Effects of Statin and Annatto-extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice.

BACKGROUND/AIM: This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. MATERIALS AND METHODS: Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. RESULTS: Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. CONCLUSION: TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.

Bioactive Compounds for Fibromyalgia-like Symptoms: A Narrative Review and Future Perspectives.

Fibromyalgia (FM) is a prevalent, chronic condition without a cure or reliable therapy. The etiopathogenesis of this syndrome is ambiguous, which has heightened the challenge of discovering treatments to minimize patients' painful symptoms. FM is characterized by diffuse musculoskeletal pain usually accompanied by functional pain syndromes, such as fatigue, sleep disturbances, cognitive difficulties, and mood issues. Currently available treatment options for FM are limited. Recent studies have suggested a potential role for dietary bioactive compounds in FM management. We performed a narrative review to evaluate the existing evidence regarding the dietary bioactive compounds for FM, and we proposed molecular mechanisms on this topic. The inclusion criteria were (i) human, in vivo, or in vitro studies, (ii) studies related to the effect of bioactive compounds on FM-like symptoms, (iii) peer-reviewed literature, and (iv) publications until February 2022 in PubMed and Google Scholar. Exclusion criteria were (i) study designs using CCI, SNI, or SNL models because they are more NP models rather than FM models, and (ii) studies published in a language other than English. Keywords were dietary bioactive compounds, fibromyalgia, cell, animals, humans. Here, we report the effects of commonly consumed bioactive compounds (capsaicin, ginger, curcumin, n-3 PUFA, grape seed extract, naringin, and genistein) on FM-like symptoms in cellular, animal, and human studies. Cellular studies demonstrated that these bioactive compounds reduce pro-inflammatory production and increase antioxidant capacity of neurons or myoblasts that regulate apoptosis/cell survival. Animal studies showed that these regularly consumed bioactive compounds have an effect on FM-like symptoms, as evidenced by decreased pain hypersensitivity and fatigue as well as improved social behaviors. Further studies are warranted to allow meaningful comparison and quantification of the efficacy of these bioactive compounds on FM-like symptoms across studies, in terms of actual changes in antioxidant capacity, pain hypersensitivity, fatigue, and social behaviors. To date, human studies regarding the efficacy of these bioactive compounds on FM-like symptoms are limited and inconclusive. Our review identifies this important knowledge gap and proposes that the development and use of improved preclinical FM models are needed, particularly concerning the usage of female animals to better mimic FM pathophysiology and symptomatology.

Tocotrienol Supplementation Led to Higher Serum Levels of Lysophospholipids but Lower Acylcarnitines in Postmenopausal Women: A Randomized Double-Blinded Placebo-Controlled Clinical Trial.

Osteoporosis is a major health problem in postmenopausal women. Herein we evaluated the effects of 12-week tocotrienols (TT) supplementation on serum metabolites in postmenopausal, osteopenic women. Eighty-nine participants (59.7 ± 6.8 yr, BMI 28.7 ± 5.7 kg/m2) were assigned to 3 treatments: placebo (860 mg olive oil/day), 300mg TT (300 mg TT/day), and 600mg TT (600 mg TT/day) for 12 weeks. TT consisted of 90% δ-TT and 10% γ-TT. In this metabolomic study, we evaluated the placebo and 600mgTT at baseline and 12 weeks. As expected, TT and its metabolite levels were higher in the supplemented group after 12 weeks. At baseline, there were no differences in demographic parameters or comprehensive metabolic panels (CMP). Metabolomics analysis of serum samples revealed that 48 biochemicals were higher and 65 were lower in the 600mg TT group at 12 weeks, compared to baseline. The results confirmed higher serum levels of tocotrienols and lysophospholipids, but lower acylcarnitines and catabolites of tryptophan and steroids in subjects given 600mg TT. In summary, 12-week TT supplementation altered many serum metabolite levels in postmenopausal women. The present study supports our previous findings that TT supplementation helps reduce bone loss in postmenopausal osteopenic women by suppressing inflammation and oxidative stress. Furthermore, the body incorporates TT which restructures biomembranes and modifies phospholipid metabolism, a response potentially linked to reduced inflammation and oxidative stress.

Safety Evaluation of Green Tea Polyphenols Consumption in Middle-aged Ovariectomized Rat Model.

This work evaluates chronic safety in middle-aged ovariectomized rats supplemented with different dosages of green tea polyphenols (GTP) in drinking water. The experiment used 6-mo-old sham (n = 39) and ovariectomized (OVX, n = 143) female rats. All sham (n = 39) and 39 of the OVX animals received no GTP treatment and their samples were collected for outcome measures at baseline, 3 mo, and 6 mo (n = 13 per group for each). The remaining OVX animals were randomized into 4 groups receiving 0.15%, 0.5%, 1%, and 1.5% (n = 26 for each) of GTP (wt/vol), respectively, in drinking water for 3 and 6 mo. No mortality or abnormal treatment-related findings in clinical observations or ophthalmologic examinations were noted. No treatment-related macroscopic or microscopic findings were noted for animals administered 1.5% GTP supplementation. Throughout the study, there was no difference in the body weight among all OVX groups. In all OVX groups, feed intake and water consumption significantly decreased with GTP dose throughout the study period. At 6 mo, GTP intake did not affect hematology, clinical chemistry, and urinalysis, except for phosphorus and blood urea nitrogen (increased), total cholesterol, lactate dehydrogenase, and urine pH (decreased). This study reveals that the no-observed-adverse-effect level (NOAEL) of GTP is 1.5% (wt/vol) in drinking water, the highest dose used in this study.

Dietary polyphenols and mechanisms of osteoarthritis.

Osteoarthritis is a condition caused in part by injury, loss of cartilage structure and function, and an imbalance in inflammatory and anti-inflammatory pathways. It primarily affects the articular cartilage and subchondral bone of synovial joints and results in joint failure, leading to pain upon weight bearing including walking and standing. There is no cure for osteoarthritis, as it is very difficult to restore the cartilage once it is destroyed. The goals of treatment are to relieve pain, maintain or improve joint mobility, increase the strength of the joints and minimize the disabling effects of the disease. Recent studies have shown an association between dietary polyphenols and the prevention of osteoarthritis-related musculoskeletal inflammation. This review discusses the effects of commonly consumed polyphenols, including curcumin, epigallocatechin gallate and green tea extract, resveratrol, nobiletin and citrus fruits, pomegranate, as well as genistein and soy protein, on osteoarthritis with an emphasis on molecular antiosteoarthritic mechanisms.

Green tea polyphenols and 1-α-OH-vitamin D3 attenuate chronic inflammation-induced myocardial fibrosis in female rats.

Studies have suggested that 1-α-OH-vitamin D3 and green tea polyphenols (GTPs) are promising dietary supplements for mitigating chronic inflammation-induced fibrosis of vessels because of their anti-inflammatory properties. This study evaluated (1) the impact of 1-α-OH-vitamin D3 on myocardial fibrosis in female rats with chronic inflammation and (2) if 1-α-OH-vitamin D3 and GTPs have an additive or synergistic effect to attenuate myocardial fibrosis in these female rats. A 3-month study of a 2 (no 1-α-OH-vitamin D3 vs. 0.05 µg/kg 1-α-OH-vitamin D3, five times per week) ×2 (no GTPs vs. 0.5% GTPs in drinking water) factorial design in lipopolysaccharide (LPS)-administered female rats was performed. Additionally, a group receiving placebo administration was used to compare with a group receiving LPS administration only to evaluate the effect of LPS. Masson's Trichrome staining evaluated myocardial fibrosis in coronary vessels and surrounding myocardium. Spleen cyclooxygenase-2 mRNA expression was determined by real-time polymerase chain reaction. Total lipid profiles were also determined. Whole blood was used for differential cell counts. Data were analyzed by two-way analysis of variance followed by mean separation procedures. At 3 months LPS administration induced myocardial fibrosis in vessels and surrounding myocardium, spleen cyclooxygenase-2 mRNA expression, and elevated leukocyte counts, whereas both 1-α-OH-vitamin D3 administration and GTPs supplementation significantly attenuated these pro-inflammatory events. The inhibitory effects of 1-α-OH-vitamin D3 and GTPs seem to be an individual effect, instead of an additive or synergistic effect. 1-α-OH-vitamin D3 and GTPs lowered red blood cell counts, hematocrit, and hemoglobin. Neither 1-α-OH-vitamin D3 nor GTPs affected lipid profiles. In summary, both 1-α-OH-vitamin D3 administration and GTPs supplementation mitigate myocardial fibrosis through suppression of a chronic inflammation innate immune response.

Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats.

OBJECTIVE: Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. TREATMENTS: Forty 3-month-old female rats were assigned to a 2 (placebo vs. lipopolysaccharide, administration) × 2 (no GTP vs. 0.5% GTP in drinking water) factorial design for 12 weeks. METHODS: Masson's trichrome staining evaluated myocardial fibrosis in coronary vessels and surrounding myocardium. Whole blood specimens were counted for differentials. Spleen tumor necrosis factor-α (TNF-α) mRNA expression was determined by real-time RT-PCR. Data were analyzed by two-way analysis of variance (ANOVA) followed by mean separation procedures. RESULTS: After 12 weeks, lipopolysaccharide administration induced myocardial fibrosis in vessels and surrounding myocardium, spleen TNF-α mRNA expression, and leukocytes, while GTP supplementation in drinking water significantly averted such observation. CONCLUSIONS: GTP attenuates myocardial fibrosis through a suppression of chronic inflammation and innate immune responses.

Effects of tai chi exercise on posturography, gait, physical function and quality of life in postmenopausal women with osteopaenia: a randomized clinical study.

OBJECTIVE: to evaluate the effects of tai chi exercise on risk factors for falls in postmenopausal women with osteopaenia through measurements of balance, gait, physical function and quality of life. DESIGN: a randomized, controlled, single-blinded, 24-week trial with stratification by age and bone mass. SETTING: general community. PARTICIPANTS: Sixty-one independently living elderly females aged 65 years and older with low bone mass. INTERVENTIONS: subjects were recruited and randomly assigned to 24 weeks of tai chi (60 minutes/session, three sessions/week, n = 30) or a control group (n = 31). OUTCOME MEASURES: computerized dynamic posturography, gait, 'timed up and go', five-chair sit-to-stand and quality of life assessed at baseline, 12 and 24 weeks. RESULTS: after 24 weeks, subjects in the tai chi group demonstrated an increase in stride width (P = 0.05) and improvement in general health (P = 0.008), vitality (P = 0.02) and bodily pain (P = 0.03) compared with those in the control group. There was no significant difference in balance parameters, 'timed up and go', five-chair sit-to-stand and other domains of quality of life. CONCLUSION: tai chi exercise may reduce risk factors for falls by increasing the stride width, and may improve quality of life in terms of general health, vitality and bodily pain in postmenopausal women with osteopaenia.

Effect of long-chain n-3 polyunsaturated fatty acid on inflammation mediators during osteoblastogenesis.

This study examined the effects of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on inflammation mediators during osteoblastogenesis, in terms of modulation of the cyclooxygenase (COX)-2 and the inducible nitric oxide (NO) synthase (iNOS) pathways. We hypothesized that n-3 polyunsaturated fatty acid (PUFA) would reduce the production of inflammation mediators, including prostaglandin E(2) (PGE(2)) and NO, and related mRNA gene expression during osteoblastogenesis. Mouse bone marrow stromal cells (ST-2) were treated with 40 microM ethanol (as a control), 40 microM AA, or 40 microM EPA in osteogenic medium for 7, 14, 21, or 28 days. Prior to harvest, cells were treated with respective treatments along with cytokine mixtures for an additional 24 hours, and then cells were harvested for mRNA expression. In addition, cells were also treated with respective treatments along with the same cytokine mixtures for an additional 48 hours for experiment measuring PGE(2) and NO production using conditioned culture medium and protein expression using cells. Except for 7 days of culture, AA treatment resulted in the highest value for PGE(2) production throughout 28 days of culture. AA treatment also enhanced COX-2 mRNA expression up to 21 days. AA treatment resulted in a higher value for NO production after 7 days, while EPA treatment yielded a higher value for NO production relative to those receiving AA treatment after 14 and 21 days. Our investigation has corroborated that the protective action of EPA on osteoblastogenesis was mediated by the modulation of PGE(2) and the NO pathway.

Solitary fibrous tumor of the orbit with epithelioid features.

Extrapleural solitary fibrous tumors have often been confused with other mesenchymal tumors, such as hemangiopericytoma, fibrous histiocytoma, fibrous meningioma, and leiomyoma, because of morphologic similarity and underrecognition, especially if some unusual features are present. Recently, epithelioid solitary fibrous tumor has been reported in the mediastinum. We report a case of solitary fibrous tumor of the orbit with biphasic architecture, including spindle cell and epithelioid components. Both components demonstrated immunohistochemical features of a solitary fibrous tumor. A background of scattered vessels was present. No evidence of significant nuclear atypia or mitotic activity was noted. In this report, we discuss the differential diagnosis of solitary fibrous tumor with unusual epithelioid features. Extrapleural solitary fibrous tumor should be included in the differential diagnosis of tumors of the orbit with a spindle cell appearance even in the presence of some epithelioid morphology.

Effects of Ganoderma lucidum on apoptotic and anti-inflammatory function in HT-29 human colonic carcinoma cells.

Ling Zhi extract (LZE) is a herbal mushroom preparation which been used world wide for the prevention and treatment of various cancers. The current study was designed to evaluate these claims in human colon cancer cells in terms of cancer preventive mechanisms. Results have demonstrated induction of apoptosis, anti-inflammatory action and differential cytokine expression during induced inflammation in the human colonic carcinoma cell line, HT-29. LZE caused no cytotoxicity in HT-29 cells at doses less than 10,000 microg/ml. Increasing concentrations of LZE reduced prostaglandin E2 production, but increased nitric oxide production. LZE treatment induced apoptosis by increasing the activity of caspase-3. RT-PCR showed that LZE at a concentration of 5000 microg/ml decreased the expression of cyclooxygenase-2 mRNA. Among 42 cytokines tested by protein array in this study, supplementation of LZE at doses of 500 and 5000 microg/ml to HT-29 cells reduced the expression of interleukin-8, macrophage inflammatory protein 1-delta, vascular epithelial growth factor, and platelet-derived growth factor. These results suggest that LZE has pro-apoptotic and anti-inflammatory functions, as well as inhibitory effects on cytokine expression during early inflammation in colonic carcinoma cells, which may be of significance in the use of Chinese herbal alternative medicines for cancer prevention.

Decreased production of inflammatory mediators in human osteoarthritic chondrocytes by conjugated linoleic acids.

Osteoarthritic chondrocytes (OC) produce excessive prostaglandin E2 (PGE2) and nitric oxide (NO), which function as inflammation mediators in the pathogenesis of osteoarthritis (OA). This study examined the effect of CLA alone and in combination with other PUFA on the FA composition and the production of PGE2 and NO in OC cultures isolated from OA patients. Human OC were grown in monolayer and treated with one of the following PUFA treatments: CLA, CLA + arachidonic acid (CLA/AA), CLA + EPA (CLA/EPA), linoleic acid (LA), LA + AA (LA/AA), LA + EPA (LA/EPA), and ethanol (as a vehicle control) at 10 and 20 microM for 6 d. Supplementation of PUFA at 10 microM for 6 d did not introduce any cytotoxic effects or morphological changes in OC, whereas 20 microM resulted in apoptosis. Cultures of OC treated with CLA, CLA/AA, and CLA/EPA had higher concentrations of CLA isomers, and these isomers were not detected in other treatments. Supplementation of CLA or LA alone to the OC led to a lower PGE2 production compared to the control. Combination of CLA/EPA resulted in the lowest PGE2 production in cultured OC. OC cultures treated with CLA were lower in NO production than the control, whereas the LA/AA treatment demonstrated the lowest NO production. The fact that CLA alone or in combination with other PUFA modulated PGE2 and NO production in human OC cultures suggests that these 18:2 isomers may have the potential to influence OA pathogenesis.