Utility of Repetitive Transcranial Magnetic Stimulation for Chronic Daily Headache Prophylaxis: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Management of chronic daily headaches (CDH) remains challenging due to the limited efficacy of standard prophylactic pharmacological measures. Several studies have reported that repetitive transcranial magnetic stimulation (rTMS) can effectively treat chronic headaches. The objective was to determine the utility of rTMS for immediate post-treatment and sustained CDH prophylaxis. RECENT FINDINGS: All procedures were conducted per PRISMA guidelines. PubMed, Scopus, Web of Science, and ProQuest databases were searched for controlled clinical trials that have tested the efficacy of rTMS on populations with CDH. DerSimonian-Laird random-effects meta-analyses were performed using the 'meta' package in R to examine the post- vs. pre-rTMS changes in standardized headache intensity and frequency compared to sham-control conditions. Thirteen trials were included with a combined study population of N = 538 patients with CDH (rTMS, N = 284; Sham, N = 254). Patients exposed to rTMS had significantly reduced standardized CDH intensity and frequency in the immediate post-treatment period (Hedges' g = -1.16 [-1.89, -0.43], p = 0.002 and Δ = -5.07 [-10.05, -0.11], p = 0.045 respectively). However, these effects were sustained marginally in the follow-up period (Hedges' g = -0.43 [-0.76, -0.09], p = 0.012 and Δ = -3.33 [-5.52, -1.14], p = 0.003). Significant between-study heterogeneity was observed, at least partially driven by variations in rTMS protocols. Despite the observed clinically meaningful and statistically significant benefits in the immediate post-treatment period, the prophylactic effects of rTMS on CDH do not seem to sustain with discontinuation. Thus, the cost-effectiveness of the routine use of rTMS for CDH prophylaxis remains questionable. REGISTRATION: Protocol preregistered in PROSPERO International Prospective Register of Systematic Reviews (CRD42021250100).

The effectiveness of botulinum toxin for chronic tension-type headache prophylaxis: A systematic review and meta-analysis.

BACKGROUND: A systematic and meta-analysis was conducted to examine the evidence of the effects of botulinum toxin A on chronic tension-type headache. METHODS: Cochrane, Embase, Ovid, ProQuest, PubMed, Scopus, Web-of-Science databases, and ClinicallTrials.gov registry were systematically searched for studies examining the effects of botulinum toxin A on tension-type headaches. The records were screened by two independent reviewers using pre-determined eligibility criteria. DerSimonian Liard random-effects meta-analyses were performed using the 'meta' package (5.2-0) in R (4.2.0). Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's Tool RoB 2 and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Clinical significance was determined using pre-defined minimal clinically important differences. RESULTS: Eleven controlled trials were included (390 botulinum toxin A, 297 controls). Botulinum toxin A was associated with significant improvements in standardized headache intensity (-0.502 standard deviations [-0.945, -0.058]), headache frequency (-2.830 days/month [-4.082, -1.578]), daily headache duration (-0.965 [-1.860, -0.069]) and the frequency of acute pain medication use (-2.200 days/month [-3.485, -0.915]) vs controls. Botulinum toxin A-associated improvements exceeded minimal clinically important differences for headache intensity, frequency, and acute pain medication use. A 79% (28%, 150%) greater response rate was observed for botulinum toxin A vs controls in improving chronic tension-type headache. Treatment of eight chronic tension-type headache patients was sufficient to elicit a therapeutic response in one patient. CONCLUSIONS: Corroborating the current mechanistic evidence, our meta-analysis supports the utility of botulinum toxin A for managing chronic tension-type headaches. However, due to limitations in the quality of evidence, adequately-powered high-quality controlled trials examining the effects of Botulinum toxin A on chronic tension-type headache are warranted. REGISTRATION: Protocol preregistered in PROSPERO International Prospective Register of Systematic Reviews (CRD42020178616).

Effect of Dietary Geranylgeraniol and Green Tea Polyphenols on Glucose Homeostasis, Bone Turnover Biomarkers, and Bone Microstructure in Obese Mice.

Previously, we demonstrated that the administration of either geranylgeraniol (GGOH) or green tea polyphenols (GTP) improved bone health. This study examined the combined effects of GGOH and GTP on glucose homeostasis in addition to bone remodeling in obese mice. We hypothesized that GGOH and GTP would have an additive or synergistic effect on improving glucose homeostasis and bone remodeling possibly in part via suppression of proinflammatory cytokines. Forty-eight male C57BL/6J mice were assigned to a high-fat diet (control), HFD + 400 mg GGOH/kg diet (GG), HFD + 0.5% GTP water (TP), or HFD + GGOH + GTP (GGTP) diet for 14 weeks. Results demonstrated that GTP supplementation improved glucose tolerance in obese mice. Neither GGOH nor GTP affected pancreas insulin or bone formation procollagen type I intact N-terminal, bone volume at the lumbar vertebrae, or bone parameters at the trabecular bone and cortical bone of the femur. There was an interactive effect for serum bone resorption collagen type 1 cross-linked C-telopeptide concentrations, resulting in no-GGOH and no-GTP groups having the highest values. GGOH increased trabecular number and decreased trabecular separation at the lumbar vertebrae. GTP increased trabecular thickness at lumbar vertebrae. The GG group produced the greatest connectivity density and the lowest structure model index. Only GTP, not GGOH, decreased adipokines concentrations (resistin, leptin, monocyte chemoattractant protein-1, and interleukin-6). In an obese male mouse model, individual GGOH and GTP supplementation improved glucose homeostasis, serum CTX, and trabecular microstructure of LV-4. However, the combined GGOH and GTP supplementation compromises such osteoprotective effects on serum CTX and trabecular bone of obese mice.

Effects of consumption of coconut oil or coconut on glycemic control and insulin sensitivity: A systematic review and meta-analysis of interventional trials.

BACKGROUND AND AIMS: The often purported claim that coconut fat is beneficial for cardiovascular health and was disputed in several recent meta-analyses. However, the evidence on the effects of coconut fat intake on glycemic control remains equivocal. We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines to determine the effects of dietary coconut fats on markers of acute and long-term glycemic control. METHODS AND RESULTS: PubMed, Scopus, ProQuest, and Web-of-Science databases were searched and the records were screened by three independent reviewers to identify interventional studies examining acute and long-term (i.e., >10 days) effects of coconut fat on glycemic control. DerSimonian-Laird random-effects meta-analyses were performed using the meta-package in R (4.0.2). Seven interventional studies on acute effects and 11 interventional studies on long-term effects of coconut fat were included. Meals with coconut fat acutely increased the incremental area under the curve (AUC) of glucose (p = 0.046) and decreased the incremental AUC of insulin (p = 0.037) vs. control meals. Long-term coconut fat intake increased HOMA-IR (p = 0.049), but did not significantly affect fasting glucose, insulin, or HOMA-ß vs. control meals. CONCLUSIONS: Coconut fat in meals seems to be associated with a diminished postprandial insulin response, resulting in a subtle increase in the postprandial glycemic response. Long-term intake of coconut fat seems to increase insulin resistance, yet does not seem to be beneficial for long-term glycemic control. Thus, our results disprove the popular claim that coconut fat improves glycemic control. REGISTRATION: PROSPERO registry (CRD42020183450).

Effect of Long-Term Green Tea Polyphenol Supplementation on Bone Architecture, Turnover, and Mechanical Properties in Middle-Aged Ovariectomized Rats.

We investigated the effects of 6-month green tea polyphenols (GTP) supplementation on bone architecture, turnover, and mechanical properties in middle-aged ovariectomized (OVX) rats. Female rats were sham-operated (n = 39, 13/group) or OVX (n = 143, 13/group). Sham-control and OVX-control rats (n = 39) receiving no GTP were assigned for sample collection at baseline, 3, or 6 months. The remaining OVX rats (n = 104) were randomized to 0.15%, 0.5%, 1%, and 1.5% (g/dL) GTP for 3 or 6 months. Blood and bone samples were collected. Relative to the OVX-control group, GTP (1% and 1.5%) lowered serum procollagen type 1 N-terminal propeptide at 3 and 6 months, C-terminal telopeptides of type I collagen at 3 months, and insulin-like growth factor-I at 6 months. GTP did not affect bone mineral content and density. At 6 months, no dose of GTP positively affected trabecular bone volume based on microCT, but a higher cortical thickness and improved biomechanical properties of the femur mid-diaphysis was observed in the 1.5% GTP-treated group. At 3 and 6 months, GTP (0.5%, 1%, and 1.5%) had lower rates of trabecular bone formation and resorption than the OVX-control group, but the inhibitory effects of GTP on periosteal and endocortical bone mineralization and formation at the tibial midshaft were only evident at 3 months. GTP at higher doses suppressed bone turnover in the trabecular and cortical bone of OVX rats and resulted in improved cortical bone structural and biomechanical properties, although it was not effective in preventing the ovariectomy-induced dramatic cancellous bone loss.

A 12-week evaluation of annatto tocotrienol supplementation for postmenopausal women: safety, quality of life, body composition, physical activity, and nutrient intake.

BACKGROUND: Evidence suggests that tocotrienols may benefit bone health in osteopenic women. However, their safety in this population has never been investigated. This study was to evaluate the safety of a 12-week supplementation of annato tocotrienol in postmenopausal osteopenic women, along with effects of the supplementation on quality of life, body composition, physical activity, and nutrient intake in this population. METHODS: Eighty nine postmenopausal osteopenic women were randomly assigned to 3 treatment arms: (1) Placebo (430 mg olive oil/day), (2) Low tocotrientol (Low TT) (430 mg tocotrienol/day from DeltaGold 70 containing 300 mg tocotrienol) and (3) High tocotrienol (High TT) (860 mg tocotrienol/day from DeltaGold 70 containing 600 mg tocotrienol) for 12 weeks. DeltaGold 70 is an extract from annatto seed with 70% tocotrienol consisting of 90% delta-tocotrienol and 10% gamma-tocotrienol. Safety was examined by assessing liver enzymes (aspartate aminotransferase, alanine aminotransferase), alkaline phosphatase, bilirubin, kidney function (blood urea nitrogen and creatinine), electrolytes, glucose, protein, albumin, and globulin at 0, 6, and 12 weeks. Serum tocotrienol and tocopherol concentrations were assessed and pills counted at 0, 6, and 12 weeks. Quality of life, body composition, physical activity, and dietary macro- and micro-nutrient intake were evaluated at 0 and 12 weeks. A mixed model of repeated measures ANOVA was applied for analysis. RESULTS: Eighty seven subjects completed the study. Tocotrienol supplementation did not affect liver or kidney function parameters throughout the study. No adverse event due to treatments was reported by the participants. Tocotrienol supplementation for 6 weeks significantly increased serum delta-tocotrienol level and this high concentration was sustained to the end of study. There was no difference in serum delta-tocotrienol levels between the Low TT and the High TT groups. No effects of tocotrienol supplementation were observed on quality of life, body composition, physical activity, and nutrient intake. CONCLUSIONS: Annatto-derived tocotrienol up to 600 mg per day for 12 weeks appeared to be safe in postmenopausal osteopenic women, particularly in terms of liver and kidney functions. Tocotrienol supplementation for 12 weeks did not affect body composition, physical activity, quality of life, or intake of macro- and micro-nutrients in these subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02058420 . TITLE: Tocotrienols and bone health of postmenopausal women.

Methylparaben and butylparaben alter multipotent mesenchymal stem cell fates towards adipocyte lineage.

Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We previously reported that parabens promoted adipocyte differentiation in vitro and increased adiposity but suppressed serum marker of bone formation in vivo. Here, we investigated the effects of parabens (methylparaben and butylparaben) on modulating cell fate of multipotent stem cell line C3H10T1/2. Both parabens modulated adipogenic, osteogenic, and chondrogenic differentiation of C3H10T1/2 cells in vitro. Butylparaben markedly promoted adipogenic differentiation, but suppressed osteogenic and chondrogenic differentiation whereas methylparaben showed similar but less pronounced effects. Moreover, butylparaben, but not methylparaben, was shown to activate peroxisome proliferator-activated receptor (PPAR) γ whereas neither of the paraben was shown to activate glucocorticoid receptor (GR) responsive reporter in C3H10T1/2 cells. The adipogenic effects of butylparaben were significantly attenuated by PPARγ knockdown, but not by GR knockdown. In contrast, paraben's effects on osteoblast differentiation were affected by both knockdowns. Collectively, the results demonstrate opposing effects of parabens on adipogenic and osteoblastogenic/chondrogenic differentiation of multipotent stem cells. In light of the recent findings that parabens are detected in human placenta and milk, our studies provide rationales to study paraben exposure during early development of life in the future.

A High-Fat Diet Decreases Bone Mass in Growing Mice with Systemic Chronic Inflammation Induced by Low-Dose, Slow-Release Lipopolysaccharide Pellets.

Background: Chronic inflammation is associated with increased bone resorption and is linked to osteopenia, or low bone mass. Obesity is also associated with low-grade chronic upregulation of inflammatory cytokines.Objective: This study investigated the effect of high-fat (HF) diet-induced obesity on bone structure changes in growing mice with existing systemic chronic inflammation induced by low-dose, slow-release lipopolysaccharide (LPS).Methods: Forty-eight 6-wk-old female C57BL/6 mice were randomly assigned to 4 treatment groups (n = 12/group) in a 2 × 2 factorial design-control (placebo) or LPS treatment (1.5 µg/d)-and consumed either a normal-fat (NF, 10% of energy as fat) or an HF (45% of energy as fat) diet ad libitum for 13 wk. Bone structure, serum biomarkers of bone turnover, and osteoclast differentiation were measured.Results: No alterations were observed in final body weights, fat mass, or lean mass in response to LPS treatment. LPS treatment increased serum concentration of tartrate-resistant acid phosphatase (TRAP, a bone resorption marker) and bone marrow osteoclast differentiation and decreased femoral and lumbar vertebral bone volume (BV):total volume (TV) by 25% and 24%, respectively, compared with the placebo. Mice fed the HF diet had greater body weight at the end of the study (P < 0.01) due to increased fat mass (P < 0.01) than did mice fed the NF diet. The HF diet increased serum TRAP concentration, bone marrow osteoclast differentiation, and expression of tumor necrosis factor α, interleukin 1ß and interleukin 6 in adipose tissue. Compared with the NF diet, the HF diet decreased BV:TV by 10% and 8% at femur and lumbar vertebrae, respectively, and the HF diet was detrimental to femoral and lumbar vertebral bone structure with decreased trabecular number and increased trabecular separation and structure model index.Conclusion: Results suggest that HF diets and systemic chronic inflammation have independent negative effects on bone structure in mice.

Relationship between Serum Resistin Level of Xinjiang Uygur and Han Subjects with Metabolic Syndrome.

BACKGROUND: Xinjiang is a multi-ethnic region of China. Many large population based cross-sectional studies have shown that Uygur, the largest ethnic group in the Xinjiang, had a higher incidence rate of metabolic syndrome (MetS) than other ethnic groups living in Xinjiang region, but the pathological mechanism is not yet clear. Insulin resistance plays a critical role in the pathogenesis of MetS. Resistin is an adipocyte- and monocyte-derived cytokine that represents a link between obesity, insulin resistance, and type 2 diabetes. The aim of this study is to examine the relationship between serum resistin levels and metabolic syndrome parameters in Uygur and Han in Xinjiang. METHODS: Subjects came from a population based cross-sectional study, a total of 465 subjects were selected for the study. Blood resistin, fasting blood sugar (FBS), fasting insulin (FINS), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG), waist circumference (WC), body mass index (BMI), systolic blood pressures (SBP), diastolic blood pressures (DBP), and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) indices were measured. Dietary intake data were obtained by food frequency questionnaire method. The International Diabetes Federation (IDF) criteria were adopted to define metabolic syndrome. RESULTS: The MetS group has higher metabolic parameters of FPG, TG, TC, DBP, SBP, WC, BMI, LDL-C, and low HDL-C than the non-MetS group, Uygurs have higher FPG and WC than Hans, and Hans have higher TC, TG, and FINS than Uygurs, even after adjusting for age, gender, and BMI, indicating ethnic differences in MetS-related parameters. There was no significant difference in serum resistin levels between the MetS and non-MetS group, as well as between the Uygur and the Han ethnic groups, but a significant positive correlation was found between serum resistin levels with FIN, HOMA, and diet fat. CONCLUSIONS: In our study, we did not observe significant differences in serum resitin levels between the MetS and non-MetS group, regardless of ethnicity. However, serum resistin was positively associated with insulin resistance markers, suggesting that resistin may be an independent determinant for insulin resistance, or indirectly contribute to the development of MetS. Therefore the role of resistin in MetS warrants further investigation.

Exerkines, Nutrition, and Systemic Metabolism.

The cornerstones of good health are exercise, proper food, and sound nutrition. Physical exercise should be a lifelong routine, supported by proper food selections to satisfy nutrient requirements based on energy needs, energy management, and variety to achieve optimal metabolism and physiology. The human body is sustained by intermediary and systemic metabolism integrating the physiologic processes for cells, tissues, organs, and systems. Recently, interest in specific metabolites, growth factors, cytokines, and hormones called exerkines has emerged to explain cooperation between nutrient supply organs and the brain during exercise. Exerkines consist of different compounds described as signaling moiety released during and after exercise. Examples of exerkines include oxylipin 12, 13 diHOME, lipid hormone adiponectin, growth factor BDNF, metabolite lactate, reactive oxygen species (ROS), including products of fatty acid oxidation, and cytokines such as interleukin-6. At this point, it is believed that exerkines are immediate, fast, and long-lasting factors resulting from exercise to support body energy needs with an emphasis on the brain. Although exerkines that are directly a product of macronutrient metabolism such as lactate, and result from catabolism is not surprising. Furthermore, other metabolites of macronutrient metabolism seem to be candidate exerkines. The exerkines originate from muscle, adipose, and liver and support brain metabolism, energy, and physiology. The purpose of this review is to integrate the actions of exerkines with respect to metabolism that occurs during exercise and propose other participating factors of exercise and brain physiology. The role of diet and macronutrients that influence metabolism and, consequently, the impact of exercise will be discussed. This review will also describe the evidence for PUFA, their metabolic and physiologic derivatives endocannabinoids, and oxylipins that validate them being exerkines. The intent is to present additional insights to better understand exerkines with respect to systemic metabolism.

Peanut Shell Extract Improves Mitochondrial Function in db/db Mice via Suppression of Oxidative Stress and Inflammation.

Accumulating evidence shows a strong correlation between type 2 diabetes mellitus, mitochondrial dysfunction, and oxidative stress. We evaluated the effects of dietary peanut shell extract (PSE) supplementation on mitochondrial function and antioxidative stress/inflammation markers in diabetic mice. Fourteen db/db mice were randomly assigned to a diabetic group (DM in AIN-93G diet) and a PSE group (1% wt/wt PSE in AIN-93G diet) for 5 weeks. Six C57BL/6J mice were fed with an AIN-93G diet for 5 weeks (control group). Gene and protein expression in the liver, brain, and white adipose tissue (WAT) were determined using qRT-PCR and Immunoblot, respectively. Compared to the control group, the DM group had (i) increased gene and protein expression levels of DRP1 (fission), PINK1 (mitophagy), and TNFα (inflammation) and (ii) decreased gene and protein expression levels of MFN1, MFN2, OPA1 (fusion), TFAM, PGC-1α (biogenesis), NRF2 (antioxidative stress) and IBA1 (microglial activation) in the liver, brain, and WAT of db/db mice. Supplementation of PSE into the diet restored the DM-induced changes in the gene and protein expression of DRP1, PINK1, TNFα, MFN1, MFN2, OPA1, TFAM, PGC-1α, NRF2, and IBA1 in the liver, brain, and WAT of db/db mice. This study demonstrates that PSE supplementation improved mitochondrial function in the brain, liver, and WAT of db/db mice, in part due to suppression of oxidative stress and inflammation.

Ginger alleviates mechanical hypersensitivity and anxio-depressive behavior in rats with diabetic neuropathy through beneficial actions on gut microbiome composition, mitochondria, and neuroimmune cells of colon and spinal cord.

The relationship among gut microbiota, mitochondrial dysfunction/neuroinflammation, and diabetic neuropathic pain (DNP) has received increased attention. Ginger has antidiabetic and analgesic effects because of its anti-inflammatory property. We examined the effects of gingerols-enriched ginger (GEG) supplementation on pain-associated behaviors, gut microbiome composition, and mitochondrial function and neuroinflammation of colon and spinal cord in DNP rats. Thirty-three male rats were randomly divided into 3 groups: control group, DNP group (high-fat diet plus single dose of streptozotocin at 35 mg/kg body weight, and GEG group (DNP+GEG at 0.75% in the diet for 8 weeks). Von Frey and open field tests were used to assess pain sensitivity and anxio-depressive behaviors, respectively. Colon and spinal cord were collected for gene expression analysis. 16S rRNA gene sequencing was done from cecal samples and microbiome data analysis was performed using QIIME 2. GEG supplementation mitigated mechanical hypersensitivity and anxio-depressive behavior in DNP animals. GEG supplementation suppressed the dynamin-related protein 1 protein expression (colon) and gene expression (spinal cord), astrocytic marker GFAP gene expression (colon and spinal cord), and tumor necrosis factor-α gene expression (colon, P < .05; spinal cord, P = .0974) in DNP rats. GEG supplementation increased microglia/macrophage marker CD11b gene expression in colon and spinal cord of DNP rats. GEG treatment increased abundance of Acinetobacter, Azospirillum, Colidextribacter, and Fournierella but decreased abundance of Muribaculum intestinale in cecal feces of rats. This study demonstrates that GEG supplementation decreased pain, anxio-depression, and neuroimmune cells, and improved the composition of gut microbiomes and mitochondrial function in rats with diabetic neuropathy.

Ginger Supplementation Attenuated Mitochondrial Fusion and Improved Skeletal Muscle Size in Type 2 Diabetic Rats.

BACKGROUND/AIM: Oxidative stress, regulated by SOD2 and mitochondrial dynamics, contributes to muscle atrophy in diabetes. Ginger root extract (GRE) reduces oxidative stress. However, its effect on oxidative stress, mitochondrial dynamics, and muscle atrophy is not known in the diabetic muscle. This study examined the effect of GRE on intramuscular oxidative stress, mitochondrial dynamics, and muscle size in diabetic rats. MATERIALS AND METHODS: Twenty-six male Sprague-Dawley rats were randomly divided into control diet (CON; n=10), high-fat diet with one dose of 35 mg/kg streptozotocin (HFD; n=9), and high-fat diet with one dose of 35 mg/kg streptozotocin and 0.75% w/w GRE (GRE; n=7) fed for seven weeks. Subsequently, the muscle was analyzed for cross-sectional area (CSA), H2O2 concentration, and DRP-1, MFN2, Parkin, PINK1, SOD2 mRNA. Additionally, the protein levels of SOD2, DRP-1, DRP-1ser616, LC3AB, MFN2, OPA1, Parkin, and PINK1 were analyzed. CSA, H2O2 concentration, and gene and protein expression levels were analyzed using a one-way ANOVA. Correlations among intramuscular H2O2, CSA, and SOD2 protein were assessed using Pearson's bivariate correlation test. RESULTS: In the soleus, the GRE group had a greater CSA and lower intramuscular H2O2 concentration compared to the HFD group. Compared to the HFD group, the GRE group had higher SOD2 and DRP-1 mRNA levels and lower MFN2 and total OPA1 protein levels. H2O2 concentration was negatively correlated with CSA and positively correlated with SOD2. CONCLUSION: GRE attenuated intramuscular H2O2, mitochondrial fusion, and muscle size loss. These findings suggest that GRE supplementation in diabetic rats reduces oxidative stress, which may contribute to muscle size preservation.

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.

Ginger Polyphenols Reverse Molecular Signature of Amygdala Neuroimmune Signaling and Modulate Microbiome in Male Rats with Neuropathic Pain: Evidence for Microbiota-Gut-Brain Axis.

Emerging evidence shows that the gut microbiota plays an important role in neuropathic pain (NP) via the gut-brain axis. Male rats were divided into sham, spinal nerve ligation (SNL), SNL + 200 mg GEG/kg BW (GEG200), and SNL + 600 mg GEG/kg BW (GEG600) for 5 weeks. The dosages of 200 and 600 mg GEG/kg BW for rats correspond to 45 g and 135 g raw ginger for human daily consumption, respectively. Both GEG groups mitigated SNL-induced NP behavior. GEG-supplemented animals had a decreased abundance of Rikenella, Muribaculaceae, Clostridia UCG-014, Mucispirillum schaedleri, RF39, Acetatifactor, and Clostridia UCG-009, while they had an increased abundance of Flavonifactor, Hungatella, Anaerofustis stercorihominis, and Clostridium innocuum group. Relative to sham rats, Fos and Gadd45g genes were upregulated, while Igf1, Ccl2, Hadc2, Rtn4rl1, Nfkb2, Gpr84, Pik3cg, and Abcc8 genes were downregulated in SNL rats. Compared to the SNL group, the GEG200 group and GEG600 group had increases/decreases in 16 (10/6) genes and 11 (1/10) genes, respectively. GEG downregulated Fos and Gadd45g genes and upregulated Hdac2 genes in the amygdala. In summary, GEG alleviates NP by modulating the gut microbiome and reversing a molecular neuroimmune signature.

Associations between tissue visfatin/nicotinamide, phosphoribosyltransferase (Nampt), retinol binding protein-4, and vaspin concentrations and insulin resistance in morbidly obese subjects.

Visfatin/Nampt, vaspin, and retinol binding protein-4 (RBP-4) play an important role in insulin resistance. The objectives of this study were to measure visfatin/Nampt, vaspin, and RBP-4 concentrations in blood, liver, muscle, subcutaneous, omental, and mesenteric adipose tissues in morbidly obese subjects and investigate their relationship to insulin resistance. Blood and tissue samples were collected from 38 morbidly obese subjects during Roux-en-Y surgery. Insulin resistance biomarkers were measured using standard kits. Visfatin/Nampt, vaspin, and RBP-4 gene expression levels in tissues were measured using real-time PCR. Their protein concentrations in blood and tissues were measured using ELISA kits. Diabetic subjects had significantly higher homeostasis model of assessment-insulin resistance and age and lower blood HDL-cholesterol concentrations than nondiabetic and prediabetic subjects. Diabetic and prediabetic subjects had significantly higher blood concentrations of visfatin/Nampt and vaspin than nondiabetic subjects. Liver RBP-4 concentrations were positively associated with blood glucose concentrations. Blood insulin resistance biomarker levels were positively associated with visfatin/Nampt concentrations in omental adipose tissue and liver, and vaspin concentrations in mesenteric adipose tissue. In conclusion, the correlations of visfatin/Nampt, vaspin, and RBP-4 with insulin resistance are tissue dependent.

Tai Chi exercise reduces circulating levels of inflammatory oxylipins in postmenopausal women with knee osteoarthritis: results from a pilot study.

Background: Tai Chi (TC) controls pain through mind-body exercise and appears to alter inflammatory mediators. TC actions on lipid biomarkers associated with inflammation and brain neural networks in women with knee osteoarthritic pain were investigated. Methods: A single-center, pre- and post-TC group (baseline and 8 wk) exercise pilot study in postmenopausal women with knee osteoarthritic pain was performed. 12 eligible women participated in TC group exercise. The primary outcome was liquid chromatography tandem mass spectrometry determination of circulating endocannabinoids (eCB) and oxylipins (OxL). Secondary outcomes were correlations between eCB and OxL levels and clinical pain/limitation assessments, and brain resting-state function magnetic resonance imaging (rs-fMRI). Results: Differences in circulating quantitative levels (nM) of pro-inflammatory OxL after TC were found in women. TC exercise resulted in lower OxL PGE1 and PGE2 and higher 12-HETE, LTB4, and 12-HEPE compared to baseline. Pain assessment and eCB and OxL levels suggest crucial relationships between TC exercise, inflammatory markers, and pain. Higher plasma levels of eCB AEA, and 1, 2-AG were found in subjects with increased pain. Several eCB and OxL levels were positively correlated with left and right brain amygdala-medial prefrontal cortex functional connectivity. Conclusion: TC exercise lowers pro-inflammatory OxL in women with knee osteoarthritic pain. Correlations between subject pain, functional limitations, and brain connectivity with levels of OxL and eCB showed significance. Findings indicate potential mechanisms for OxL and eCB and their biosynthetic endogenous PUFA precursors that alter brain connectivity, neuroinflammation, and pain. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04046003.

Turmeric Bioactive Compounds Alleviate Spinal Nerve Ligation-Induced Neuropathic Pain by Suppressing Glial Activation and Improving Mitochondrial Function in Spinal Cord and Amygdala.

This study examined the effects of turmeric bioactive compounds, curcumin C3 complex® (CUR) and bisdemethoxycurcumin (BDMC), on mechanical hypersensitivity and the gene expression of markers for glial activation, mitochondrial function, and oxidative stress in the spinal cord and amygdala of rats with neuropathic pain (NP). Twenty-four animals were randomly assigned to four groups: sham, spinal nerve ligation (SNL, an NP model), SNL+100 mg CUR/kg BW p.o., and SNL+50 mg BDMC/kg BW p.o. for 4 weeks. Mechanical hypersensitivity was assessed by the von Frey test (VFT) weekly. The lumbosacral section of the spinal cord and the right amygdala (central nucleus) were collected to determine the mRNA expression of genes (IBA-1, CD11b, GFAP, MFN1, DRP1, FIS1, PGC1α, PINK, Complex I, TLR4, and SOD1) utilizing qRT-PCR. Increased mechanical hypersensitivity and increased gene expression of markers for microglial activation (IBA-1 in the amygdala and CD11b in the spinal cord), astrocyte activation (GFAP in the spinal cord), mitochondrial dysfunction (PGC1α in the amygdala), and oxidative stress (TLR4 in the spinal cord and amygdala) were found in untreated SNL rats. Oral administration of CUR and BDMC significantly decreased mechanical hypersensitivity. CUR decreased CD11b and GFAP gene expression in the spinal cord. BDMC decreased IBA-1 in the spinal cord and amygdala as well as CD11b and GFAP in the spinal cord. Both CUR and BDMC reduced PGC1α gene expression in the amygdala, PINK1 gene expression in the spinal cord, and TLR4 in the spinal cord and amygdala, while they increased Complex I and SOD1 gene expression in the spinal cord. CUR and BDMC administration decreased mechanical hypersensitivity in NP by mitigating glial activation, oxidative stress, and mitochondrial dysfunction.

Training Self-Administered Acupressure Exercise among Postmenopausal Women with Osteoarthritic Knee Pain: A Feasibility Study and Lessons Learned.

Background. Osteoarthritis (OA) is more prevalent in women, particularly after menopausal age. Women are more likely to seek complementary and alternative medicine (CAM) approaches. We examined the feasibility of training self-administered acupressure exercise and assessed its impact on OA symptoms among women with knee OA. Methods. Thirty-six eligible postmenopausal women were randomly assigned in the acupressure exercise group (n = 15) or the control group (n = 21) for 12 weeks. Feasibility outcomes (e.g., compliance and adverse effects) and clinical outcomes (e.g., pain, stiffness, and physical function) were assessed. Data were collected at baseline, 6 weeks and 12 weeks. Both per-protocol and intention-to-treat analysis were employed. Results. The training materials were well received. The feedback from participants suggests that self-administered acupressure exercise is easy to learn and safe to perform at home, although no statistically significant results of the clinical outcome were observed. Our findings didn't reveal superiority or inferiority of acupressure compared with usual care. Conclusion. Acupressure exercise is feasible to be trained among postmenopausal women with knee osteoarthritis. Due to the limitations of this study such as small sample size and high attrition rate, acupressure's efficacy needs to be further explored in larger scale studies with more rigorous design.

Geranylgeraniol Supplementation Mitigates Soleus Muscle Atrophy via Changes in Mitochondrial Quality in Diabetic Rats.

BACKGROUND/AIM: With diabetes, skeletal muscle mitochondrial quality (fusion, fission & mitophagy) and muscle mass are compromised. Geranylgeraniol (GGOH) can prevent mitochondrial damage, inflammation, and improve muscle health; however, the effect of GGOH on a diabetic model is not known. This study aimed to determine the effect of GGOH on mitochondrial quality and muscle mass in diabetic rats. MATERIALS AND METHODS: Sprague-Dawley rats were divided into three groups: regular diet (CON; n=7), high-fat-diet with 35 mg/kg body weight of streptozotocin (STZ) (HFD; n=7), and HFD/STZ with 800 mg/kg of GGOH (GG; n=7) for a total of 8 weeks. At the end of the study, soleus and gastrocnemius muscles were collected and analyzed for gene and protein expression of OPA1, MFN2, DRP1, p-DRP, LC3AB, PINK1, Parkin, SOD2, NF-[Formula: see text]B, IL-6, TNF-α, and IL-1ß. Additionally, the cross-sectional area (CSA) of soleus muscles was analyzed. RESULTS: In soleus, HFD group had significantly higher IL-1ß and lower LC3A, MFN2, DRP1, and SOD2 mRNA expression compared to CON group. The GG group had higher PINK1 mRNA expression than the HFD group. Additionally, the GG group had lower LC3B and DRP1 protein than the HFD group and lower LC3A and MFN2 protein than the HFD and CON groups. Lastly, HFD and GG groups had a smaller CSA than CON group, whereas GG had a greater CSA than HFD. CONCLUSION: GGOH supplementation could prevent mitochondrial fragmentation and potentially decrease the demand for mitochondrial fusion. Additionally, autophagosome degradation occurred at a greater rate than formation, indicating increased clearance of damaged organelles. Improved mitochondrial quality could potentially rescue muscle CSA in diabetic rats with GGOH supplementation.