Pretreatment of SUL (5 mg/kg, i.p.), 10 min before 1 mg/kg of APO, significantly enhanced the failure behavior. The present data suggest that the activity of D2 receptor may be associated with the adaptive or protective role in the prevention of escape deficits after exposure to inescapable stress. However, the excessive stimulation of D1 receptor may participate in the failure of coping behavior leading to learned helplessness and therefore in the pathophysiological mechanisms underling the development of depression.

DATS reduces LPS-induced iNOS expression, NO production, oxidative stress, and NF-kappaB activation in RAW 264.7 macrophages.

Diallyl trisulfide (DATS), diallyl sulfide (DAS), and diallyl disulfide (DADS) are the three major organosulfur compounds (OSCs) in garlic oil. In contrast to DADS and DATS, evidence of an anti-inflammatory effect of DATS is limited. In this study compares the efficacy of DATS with those of DAS and DADS on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in RAW 264.7 macrophages. The NO production in LPS-activated RAW 264.7 macrophages was suppressed by both DADS and DATS in a dose-dependent manner. At 100 muM, the nitrite levels of DADS- and DATS-treated cells were 57 and 34%, respectively, of cells treated with LPS alone. DAS, however, had no influence on NO production even at a concentration of 1 mM. Western blot and Northern blot assays showed that DADS and DATS but not DAS dose-dependently suppressed LPS-induced iNOS protein and mRNA expression in a pattern similar to that noted for NO production. LPS-induced cellular peroxide production was significantly inhibited by DADS and DATS (P < 0.05) but not by DAS. Electrophoresis mobility shift assays further indicated that DADS and DATS effectively inhibited the activation of NF-kappaB induced by LPS. Taken together, these results indicate that the differential efficacy of three major OSCs of garlic oil on suppression of iNOS expression and NO production is related to the number of sulfur atoms and is in the order DATS > DADS > DAS. The inhibitory effect of DATS on LPS-induced iNOS expression is likely attributed to its antioxidant potential to inhibit NF-kappaB activation.

The protective role of carotenoids and polyphenols in patients with head and neck cancer.

Head and neck cancer is a critical global health problem and approximately 650,000 patients per year are diagnosed with this type of cancer. In addition, head and neck cancer exhibits a high recurrence rate, readily causing second primary cancers in other locations, often yielding a poor prognosis. Current medical and surgical treatment options result in considerable impairment of speaking and swallowing functions, with side effects such as nausea, vomiting, bone marrow suppression, and renal damage, thereby impairing patients' quality of life. Thus, developing a prevention and therapeutic intervention strategy for head and neck cancer is vital. Phytochemicals have been shown to have a unique ability to protect cells from damage and modulation of cell repair. The chemopreventive activities of phytochemicals have also been demonstrated to be associated with their antioxidant properties and the induction and stimulation of intercellular communication via gap junctions, which play a role in the regulation of cancer cell cycle, differentiation, apoptosis, and stagnate cancer cell growth. Phytochemicals can also regulate cancer cell signaling pathways, reduce the invasion and metastasis of cancer cells, and protect normal cells during treatment, thus reducing the damage caused by chemotherapy and radiotherapy. The most studied of the chemopreventive effects of phytochemicals are the carotenoids and phenolics. In this review, we investigated the multiple mechanisms of carotenoids and polyphenols (PPs) for use in preventing head and neck cancer, reducing the side effects of chemotherapy and radiotherapy, improving patient survival rates, and reducing the occurrence rate of second primary cancers.

Effects of periodontal therapy on metabolic control in patients with type 2 diabetes mellitus and periodontal disease: a meta-analysis.

Epidemiologic studies have reported increased incidence, prevalence and acuity of periodontitis in adults with diabetes and some have also suggested that treating periodontal disease may improve glycemic control in diabetic patients. This meta-analysis was conducted to evaluate the effects of different periodontal therapies on metabolic control in patients with type 2 diabetes mellitus (T2DM) and periodontal disease. We searched the Medline, EMBASE and Cochrane Library (Central) databases up to January 2014 for relevant studies pertaining to periodontal treatments and glycemic control in adults with T2DM. The search terms were periodontal treatment/periodontal therapy, diabetes/diabetes mellitus, periodontitis/periodontal and glycemic control. The primary outcome measure taken from the included studies was glycated hemoglobin (HbA1c). We compared differences in patients' pre- and post-intervention HbA1c results between a treatment group receiving scaling and root planing (SRP) combined with administration of oral doxycycline (n=71) and controls receiving SRP alone or SRP plus placebo (n=72). Meta-analysis was performed using Comprehensive Meta Analysis software. Nineteen randomized controlled trials (RCTs) were identified. Four trials involving a total of 143 patients with T2DM and periodontal disease were determined to be eligible for analysis. Data of 1 study were not retained for meta-analysis because HbA1c results were recorded as median with IQR. Meta-analysis of the included 3 studies revealed no significant differences in HbA1c results between the periodontal treatment group (n=71) and control group (n=72) (HbA1c SMD=-0.238, 95% CI=-0.616 to 0.140; P=0.217). Systemic doxycycline added to SRP does not significantly improve metabolic control in patients with T2DM and chronic periodontitis. Current evidence is insufficient to support a significant association between periodontal therapy and metabolic control in this patient population. However, evidence suggests that periodontal therapy itself improves metabolic control and reinforces that T2DM is a risk factor for periodontitis.

Roles of autophagy in MPP+-induced neurotoxicity in vivo: the involvement of mitochondria and α-synuclein aggregation.

Macroautophagy (also known as autophagy) is an intracellular self-eating mechanism and has been proposed as both neuroprotective and neurodestructive in the central nervous system (CNS) neurodegenerative diseases. In the present study, the role of autophagy involving mitochondria and α-synuclein was investigated in MPP+ (1-methyl-4-phenylpyridinium)-induced oxidative injury in chloral hydrate-anesthetized rats in vivo. The oxidative mechanism underlying MPP+-induced neurotoxicity was identified by elevated lipid peroxidation and heme oxygenase-1 levels, a redox-regulated protein in MPP+-infused substantia nigra (SN). At the same time, MPP+ significantly increased LC3-II levels, a hallmark protein of autophagy. To block MPP+-induced autophagy in rat brain, Atg7siRNA was intranigrally infused 4 d prior to MPP+ infusion. Western blot assay showed that in vivo Atg7siRNA transfection not only reduced Atg7 levels in the MPP+-infused SN but attenuated MPP+-induced elevation in LC3-II levels, activation of caspase 9 and reduction in tyrosine hydroxylase levels, indicating that autophagy is pro-death. The immunostaining study demonstrated co-localization of LC3 and succinate dehydrogenase (a mitochondrial complex II) as well as LC3 and α-synuclein, suggesting that autophagy may engulf mitochondria and α-synuclein. Indeed, in vivo Atg7siRNA transfection mitigated MPP+-induced reduction in cytochrome c oxidase. In addition, MPP+-induced autophagy differentially altered the α-synuclein aggregates in the infused SN. In conclusion, autophagy plays a prodeath role in the MPP+-induced oxidative injury by sequestering mitochondria in the rat brain. Moreover, our data suggest that the benefits of autophagy depend on the levels of α-synuclein aggregates in the nigrostriatal dopaminergic system of the rat brain.

Neuroprotective effects of longan ( Dimocarpus longan Lour.) flower water extract on MPP+-induced neurotoxicity in rat brain.

In this study, the neuroprotective effect of Dimocarpus longan Lour. flower water extract (LFWE) was investigated. First, an in vitro study showed that LFWE concentration-dependently inhibited lipid peroxidation of brain homogenates incubated at 37 °C. The antioxidative activity of LFWE was more potent than that of glutathione or Trolox. Furthermore, an ex vivo study found that the basal lipid peroxidation (0 °C) and lipid peroxidation incubated at 37 °C were lower in the brain homogenates of LFWE-treated (500 mg/day) rats, indicating that the brain of LFWE-treated rats was more resistant to oxidative stress. Moreover, a Parkinsonian animal model was employed to demonstrate that oral administration of LFWE (125-500 mg/kg/day) dose-dependently attenuated 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in the nigrostriatal dopaminergic system of rat brain. In conclusion, this study suggests that LFWE is antioxidative, anti-inflammatory, and anti-apoptotic. Furthermore, oral administration of LFWE appears to be useful in preventing and/or treating central nervous system neurodegenerative diseases, including Parkinsonism.

Diallyl disulfide and diallyl trisulfide protect endothelial nitric oxide synthase against damage by oxidized low-density lipoprotein.

Garlic is viewed as an effective health food against atherosclerosis. In this study, we examined whether diallyl disulfide (DADS) and diallyl trisulfide (DATS) protect endothelial nitric oxide synthase (eNOS) activation against oxidized LDL (ox-LDL) insult and through what mechanism. We found that DADS and DATS reversed the suppression of eNOS Ser1177 phosphorylation by ox-LDL, and wortmannin abolished the reversal by DADS and DATS. Similarly, the inhibition of cellular cGMP and nitric oxide production by ox-LDL was reversed by DADS and DATS (p<0.05). This increase in nitric oxide bioavailability by the allyl sulfides was attenuated by wortmannin. Immunoprecipitation assay revealed that DADS and DATS preserved the interaction of eNOS with caveolin-1 in the membrane. In addition, DADS and DATS suppressed the reduction of the cellular eNOS protein content by ox-LDL. When cycloheximide was added to block protein synthesis, DADS and DATS suppressed eNOS protein degradation similarly to that noted by MG132. Ox-LDL increased chymotrypsin-like proteasome activity, and this increase was inhibited by the allyl sulfides and MG132 (p<0.05). These results suggest that DADS and DATS protect eNOS activity against ox-LDL insult. This protection can be attributed partly to their mediation of phosphatidylinositol 3-kinase/protein kinase B signaling and prevention of eNOS degradation.

Chrysanthemum morifolium Ramat. reduces the oxidized LDL-induced expression of intercellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The flower of Chrysanthemum morifolium Ramat. (CM) with antioxidant, cardiovascular protective and anti-inflammatory functions, has been widely used in China for hundreds of years as a healthy beverage and medicine. AIMS OF THE STUDY: The purpose of the present study is to investigate the effects of HCM (a hot water extract of the flower of Chrysanthemum morifolium Ramat. [CM]), ECM (an ethanol extract of CM), and the abundant flavonoids apigenin and luteolin in CM on the oxidized LDL (oxLDL)-induced expression of ICAM-1 and E-selectin in human umbilical vein endothelial cells (HUVECs). The possible mechanism of these effects was also determined. MATERIALS AND METHODS: MTT assay was for cell viability. Western blot was used for ICAM-1 and E-selection protein expression, and for activation of protein kinase B (PKB) and cAMP responsive element binding protein (CREB) proteins. Fluorescence flow cytometry was for ICAM-1 and E-selectin expression on cell surface. DCF-DA flow cytometric assay was used for reactive oxygen species (ROS) production. RESULTS: HCM, ECM, apigenin, and luteolin dose-dependently inhibited ICAM-1 and E-selectin expression and adhesion of HL-60 by oxLDL. HCM, ECM, apigenin, and luteolin reversed the inhibition of phosphorylation of Akt and CREB by oxLDL; however, this reversion was abolished by wortmannin. In addition, wortmannin abrogated the inhibitory effects of CM extracts, apigenin and luteolin on adhesion molecule expression. The ROS scavenging capability of HCM, ECM, apigenin, and luteolin proceeded dose-dependently in the presence of oxLDL. CONCLUSION: CM is a plant with cardiovascular-protective potential and the inhibitory effects of CM on ICAM-1 and E-selectin expression are, at least partially, attributed to its antioxidant activity and modulation of the PI3K/Akt signaling pathway.