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Scientific Reports Jun 2024Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction....
Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.
Topics: Animals; MicroRNAs; Astrocytes; Mice; Septins; Diabetic Neuropathies; Diabetes Mellitus, Type 2; Male; Neuralgia; Disease Models, Animal
PubMed: 38906977
DOI: 10.1038/s41598-024-65096-z -
Frontiers in Neurology 2024Transcutaneous auricular vagus nerve stimulation (taVNS) has garnered attention for stroke rehabilitation, with studies demonstrating its benefits when combined with...
BACKGROUND
Transcutaneous auricular vagus nerve stimulation (taVNS) has garnered attention for stroke rehabilitation, with studies demonstrating its benefits when combined with motor rehabilitative training or delivered before motor training. The necessity of concurrently applying taVNS with motor training for post-stroke motor rehabilitation remains unclear. We aimed to investigate the necessity and advantages of applying the taVNS concurrently with motor training by an electromyography (EMG)-triggered closed-loop system for post-stroke rehabilitation.
METHODS
We propose a double-blinded, randomized clinical trial involving 150 stroke patients assigned to one of three groups: concurrent taVNS, sequential taVNS, or sham control condition. In the concurrent group, taVNS bursts will synchronize with upper extremity motor movements with EMG-triggered closed-loop system during the rehabilitative training, while in the sequential group, a taVNS session will precede the motor rehabilitative training. TaVNS intensity will be set below the pain threshold for both concurrent and sequential conditions and at zero for the control condition. The primary outcome measure is the Fugl-Meyer Assessment of Upper Extremity (FMA-UE). Secondary measures include standard upper limb function assessments, as well as EMG and electrocardiogram (ECG) features.
ETHICS AND DISSEMINATION
Ethical approval has been granted by the Medical Ethics Committee, affiliated with Zhujiang Hospital of Southern Medical University for Clinical Studies (2023-QX-012-01). This study has been registered on ClinicalTrials (NCT05943431). Signed informed consent will be obtained from all included participants. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings.
DISCUSSION
This study represents a pioneering effort in directly comparing the impact of concurrent taVNS with motor training to that of sequential taVNS with motor training on stroke rehabilitation. Secondly, the incorporation of an EMG-triggered closed-loop taVNS system has enabled the automation and individualization of both taVNS and diverse motor training tasks-a novel approach not explored in previous research. This technological advancement holds promise for delivering more precise and tailored training interventions for stroke patients. However, it is essential to acknowledge a limitation of this study, as it does not delve into examining the neural mechanisms underlying taVNS in the context of post-stroke rehabilitation.
PubMed: 38903173
DOI: 10.3389/fneur.2024.1379451 -
Zhen Ci Yan Jiu = Acupuncture Research Jun 2024To observe the effect of heat-reinforcing needling (HRN) on synovial inflammation, hypoxia-inducible factor-1α (HIF-1α) and glycolytic activity in serum and synovial...
OBJECTIVES
To observe the effect of heat-reinforcing needling (HRN) on synovial inflammation, hypoxia-inducible factor-1α (HIF-1α) and glycolytic activity in serum and synovial tissue in rabbits with cold syndrome of rheumatoid arthritis (RA), so as to explore its mechanisms underlying improvement of RA.
METHODS
A total of 32 rabbits were randomly divided into normal, model, inhibitor and HRN groups, with 8 rabbits in each group. The RA with cold syndrome model was induced by injecting ovalbumin dry powder and Freund's complete adjuvant combined with cold freezing. Rabbits in the inhibitor group were intraperitoneally injected with 2-methoxyestradiol (2.5 mg/kg), rabbits in the HRN group were received HRN at bilateral "Zusanli" (ST36) for 30 min. The treatments were conducted once daily for 14 consecutive days. After the interventions, the knee circumference and pain threshold were measured. The contents of nicotinamide adenine dinucleotide phosphoric (NADPH), Hexokinase II (HK2) and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) in serum of rabbits were detected by ELISA. The pathological morphology of synovial tissue of the knee joints were observed by HE staining. The positive expressions of tumor necrosis factor (TNF-α), interleukin (IL)-1β, IL-6 and IL-17 in synovial tissue of knee joint were detected by immunohistochemistry. The content of lactic acid in synovial tissue of rabbit knee joint was detected by spectrophotometry. The expression levels of HIF-1α, pyruvate kinase 2 (PKM2) and lactate dehydrogenase (LDHA) in synovial tissue of knee joint were detected by Western blot.
RESULTS
After intervention, compared with the normal group, the knee circumference was significantly enlarged (<0.05), the pain threshold was significantly decreased (<0.05);the synovial tissue of knee joints showed significant cell proliferation and inflammatory infiltration, the pathological score was significantly increased (<0.05);positive expressions of TNF-α, IL-1β, IL-6 and IL-17, the content of lactic acid in synovial tissue, the contents of NADPH, HK2 and PFKFB3 in serum, and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were increased (all <0.05) in the model group. Compared with model group, the circumference of knee joint was significantly decreased (<0.05), the pain threshold was significantly increased (<0.05);in synovial tissue, the pathological score was decreased (<0.05);the positive expressions of TNF-α, IL-1β, IL-6 and IL-17 in synovial tissue were decreased (<0.05), the lactic acid content in synovial tissue was decreased (<0.05);the contents of NADPH, HK2 and PFKFB3 in serum and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were decreased (<0.05) in inhibitor group and HRN group. Compared with the inhibitor group, the synovial pathological score was significantly increased (<0.05), positive expressions of TNF-α, IL-1β, IL-6 and IL-17, the content of lactic acid in synovial tissue, the contents of NADPH, HK2 and PFKFB3 in serum, and the protein expression levels of HIF-1α, PKM2 and LDHA in synovial tissue were increased (all <0.05) in HRN group.
CONCLUSIONS
HRN can increase the pain threshold, reduce the knee circumference and inhibit the inflammatory response in rabbits with cold syndrome of RA. The possible mechanism is related to the down-regulation of HIF-1α and glycolysis activity.
Topics: Animals; Rabbits; Hypoxia-Inducible Factor 1, alpha Subunit; Glycolysis; Humans; Arthritis, Rheumatoid; Male; Acupuncture Therapy; Female; Tumor Necrosis Factor-alpha; Acupuncture Points; Interleukin-6
PubMed: 38897802
DOI: 10.13702/j.1000-0607.20230487 -
Journal of Neuroscience Research Jun 2024This work attempted to clarify the interaction of cognition and pain sensitization during a paradigm of Temporal Summation of Second Pain (TSSP). We analyzed pain...
This work attempted to clarify the interaction of cognition and pain sensitization during a paradigm of Temporal Summation of Second Pain (TSSP). We analyzed pain ratings and electroencephalographic (EEG) activity obtained from 21 healthy participants during the presentation of four experimental conditions that differed in the manipulation of attention to painful stimuli or working memory load (Attention to hand & TSSP; 0-back & TSSP (low cognitive load); 2-back & TSSP (high cognitive load); 2-back (without pain)). We found that the TSSP was reduced when the attention was diverted and the cognitive load increased, and this reduction was accompanied by higher midfrontal theta activity and lower posterior alpha and central beta activity. Although it is well established that TSSP is a phenomenon that occurs at the spinal level, here we show that it is also affected by supraspinal attentional mechanisms. Delivery of painful repeated stimuli did not affect the performance of the 2-back task but was associated with smaller amplitudes of attentional event-related potentials (ERPs) after standard stimuli (not the target). The study of brain activity during TSSP allowed to clarify the role of top-down attentional modulation in pain sensitization processes. Results contribute to a better understanding of cognitive dysfunction in pain conditions and reinforce the use of therapeutic strategies based on distracting attention away from pain.
Topics: Humans; Male; Female; Electroencephalography; Adult; Young Adult; Pain; Cognition; Attention; Pain Measurement; Evoked Potentials; Memory, Short-Term; Brain; Pain Threshold
PubMed: 38895850
DOI: 10.1002/jnr.25363 -
BioRxiv : the Preprint Server For... Jun 2024G protein-coupled receptors (GPCRs) are efficient Guanine nucleotide exchange factors (GEFs) and exchange GDP to GTP on the Gα subunit of G protein heterotrimers in...
G protein-coupled receptors (GPCRs) are efficient Guanine nucleotide exchange factors (GEFs) and exchange GDP to GTP on the Gα subunit of G protein heterotrimers in response to various extracellular stimuli, including neurotransmitters and light. GPCRs primarily broadcast signals through activated G proteins, GαGTP, and free Gβγ, and are major disease drivers. Evidence shows that the ambient low threshold signaling required for cells is likely supplemented by signaling regulators such as non-GPCR GEFs and Guanine nucleotide Dissociation Inhibitors (GDIs). Activators of G protein Signaling 3 (AGS3) are recognized as a GDI involved in multiple health and disease-related processes. Nevertheless, understanding of AGS3 is limited, and no significant information is available on its structure-function relationship or signaling regulation in living cells. Here, we employed structure-guided engineering of a novel optogenetic GDI, based on the AGS3's G protein regulatory (GPR) motif, to understand its GDI activity and induce standalone Gβγ signaling in living cells on optical command. Our results demonstrate that plasma membrane recruitment of OptoGDI efficiently releases Gβγ, and its subcellular targeting generated localized PIP3 and triggered macrophage migration. Therefore, we propose OptoGDI as a powerful tool for optically dissecting GDI-mediated signaling pathways and triggering GPCR-independent Gβγ signaling in cells and .
PubMed: 38895415
DOI: 10.1101/2024.06.04.597473 -
Journal of Oral Rehabilitation Jun 2024Although awake bruxism is associated with temporomandibular disorder (TMD) as well as head and neck pain, the effects of physical therapy and bruxism education to...
BACKGROUND
Although awake bruxism is associated with temporomandibular disorder (TMD) as well as head and neck pain, the effects of physical therapy and bruxism education to address these factors have not been investigated.
OBJECTIVE
The aim of this study was to evaluate the effects of oro-facial manual therapy and bruxism neuroscience education (BNE) on awake bruxism over a 3-week period with an open-ended follow-up questionnaire after 3 months.
METHODS
Subjects (n = 28) were randomly allocated to one of two groups, an intervention group and a control group. Data regarding disability, function and pain were collected pre- and post-assessment, with all measures administered in a single-blind fashion. Participants in both groups received six treatment sessions during this period. In addition to manual therapy, participants were provided with information on the neurophysiological mechanisms of bruxism and contributing factors. Individual behavioural guidelines and daily exercises were determined in consultation with the therapist. An introduction to a bruxism specific app (Brux.App) was also provided, which all participants used as an adjunct to their treatment.
RESULTS
The intervention group demonstrated notable improvement as indicated by their scores in the Neck Disability Index (NDI) (p = .008), Pain Disability Index (PDI) (p = .007) and Jaw Disability List (JDL) (p = .03). Furthermore, clinical assessments of the temporomandibular joint (TMJ) revealed a significant progress in terms of mouth opening (p = .03) and lateral jaw movement (laterotrusion) (p = .03). The mechanical pain threshold (PTT) of both the masseter (p = .02) and temporalis muscle (p = .05) also showed significant improvement. At 3-month follow-up, the questionnaire revealed that the majority of the intervention group (13/15, 87%) reported a benefit from the treatment.
CONCLUSION
The reduction in pain and disability together with improvement in function and increased coping suggest a potential modification of awake bruxism through specialised musculoskeletal intervention and BNE tailored to the individual patient.
PubMed: 38894567
DOI: 10.1111/joor.13740 -
Journal of Oral Rehabilitation Jun 2024Activation of β adrenergic receptors reduces cutaneous mechanical pain thresholds in rats. While β adrenergic receptor activation may contribute to mechanisms that...
BACKGROUND
Activation of β adrenergic receptors reduces cutaneous mechanical pain thresholds in rats. While β adrenergic receptor activation may contribute to mechanisms that underlie temporomandibular joint pain, its effect on masticatory muscle pain sensitivity is uncertain.
OBJECTIVES
The current study sought to determine the extent to which β adrenergic receptors are expressed by masticatory muscle afferent fibres, and to assess the effect of local activation of these receptors on the mechanical sensitivity of masticatory muscle afferent fibres in rats.
METHODS
Trigeminal ganglion neurons that innervate the rat (n = 12) masseter muscle and lower lip were identified by tissue injection of fluorescent dyes and were then stained with antibodies against β or β adrenergic receptors. Extracellular recordings from 60 trigeminal ganglion neurons that innervate the masticatory muscle were undertaken in a second group of anaesthetised rats of both sexes (n = 37) to assess afferent mechanical activation thresholds. Thresholds were assessed before and after injection of the β adrenergic receptor agonists into masticatory muscle.
RESULTS
β and β adrenergic receptor expression was greater in labial skin than in masticatory muscle ganglion neurons (p < .05, one-way ANOVA, Holm-Sidak test). There was a higher expression of β adrenergic receptors in masticatory muscle ganglion neurons in males than in females. The mixed β agonist isoproterenol increased afferent mechanical activation threshold in male but not female rats (p < .05, Mann-Whitney test). In male rats, salbutamol, a β selective agonist, also increased afferent mechanical activation threshold but hydralazine, a vasodilator, did not (p < .05, Mann-Whitney test).
CONCLUSION
Activation of β adrenergic receptors decreases the mechanical sensitivity of masticatory muscle afferent fibres in a sex-related manner.
PubMed: 38894554
DOI: 10.1111/joor.13787 -
Journal of Clinical Medicine May 2024: The investigation of C-fiber-evoked ultralow-level responses (ULEPs) at somatic sites is difficult in clinical practice but may be useful in patients with small fiber...
: The investigation of C-fiber-evoked ultralow-level responses (ULEPs) at somatic sites is difficult in clinical practice but may be useful in patients with small fiber neuropathy. Aim: The aim of the study was to investigate changes in LEPs and ULEPs in patients with fibromyalgia affected or not by abnormal intraepidermal innervation. : We recorded LEPs and ULEPs of the hand, thigh and foot in 13 FM patients with a normal skin biopsy (NFM), 13 patients with a reduced intraepidermal nerve fiber density (IENFD) (AFM) and 13 age-matched controls. We used a YAP laser, changing the energy and spot size at the pain threshold for LEPs and at the heat threshold for ULEPs. : ULEPs occurred at a small number of sites in both the NFM and AFM groups compared to control subjects. The absence of ULEPs during foot stimulation was characteristic of AFM patients. The amplitude of LEPs and ULEPs was reduced in patients with AFM at the three stimulation sites, and a slight reduction was also observed in the NFM group. : The present preliminary results confirmed the reliability of LEPs in detecting small fiber impairments. The complete absence of ULEPs in the upper and lower limbs, including the distal areas, could confirm the results of LEPs in patients with small fiber impairments. Further prospective studies in larger case series could confirm the present findings on the sensitivity of LEP amplitude and ULEP imaging in detecting small fiber impairments and the development of IENFD in FM patients.
PubMed: 38892789
DOI: 10.3390/jcm13113078 -
Journal of Clinical Medicine May 2024: The aim of this meta-analysis was to determine the effects of respiratory muscle training (RMT) on functional ability, pain-related outcomes, and respiratory function... (Review)
Review
Effects of Respiratory Muscle Training on Functional Ability, Pain-Related Outcomes, and Respiratory Function in Individuals with Low Back Pain: Systematic Review and Meta-Analysis.
: The aim of this meta-analysis was to determine the effects of respiratory muscle training (RMT) on functional ability, pain-related outcomes, and respiratory function in individuals with sub-acute and chronic low back pain (LBP). : The study selection was as follows: (participants) adult individuals with >4 weeks of LBP; (intervention) RMT; (comparison) any comparison RMT (inspiratory or expiratory or mixed) versus control; (outcomes) postural control, lumbar disability, pain-related outcomes, pain-related fear-avoidance beliefs, respiratory muscle function, and pulmonary function; and (study design) randomized controlled trials. : 11 studies were included in the meta-analysis showing that RMT produces a statistically significant increase in postural control (mean difference (MD) = 21.71 [12.22; 31.21]; decrease in lumbar disability (standardized mean difference (SMD) = 0.55 [0.001; 1.09]); decrease in lumbar pain intensity (SMD = 0.77 [0.15; 1.38]; increase in expiratory muscle strength (MD = 8.05 [5.34; 10.76]); and increase in forced vital capacity (FVC) (MD = 0.30 [0.03; 0.58]) compared with a control group. However, RMT does not produce an increase in inspiratory muscle strength (MD = 18.36 [-1.61; 38.34]) and in forced expiratory volume at the first second (FEV1) (MD = 0.36 [-0.02; 0.75]; and in the FEV1/FVC ratio (MD = 1.55 [-5.87; 8.96]) compared with the control group. : RMT could improve expiratory muscle strength and FVC, with a moderate quality of evidence, whereas a low quality of evidence suggests that RMT could improve postural control, lumbar disability, and pain intensity in individuals with sub-acute and chronic LBP. However, more studies of high methodological quality are needed to strengthen the results of this meta-analysis.
PubMed: 38892764
DOI: 10.3390/jcm13113053 -
International Journal of Molecular... May 2024Synthetic deer antler peptides (TSKYR, TSK, and YR) stimulate the proliferation of human chondrocytes and osteoblasts and increase the chondrocyte content of collagen...
Synthetic deer antler peptides (TSKYR, TSK, and YR) stimulate the proliferation of human chondrocytes and osteoblasts and increase the chondrocyte content of collagen and glycosamino-glycan in vitro. This study investigated the peptide mixture's pain relief and chondroprotective effect in a rat model of collagenase-induced osteoarthritis. Thirty-six adult male Sprague-Dawley rats were divided into three groups: control (saline), positive control (hyaluronic acid), and ex-perimental (peptides). Intra-articular collagenase injections were administered on days 1 and 4 to induce osteoarthritis in the left knees of the rats. Two injections of saline, hyaluronic acid, or the peptides were injected into the same knees of each corresponding group at the beginning of week one and two, respectively. Joint swelling, arthritic pain, and histopathological changes were evaluated. Injection of the peptides significantly reduced arthritic pain compared to the control group, as evidenced by the closer-to-normal weight-bearing and paw withdrawal threshold test results. Histological analyses showed reduced cartilage matrix loss and improved total cartilage degeneration score in the experimental versus the control group. Our findings suggest that intra-articular injection of synthetic deer antler peptides is a promising treatment for osteoarthritis.
Topics: Animals; Injections, Intra-Articular; Antlers; Osteoarthritis, Knee; Male; Deer; Rats; Rats, Sprague-Dawley; Peptides; Disease Models, Animal; Hyaluronic Acid; Cartilage, Articular; Collagenases
PubMed: 38892229
DOI: 10.3390/ijms25116041