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.

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.

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.

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.

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).

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.

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.

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.

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.

Geranylgeraniol and Green Tea Polyphenols Mitigate Negative Effects of a High-Fat Diet on Skeletal Muscle and the Gut Microbiome in Male C57BL/6J Mice.

Natural bioactive compounds are proposed as alternatives in mitigating obesity-associated skeletal muscle dysfunction. The objective of this study was to test the hypothesis that the combination of geranylgeraniol (GGOH) and green tea polyphenols (GTPs) can alleviate high-fat-diet (HFD)-induced muscle atrophy and alter gut microbiome composition. Male C57BL/6J mice fed an HFD were assigned to four groups (12 mice each) in a 2 (no GGOH vs. 400 mg GGOH/kg diet) × 2 (no GTPs vs. 0.5% weight/volume GTPs in water) factorial design. After 14 weeks of diet intervention, skeletal muscle and cecal samples were collected and examined. Compared to the control groups, the group that consumed a combination of GGOH and GTPs (GG + GTPs) had significantly decreased body and fat mass but increased skeletal muscle mass normalized by body weight and cross-sectional area. In soleus muscle, the GG + GTP diet increased citrate synthase activity but decreased lipid peroxidation. Gut microbiome beta-diversity analysis revealed a significant difference in the microbiome composition between diet groups. At the species level, the GG + GTP diet decreased the relative abundance of Dorea longicatena, Sporobacter termitidis, and Clostridium methylpentosum, and increased that of Akkermansia muciniphila and Subdoligranulum variabile. These results suggest that the addition of GGOH and GTPs to an HFD alleviates skeletal muscle atrophy, which is associated with changes in the gut microbiome composition.

Ginger Root Extract Improves GI Health in Diabetic Rats by Improving Intestinal Integrity and Mitochondrial Function.

Background Emerging research suggests hyperglycemia can increase intestinal permeability. Ginger and its bioactive compounds have been reported to benefit diabetic animals due to their anti-inflammatory and antioxidant properties. In this study, we revealed the beneficial effect of gingerol-enriched ginger (GEG) on intestinal health (i.e., barrier function, mitochondrial function, and anti-inflammation) in diabetic rats. Methods Thirty-three male Sprague Dawley rats were assigned to three groups: low-fat diet (control group), high-fat-diet (HFD) + streptozotocin (single low dose 35 mg/kg body weight (BW) after 2 weeks of HFD feeding) (DM group), and HFD + streptozotocin + 0.75% GEG in diet (GEG group) for 42 days. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were conducted at baseline and prior to sample collection. Total pancreatic insulin content was determined by ELISA. Total RNA of intestinal tissues was extracted for mRNA expression using qRT-PCR. Results Compared to the DM group, the GEG group had improved glucose tolerance and increased pancreatic insulin content. Compared to those without GEG (DM group), GEG supplementation (GEG group) increased the gene expression of tight junction (Claudin-3) and antioxidant capacity (SOD1), while it decreased the gene expression for mitochondrial fusion (MFN1), fission (FIS1), biogenesis (PGC-1α, TFAM), mitophagy (LC3B, P62, PINK1), and inflammation (NF-κB). Conclusions Ginger root extract improved glucose homeostasis in diabetic rats, in part, via improving intestinal integrity and mitochondrial dysfunction of GI health.

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.

Impact of Local Vibration Training on Neuromuscular Activity, Muscle Cell, and Muscle Strength: A Review.

This paper presents a review of studies on the effects of local vibration training (LVT) on muscle strength along with the associated changes in neuromuscular and cell dynamic responses. Application of local/direct vibration can significantly change the structural properties of muscle cell and can improve muscle strength. The improvement is largely dependent on vibration parameters such as amplitude and frequency. The results of 20 clinical studies reveal that electromyography (EMG) and maximal voluntary contraction (MVC) vary depending on vibration frequency, and studies using frequencies of 28-30 Hz reported greater increases in muscle activity in terms of EMG (rms) value and MVC data than the studies using higher frequencies. A greater muscle activity can be related to the recruitment of large motor units due to the application of local vibration. A greater increase in EMG (rms) values for biceps and triceps during extension than flexion under LVT suggests that types of muscles and their functions play an important role. Although a number of clinical trials and animal studies have demonstrated positive effects of vibration on muscle, an optimum training protocol has not been established. An attempt is made in this study to investigate the optimal LVT conditions on different muscles through review and analysis of published results in the literature pertaining to the changes in the neuromuscular activity. Directions for future research are discussed with regard to identifying optimal conditions for LVT and better understanding of the mechanisms associated with effects of vibration on muscles.

Gingerol-Enriched Ginger Supplementation Mitigates Neuropathic Pain via Mitigating Intestinal Permeability and Neuroinflammation: Gut-Brain Connection.

Objectives: Emerging evidence suggests an important role of the gut-brain axis in the development of neuropathic pain (NP). We investigated the effects of gingerol-enriched ginger (GEG) on pain behaviors, as well as mRNA expressions of inflammation via tight junction proteins in GI tissues (colon) and brain tissues (amygdala, both left and right) in animals with NP. Methods: Seventeen male rats were randomly divided into three groups: Sham, spinal nerve ligation (SNL, pain model), and SNL+0.375% GEG (wt/wt in diet) for 4 weeks. Mechanosensitivity was assessed by von Frey filament tests and hindpaw compression tests. Emotional responsiveness was measured from evoked audible and ultrasonic vocalizations. Ongoing spontaneous pain was measured in rodent grimace tests. Intestinal permeability was assessed by the lactulose/D-mannitol ratio in urine. The mRNA expression levels of neuroinflammation (NF-κB, TNF-α) in the colon and amygdala (right and left) were determined by qRT-PCR. Data was analyzed statistically. Results: Compared to the sham group, the SNL group had significantly greater mechanosensitivity (von Frey and compression tests), emotional responsiveness (audible and ultrasonic vocalizations to innocuous and noxious mechanical stimuli), and spontaneous pain (rodent grimace tests). GEG supplementation significantly reduced mechanosensitivity, emotional responses, and spontaneous pain measures in SNL rats. GEG supplementation also tended to decrease SNL-induced intestinal permeability markers. The SNL group had increased mRNA expression of NF-κB and TNF-α in the right amygdala and colon; GEG supplementation mitigated these changes in SNL-treated rats. Conclusion: This study suggests GEG supplementation palliated a variety of pain spectrum behaviors in a preclinical NP animal model. GEG also decreased SNL-induced intestinal permeability and neuroinflammation, which may explain the behavioral effects of GEG.

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.

Bioactive compounds for neuropathic pain: An update on preclinical studies and future perspectives.

Among different types of chronic pain, neuropathic pain (NP), arising from damage to the nervous system, including peripheral fibers and central neurons, is notoriously difficult to treat and affects 7-10% of the general population. Currently available treatment options for NP are limited and opioid analgesics have severe side effects and can result in opioid use disorder. Recent studies have exhibited the role of dietary bioactive compounds in the mitigation of NP. Here, we assessed the effects of commonly consumed bioactive compounds (ginger, curcumin, omega-3 polyunsaturated fatty acids, epigallocatechin gallate, resveratrol, soy isoflavones, lycopene, and naringin) on NP and NP-related neuroinflammation. Cellular studies demonstrated that these bioactive compounds reduce inflammation via suppression of NF-κB and MAPK signaling pathways that regulate apoptosis/cell survival, antioxidant, and anti-inflammatory responses. Animal studies strongly suggest that these regularly consumed bioactive compounds have a pronounced anti-NP effect as shown by decreased mechanical allodynia, mechanical hyperalgesia, thermal hyperalgesia, and cold hyperalgesia. The proposed molecular mechanisms include (1) the enhancement of neuron survival, (2) the reduction of neuronal hyperexcitability by activation of antinociceptive cannabinoid 1 receptors and opioid receptors, (3) the suppression of sodium channel current, and (4) enhancing a potassium outward current in NP-affected animals, triggering a cascade of chemical changes within, and between neurons for pain relief. Human studies administered in this area have been limited. Future randomized controlled trials are warranted to confirm the findings of preclinical efficacies using bioactive compounds in patients with NP.

Self-Reported Patient Compliance With Physician Advised Lifestyle Behavior Changes Among Adults With Musculoskeletal Conditions.

Introduction: Approximately half of adult Americans suffer from musculoskeletal disorders (MSD). Significant risk factors for musculoskeletal disorders include poor diet, obesity, and insufficient physical activity. Studies show that lifestyle change education and interventions reduce MSD risk factors. However, little is known about the relationship between physician advice for behavior change and reported behavior change by MSD patients. This study explored the association between physician advice for lifestyle change and reported change in MSD patients, as well as the effects that patient education levels have on compliance. Methods: This study used data from the 2017 National Health Interview Survey, a nationally representative cross-sectional survey of non-institutionalized US adults. The research team limited analysis to adults who reported a limitation due to musculoskeletal problems (n = 2,672). Outcomes included physician recommendations to increase physical activity, reduce fat/calories, or lose weight, and whether they enacted these behavioral changes. Adjusted logistic regression models examined whether compliance with doctor's instructions differed by education level. Results: Adjusted models show patients advised to change physical activity, diet, and weight were more likely to report attempted behavior change. Education was positively associated with likelihood of complying with physician advice to increase physical activity. Among patients not advised to change behaviors by a physician, education was positively associated with current behavior change attempts. Conclusion: This study suggests that physician recommendations are relevant predictors of reported behavior change in individuals with MSD. Although education plays an important role in this association, the relationship is complex and multifaceted. Future studies should explore how compliance may be impacted by other factors, such as physician message type.

Dietary supplementation of gingerols- and shogaols-enriched ginger root extract attenuate pain-associated behaviors while modulating gut microbiota and metabolites in rats with spinal nerve ligation.

Neuroinflammation is a central factor in neuropathic pain (NP). Ginger is a promising bioactive compound in NP management due to its anti-inflammatory property. Emerging evidence suggests that gut microbiome and gut-derived metabolites play a key role in NP. We evaluated the effects of two ginger root extracts rich in gingerols (GEG) and shogaols (SEG) on pain sensitivity, anxiety-like behaviors, circulating cell-free mitochondrial DNA (ccf-mtDNA), gut microbiome composition, and fecal metabolites in rats with NP. Sixteen male rats were divided into four groups: sham, spinal nerve ligation (SNL), SNL+0.75%GEG in diet, and SNL+0.75%SEG in diet groups for 30 days. Compared to SNL group, both SNL+GEG and SNL+SEG groups showed a significant reduction in pain- and anxiety-like behaviors, and ccf-mtDNA level. Relative to the SNL group, both SNL+GEG and SNL+SEG groups increased the relative abundance of Lactococcus, Sellimonas, Blautia, Erysipelatoclostridiaceae, and Anaerovoracaceae, but decreased that of Prevotellaceae UCG-001, Rikenellaceae RC9 gut group, Mucispirillum and Desulfovibrio, Desulfovibrio, Anaerofilum, Eubacterium siraeum group, RF39, UCG-005, Lachnospiraceae NK4A136 group, Acetatifactor, Eubacterium ruminantium group, Clostridia UCG-014, and an uncultured Anaerovoracaceae. GEG and SEG had differential effects on gut-derived metabolites. Compared to SNL group, SNL+GEG group had higher level of 1'-acetoxychavicol acetate, (4E)-1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one, NP-000629, 7,8-Dimethoxy-3-(2-methyl-3-buten-2-yl)-2H-chromen-2-one, 3-{[4-(2-Pyrimidinyl)piperazino]carbonyl}-2-pyrazinecarboxylic acid, 920863, and (1R,3R,7R,13S)-13-Methyl-6-methylene-4,14,16-trioxatetracyclo[11.2.1.0∼1,10∼.0∼3,7∼]hexadec-9-en-5-one, while SNL+SEG group had higher level for (±)-5-[(tert-Butylamino)-2'-hydroxypropoxy]-1_2_3_4-tetrahydro-1-naphthol and dehydroepiandrosteronesulfate. In conclusion, ginger is a promising functional food in the management of NP, and further investigations are necessary to assess the role of ginger on gut-brain axis in pain management.