Role of Exercise on Inflammation Cytokines of Neuropathic Pain in Animal Models.

Neuropathic pain (NP) resulting from a lesion or disease of the somatosensory system can lead to loss of function and reduced life quality. Neuroinflammation plays a vital role in the development and maintenance of NP. Exercise as an economical, effective, and nonpharmacological treatment, recommended by clinical practice guidelines, has been proven to alleviate chronic NP. Previous studies have shown that exercise decreases NP by modifying inflammation; however, the exact mechanisms of exercise-mediated NP are unclear. Therefore, from the perspective of neuroinflammation, this review mainly discussed the effects of exercise on inflammatory cytokines in different parts of NP conduction pathways, such as the brain, spinal cord, dorsal root ganglion, sciatic nerve, and blood in rat/mice models. Results suggested that exercise training could modulate neuroinflammation, inhibit astrocyte glial cell proliferation and microglial activation, alter the macrophage phenotype, reduce the expression of proinflammatory cytokines, increase anti-inflammatory cytokine levels, and positively modulate the state of the immune system, thereby relieving NP.

Associations between back pain incidence, and physical activity and sedentary behaviours: A prospective cohort study with data from over 365,000 participants.

OBJECTIVE: To examine the associations between (i) various types of physical activity and the risk of back pain incidence, and (ii) the influence of substituting sedentary behaviours with physical activities on back pain incidence. DESIGN: A prospective cohort study. METHODS: We analyzed UK Biobank data collected from 365,307 participants who were free of back pain at baseline. The exposures were total, light, moderate and vigorous physical activity, and sedentary behaviours. The outcome was back pain incidence. The main statistical models were the Cox proportional hazard model and the isotemporal substitution model. RESULTS: In the follow-up time (median, 12.97 years; inter-quartile range, 12.10-13.71), 25,189 individuals developed back pain. The associations between all types of physical activity and incident back pain were significantly non-linear (p < 0.001) among the general population and other subgroups. High physical activity was associated with a decreased risk of back pain compared with no physical activity. The lowest risk occurred in the 1801-2400 MET-min/week subgroup of total physical activity (HR 0.64, 95% CI 0.59-0.69), approximately consisting of 1200, 600, and 600 MET-min/week of light, moderate and vigorous physical activity, respectively. Extremely high vigorous physical activity was related to high risk, specifically in males (HR 1.13, 95% CI 1.02-1.25). Replacing 1 hour/day of sedentary behaviours with an equal time of physical activity reduced the risk of incident back pain by 2%-8% (p < 0.05). CONCLUSION: Physical activity was related to a reduced risk of back pain incidence (except over-high vigorous physical activity). Substituting sedentary behaviours with physical activities reduced the risk of future back pain.

Demographic and clinical characteristics associated with failure of physical therapy in chronic low back pain: a secondary analysis from a randomized controlled trial.

BACKGROUND: The effect of physical therapy on pain and disability alleviation in patients with chronic low back pain (cLBP) has been demonstrated, but the risk factors for treatment failure remain unknown. AIM: To explore the associations of baseline demographic and clinical characteristics with treatment failure after physical therapy intervention for cLBP. DESIGN: A secondary analysis of a single-blind randomized clinical trial. SETTING: A rehabilitation hospital. POPULATION: A total of 98 patients with cLBP completed the 12-month measurement. METHODS: Patients were randomly grouped into 3-month therapeutic aquatic exercise or physical therapy modalities. The primary outcome was treatment failure, which was defined as a decrease in the numeric rating scale to less than 2.0 points at 12-month follow-up. Associations between baseline demographic and clinical characteristics with risk of treatment failure were assessed by logistic regressions. RESULTS: The pain intensity in the failure cases was alleviated after 3-month intervention but continuously increased at 6- and 12-month follow-up (P<0.05). Old age was significantly associated with an increased risk of treatment failure (adjusted OR 3.26, 95% CI 1.11-9.60). Compared with those receiving physical therapy modalities, the patients receiving therapeutic aquatic exercise had less risk of treatment failure (adjusted OR 0.19, 95% CI 0.08-0.47), and age (P=0.022) was a modifier for this association. CONCLUSIONS: Compared with younger ones, older patients with cLBP had a higher risk of treatment failure after physical therapy and gained a stronger benefit of long-term pain alleviation from therapeutic aquatic exercise. CLINICAL REHABILITATION IMPACT: Therapeutic aquatic exercise is an effective therapy for cLBP and more helpful for preventing treatment failure than physical therapy modalities, especially for older patients.

The effect and mechanism of motor control exercise on low back pain: a narrative review.

Low back pain (LBP) is a common symptom that can occur in all ages. It is the first common cause of disability globally and is associated with over 60 million disability-adjusted life-years in a single year. Motor control exercise (MCE) has obtained increasing attention in treating LBP. However, the findings from distinct meta-analyses differed and some even reached controversial conclusions. More importantly, how MCE improves LBP-related symptoms remains unclear. The primary aim of this study is to describe the possible improvement mechanisms of MCE on LBP from brain, biochemistry, inflammatory, and neuromuscular aspects. The secondary aim is to further conclude its effectiveness and clinical application. Further understanding of mechanisms and effectiveness could be instructive for future LBP treatments and provide more information for clinicians when making prescriptions. MCE is effective in alleviating pain and disability among patients with acute and chronic LBP. Notably, the evidence for acute LBP is relatively low-quality and limited. MCE might be more effective for patients with specific LBP characteristics, especially those with pre-diagnosis of impaired transversus abdominis recruitment, intermediate pain intensity, and longer MCE training duration. MCE could remap brain representation and reverse negative brain alternation, induce exercise-induced hypoalgesia, mediate anti-inflammatory response, retain normal activation, and improve morphological deficits.

The emerging roles of N6-methyladenosine in osteoarthritis.

Finding new biomarkers and molecular targets to guide OA treatment remains a significant challenge. One of the most frequent forms of RNA methylation, N6-methyladenosine (m6A), can affect gene expression and RNA transcription, processing, translation, and metabolism. Osteoarthritis (OA) can cause disability and pain degenerative disease, reduce the quality of life of the elderly, and increase the social and economic burden. Changes in m6A levels are crucial in OA progress. In this review, the discussion will concentrate on the role that m6A plays in OA occurrence and progression. The m6A involved in the OA process mainly includes METTL3 and FTO. Current studies on m6A and OA primarily focus on four signaling pathways, namely, NF-κB, LNCRNAs, ATG7, and Bcl2. m6A participates in these signaling pathways and affects cellular inflammation, apoptosis, senescence, and autophagy, thus controlling the OA process. The modification of m6A affects so many signaling pathways. For the treatment of OA, it may represent a viable new therapeutic target.

Mechanisms of exercise for diabetic neuropathic pain.

Diabetic neuropathic pain (DNP) is a common disease that affects the daily lives of diabetic patients, and its incidence rate is very high worldwide. At present, drug and exercise therapies are common treatments for DNP. Drug therapy has various side effects. In recent years, exercise therapy has received frequent research and increasing attention by many researchers. Currently, the treatment of DNP is generally symptomatic. We can better select the appropriate exercise prescription for DNP only by clarifying the exercise mechanism for its therapy. The unique pathological mechanism of DNP is still unclear and may be related to the pathological mechanism of diabetic neuropathy. In this study, the mechanisms of exercise therapy for DNP were reviewed to understand better the role of exercise therapy in treating DNP.

Research trends and frontiers in exercise for movement disorders: A bibliometric analysis of global research from 2010 to 2021.

Objective: To conduct a bibliometric analysis of trends and frontiers on exercise-based non-pharmacological treatments for movement disorders published between 2010 and 2021. Methods: The Web of Science (WOS) Core Collection database was searched for articles published between 2010 and 2021. The CiteSpace software was used for in-depth analysis of the countries, institutions, journals, and collaboration networks among authors and their types of articles, developmental directions, references, and hot keywords of published articles. Results: A total of 2,626 published articles were retrieved by search formula and included in the analysis. The number of publications fluctuated during this period, with 96 countries, 3,058 institutions, and 886 academic journals having published articles in this area, with subject classifications that focused on Clinical Neurology and Neurosciences. The United States has maintained its dominant and most influential position in exercise-based non-pharmacological research on movement disorders. Among research institutions and journals, the League of European Research Universities and Movement Disorders journals published the highest number of academic articles. In the last five years, the hot research topics by burst keyword analysis, are focused on treatments, research advances, and clinical treatments. Conclusion: Research on exercise-based non-pharmacological treatments for movement disorders is generally on the rise from 2010 to 2021. The bibliometric analysis of this area will help provide potential collaborations among researchers, frontiers, and directions for development.

Exercise for osteoporosis: A literature review of pathology and mechanism.

Osteoporosis (OP) is a disease that weakens bones and has a high morbidity rate worldwide, which is prevalent among the elderly, particularly, women of postmenopausal age. The dynamic balance between bone formation and resorption is necessary for normal bone metabolism. Many factors, including aging, estrogen deficiency, and prolonged immobilization, disrupt normal apoptosis, autophagy, and inflammation, leading to abnormal activation of osteoclasts, which gradually overwhelm bone formation by bone resorption. Moderate exercise as an effective non-drug treatment helps increase bone formation and helps relieve OP. The possible mechanisms are that exercise affects apoptosis and autophagy through the release of exercise-stimulated myohormone and the secretion of anti-inflammatory cytokines via mechanical force. In addition, exercise may also have an impact on the epigenetic processes involved in bone metabolism. Mechanical stimulation promotes bone marrow mesenchymal stem cells (BMSCs) to osteogenic differentiation by altering the expression of non-coding RNAs. Besides, by reducing DNA methylation, the mechanical stimulus can also alter the epigenetic status of osteogenic genes and show associated increased expression. In this review, we reviewed the possible pathological mechanisms of OP and summarized the effects of exercise on bone metabolism, and the mechanisms by which exercise alleviates the progression of OP, to provide a reference for the prevention and treatment of OP.

The Last Decade Publications on Diabetic Peripheral Neuropathic Pain: A Bibliometric Analysis.

Background: Diabetic peripheral neuropathic pain (DPNP) is a usual complication of diabetes with a high incidence and mortality. Many diabetes-related studies have been published in various journals. However, bibliometrics and visual analyses in the domain of DPNP research are still lacking. The study aimed to offer a visual method to observe the systematic overview of global research in this field from 2011 to 2021. Methods: The publications from the Science Citation Index Expanded in Web of Science (WOS) in the past 11 years (from 2011 to 2021) were collected and sorted out, and those related to DPNP were extracted and analyzed. The article language was limited in English. Then, CiteSpace V was used for the bibliometric analysis of the extracted literature. Results: A total of 1,422 articles met the inclusion criteria. A continuous but unstable growth in the amounts of papers published on DPNP was observed over the last 11 years. The subject sort of the 1,422 papers mainly concentrates on Endocrinology Metabolism, Clinical neurology and Neurosciences from the WOS. According to the research contribution in the field of DPNP, the United States occupies a leading position, with the highest amounts of publications, citations, open access, and the H- index. Conclusion: This study provides a visual analysis method for the trend of DPNP, and offers some hidden serviceable information that may define new directions for future research.

Long Non-coding RNA and mRNA Expression Change in Spinal Dorsal Horn After Exercise in Neuropathic Pain Rats.

Exercise can help inhibition of neuropathic pain (NP), but the related mechanism remains being explored. In this research, we performed the effect of swimming exercise on the chronic constriction injury (CCI) rats. Compared with CCI group, the mechanical withdrawal threshold of rats in the CCI-Swim group significantly increased on the 21st and 28th day after CCI surgery. Second-generation RNA-sequencing technology was employed to investigate the transcriptomes of spinal dorsal horns in the Sham, CCI, and CCI-Swim groups. On the 28th day post-operation, 306 intersecting long non-coding RNAs (lncRNAs) and 173 intersecting mRNAs were observed between the CCI vs Sham group and CCI-Swim vs CCI groups. Then, the biological functions of lncRNAs and mRNAs in the spinal dorsal horn of CCI rats were then analyzed. Taking the results together, this study could provide a novel perspective for the treatment for NP.

The role of circular RNAs in neuropathic pain.

Neuropathic pain (NP) results from a lesion or disease of the nervous system and accompanied by chronic pain, leading a serious public health issue and economic burden. In terms of the NP mechanisms remaining poorly understood, circular RNAs (circRNAs), owing to their high stability and evolutionary conservation, are expected to be used as potential therapeutic targets or diagnostic biomarkers. In this review, we concisely discuss the characteristics and biological functions of circRNAs. As emerging evidence we reviewed, deregulation of circRNAs (e.g., circ-Filip1l, circHIPK3, ciRS-7, circRNA.2837, circ-Ankib1 and circAnks1a) were involved in NP development. It suggested that specific circRNAs modulated through sponging their target miRNAs and thus regulated the homologous downstream mRNAs and proteins in neuropathic pain. These findings provide a theoretical basis for circRNAs use as biomarkers and therapeutic targets in neuropathic pain.

Excessive Treadmill Training Produces different Cardiac-related MicroRNA Profiles in the Left and Right Ventricles in Mice.

High-volume training followed by inadequate recovery may cause overtraining. This process may undermine the protective effect of regular exercise on the cardiovascular system and may increase the risk of pathological cardiac remodelling. We evaluated whether chronic overtraining changes cardiac-related microRNA profiles in the left and right ventricles. C57BL/6 mice were divided into the control, normal training, and overtrained by running without inclination, uphill running or downhill running groups. After an 8-week treadmill training protocol, the incremental load test and training volume results showed that the model had been successfully established. The qRT-PCR results showed increased cardiac miR-1, miR-133a, miR-133b, miR-206, miR-208b and miR-499 levels in the left ventricle of the downhill running group compared with the left ventricle of the control group. Similarly, compared with the control group, the downhill running induced increased expression of miR-21, miR-17-3p, and miR-29b in the left ventricle. Unlike the changes in the left ventricle, no difference in the expression of the tested miRNAs was observed in the right ventricle. Briefly, our results indicated that overtraining generally affects key miRNAs in the left ventricle (rather than the right ventricle) and that changes in individual miRNAs may cause either adaptive or maladaptive remodelling with overtraining.

Crosstalk Between MicroRNAs and Circular RNAs in Human Diseases: A Bibliographic Study.

Background: Crosstalk of circular RNAs (circRNAs) and microRNAs (miRNAs) refers to the communication and co-regulation between them. circRNAs can act as miRNAs sponges, and miRNAs can mediate circRNAs. They interact to regulate gene expression and participate in the occurrence and development of various human diseases. Methods: Publications on the crosstalk between miRNAs and circRNAs in human diseases were collected from Web of Science. The collected material was limited to English articles and reviews. CiteSpace and Microsoft Excel were used for bibliographic analysis. Results: A total of 1,013 papers satisfied the inclusion criteria. The publication outputs and types of researched diseases were analyzed, and bibliographic analysis was used to characterize the most active journals, countries, institutions, keywords, and references. The annual number of publications remarkably increased from 2011 to 2020. Neoplasm was the main research hotspot (n = 750 publications), and Biochemical and Biophysical Research Communications published the largest number of papers (n = 64) on this topic. Nanjing Medical University ranked first among institutions actively engaged in this field by publishing 72 papers, and China contributed 96.84% of the 1,013 papers (n = 981 publications) analyzed. Burst keywords in recent years included glioblastoma, miR-7, skeletal muscle, and non-coding RNA. Conclusion: Crosstalk between miRNAs and circRNAs in human diseases is a popular research topic. This study provides important clues on research trends and frontiers.

Interactions Among lncRNA/circRNA, miRNA, and mRNA in Musculoskeletal Degenerative Diseases.

Musculoskeletal degenerative diseases (MSDDs) are pathological conditions that affect muscle, bone, cartilage, joint and connective tissue, leading to physical and functional impairments in patients, mainly consist of osteoarthritis (OA), intervertebral disc degeneration (IDD), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression that play an important role in biological regulation, involving in chondrocyte proliferation and apoptosis, extracellular matrix degradation and peripheral blood mononuclear cell inflammation. Research on MSDD pathogenesis, especially on RA and AS, is still in its infancy and major knowledge gaps remain to be filled. The effects of lncRNA/circRNA-miRNA-mRNA axis on MSDD progression help us to fully understand their contribution to the dynamic cellular processes, provide the potential OA, IDD, RA and AS therapeutic strategies. Further studies are needed to explore the mutual regulatory mechanisms between lncRNA/circRNA regulation and effective therapeutic interventions in the pathology of MSDD.

Comparative Transcriptome Profiling Reveals Changes of microRNAs Response to Exercise in Rats with Neuropathic Pain.

There is accumulating evidence showing that exercise therapy may play an active role in peripheral neuropathic pain (NP), but its mechanism is still unclear. Studies have found that microRNAs (miRNAs) may play a role in NP by regulating pain-related target genes. Therefore, we aimed to explore the changes of miRNA and mRNA of dorsal root ganglion (DRG) after NP in response to exercise with transcriptome technology. The chronic constriction injury (CCI) model was established, and rats were randomly allocated into three groups, namely, the sham-operated, CCI, and CCI-exercised groups. L4-L6 DRG tissue was taken for RNA-sequencing, and the differentially expressed genes (DEGs) were determined through bioinformatics analysis. Real-time PCR was used to confirm the accuracy. A total of 4 overlapping differentially expressed miRNAs and 186 overlapping differentially expressed mRNAs were identified in the two comparisons of the sham-operated group versus the CCI group and the CCI group versus the CCI-exercised group. Among these DEGs, miR-145-5p, miR-341, miR-300-5p, miR-653-5p, Atf3, Cacna2d1, Gal, and Ctss related to NP were validated by real-time PCR. DEGs between the CCI and CCI-exercised groups were enriched in HIF-1 signaling pathway, Rap1 signaling pathway, and neurotrophin signaling pathway. This study provides an understanding of the adaptive mechanisms after exercise of NP, and these DEGs in DRG might play a role in NP by stimulating the enriched pathways.

The Effects of Whole-Body Vibration Exercise on Anticipatory Delay of Core Muscles in Patients with Nonspecific Low Back Pain.

Objective: The objective of this study is to determine the effect of whole-body vibration (WBV) exercise on the anticipatory delay of core muscles in nonspecific low back pain (NSLBP) patients. Methods: Forty participants with NSLBP were randomly divided into the WBV group and the control group. The sEMG signals of deltoid, erector spines (ES), multifidus (MF), rectus abdominis (RA), and transversus abdominus/internal oblique muscles (TrA/IO) were recorded before and after the intervention in the weight-shifting task. The relative activation time of each muscle was calculated. Results: In the WBV group, the relative activation time of bilateral MF and bilateral TrA/IO was significantly reduced on shoulder flexion (right MF: P=0.014; left MF: P=0.011; right TrA/IO: P=0.008; left TrA/IO: P=0.026). As for shoulder abduction, except for the left TrA/IO and the left RA, the relative activation time of other muscles was significantly reduced (right ES: P=0.001; left ES: P < 0.001; right MF: P=0.001; left MF: P=0.009; right TrA/IO: P < 0.001; right RA: P=0.001). In the control group, there was no significant difference in the relative activation time of each muscle before and after the intervention (P > 0.05). Conclusions: WBV exercise can effectively alleviate the anticipatory delay of core muscles in NSLBP patients, but the long-term effects still need further study. This trial is registered with ChiCTR-TRC-13003708.

microRNA-Based Network and Pathway Analysis for Neuropathic Pain in Rodent Models.

Neuropathic pain (NP) is poorly managed, and in-depth mechanisms of gene transcriptome alterations in NP pathogenesis are not yet fully understood. To determine microRNA-related molecular mechanisms of NP and their transcriptional regulation in NP, PubMed, Embase, Web of Science and CINAHL Complete (EBSCO) were searched from inception to April 2021. Commonly dysregulated miRNAs in NP were assessed. The putative targets of these miRNAs were determined using TargetScan, Funrich, Cytoscape and String database. A total of 133 literatures containing miRNA profiles studies and experimentally verify studies were included. Venn analysis, target gene prediction analysis and functional enrichment analysis indicated several miRNAs (miR-200b-3p, miR-96, miR-182, miR-183, miR-30b, miR-155 and miR-145) and their target genes involved in known relevant pathways for NP. Targets on transient receptor potential channels, voltage-gated sodium channels and voltage-gated calcium channels may be harnessed for pain relief. A further delineation of signal processing and modulation in neuronal ensembles is key to achieving therapeutic success in future studies.

The top 100 most-cited papers in long non-coding RNAs: a bibliometric study.

Up to 90% of the human genome is transcribed into Long-noncoding RNAs (lncRNAs) that longer than 200 nucleotides but do not code for proteins. LncRNAs play a vital role in a broad range of biological process, it's dysregulations and mutations are linked to the development and progression of various complex human diseases. Given the dramatic changes and growing scientific outputs in lncRNAs field, using a quantitative measurement to analyze and characterize the existing studies has become imperative.Bibliometric analysis is a widely used tool to assess the academic influence of a publication or a country in a specific field. However, a bibliometric analysis of the top 100 most-cited papers in lncRNAs area has not been conducted. Thus, we executed a bibliometric study to identify the authors, journals, countries and institutions that contributed most to the top 100 lncRNAs list, characterize the key words and focus of top 100 most-cited papers, and detect the factors related to their successful citation. This study provides a comprehensive list of the most influential papers on lncRNAs research and demonstrates the important advances in this field, which might be benefit to researchers in their paper publication and scientific cooperation.

Association between ageing population, median age, life expectancy and mortality in coronavirus disease (COVID-19).

As of May 5, 2020, the number of confirmed coronavirus disease (COVID-19) cases has been more than 3.5 million with 243,540 deaths. We aimed to determine the associations between ageing population, median age, life expectancy at birth and COVID-19 mortality. The numbers of COVID-19 cases and deaths in the European region were obtained from the World Health Organization database. The data on percentage of the population aged 65 and over, median age and life expectancy at birth were extracted from the World Factbook of Central Intelligence Agency. A total of 56 countries/areas in the Europe reported COVID-19 cases and deaths (1,121,853 cases and 100,938 deaths) on April 20, 2020. The results showed significant positive associations between COVID-19 mortality and ageing population (r =0.274; P =0.021), median age (r =0.255; P=0.029), male median age (r =0.284; P =0.017), female median age (r =0.224; P=0.049), life expectancy at birth (r =0.336; P=0.006), male life expectancy at birth (r =0.342; P=0.005), female life expectancy at birth (r =0.312; P=0.01) in the 56 European countries/areas. This study illustrated that COVID-19 mortality was positively associated with ageing population, median age, and life expectancy at birth.