Acupressure bladder meridian alleviates anxiety disorder via HMGB1.

The aim of this study was to investigate the effects of acupressure bladder meridian (ABM) on anxiety in rats with chronic stress. METHODS: The sugar water preference (SPF), tail suspension time (TST) and forced swimming time (FST) of rats were measured. The levels of reactive oxygen species (ROS), myeloperoxidase (MPO) in hippocampus tissue, oxidative stress parameters and inflammatory cytokines were detected. Underlying mechanisms of ABM on anxiety were detected. lipopolysaccharide (LPS) stimulated PC12 cells were adopted in vitro. HMGB1 knockdown were used in PC12 cells, and related signaling was further detected. RESULTS: ABM significantly increased SPF, decreased TST and FST. ABM decreased ROS, MPO levels, decreased the levels of inflammatory cytokines. Furthermore, ABM decreased the levels of oxidative stress index. ABM reduced the expression of inflammation-related proteins mediated by HMGB1, increased nuclear factor erythroid2-related factor 2 (Nrf-2) and hemeoxygenase-1 (HO-1). In vitro PC12 cells, Rat serum (RS-ABM) treated with ABM significantly decreased LPS induced inflammation-related proteins and increased Nrf-2/HO-1 pathway. HMGB1 knockdown inhibited LPS-induced PC12 cell inflammatory signaling pathway and increased Nrf-2/HO-1 pathway. CONCLUSION: Our results demonstrated that ROS-dependent HMGB1 plays an important role in anxiety, and ABM exhibits inhibited inflammation in anxiety.

Abnormal brain activity in lumbar disc herniation patients with chronic pain is associated with their clinical symptoms.

Introduction: Lumbar disc herniation, a chronic degenerative disease, is one of the major contributors to chronic low back pain and disability. Although many studies have been conducted in the past on brain function in chronic low back pain, most of these studies did not classify chronic low back pain (cLBP) patients according to their etiology. The lack of etiologic classification may lead to inconsistencies between findings, and the correlation between differences in brain activation and clinical symptoms in patients with cLBP was less studied in the past. Methods: In this study, 36 lumbar disc herniation patients with chronic low back pain (LDHCP) and 36 healthy controls (HCs) were included to study brain activity abnormalities in LDHCP. Visual analogue scale (VAS), oswestry disability index (ODI), self-rating anxiety scale (SAS), self-rating depression scale (SDS) were used to assess clinical symptoms. Results: The results showed that LDHCP patients exhibited abnormally increased and diminished activation of brain regions compared to HCs. Correlation analysis showed that the amplitude of low frequency fluctuations (ALFF) in the left middle frontal gyrus is negatively correlated with SAS and VAS, while the right superior temporal gyrus is positively correlated with SAS and VAS, the dorsolateral left superior frontal gyrus and the right middle frontal gyrus are negatively correlated with VAS and SAS, respectively. Conclusion: LDHCP patients have brain regions with abnormally increased and abnormally decreased activation compared to healthy controls. Furthermore, some of the abnormally activated brain regions were correlated with clinical pain or emotional symptoms.

Exploring the bidirectional relationship between pain and mental disorders: a comprehensive Mendelian randomization study.

BACKGROUND: The close relationship between pain and mental health problems is well-known, and psychological intervention can provide an effective alternative to medication-based pain relief. However, previous studies on the connection between pain and psychological problems, the findings thus far have been inconclusive, limiting the potential for translating psychological interventions into clinical practice. To complement the gap, this study utilized genetic data and Mendelian randomization (MR) to examine the potential relationship between pain in different parts and common mental disorders. METHODS: Based on the instrumental variables selected from the Genome-wide association study summary statistics of localized pain and mental disorders, we conducted bidirectional two-sample MR analyses to infer bidirectional causal associations between pain and mental disorders. The inverse-variance weighted MR method and MR-Egger were used as the primary statistical method according to the horizontal pleiotropy and heterogeneity level. We reported the odds ratio to infer the causal effect between pain and mental disorders. F statistic was calculated to measure the statistical efficacy of the analyses. RESULTS: Insomnia is causally related to the genetic susceptibility of multisite pain including head (OR = 1.09, 95% CI: 1.06-1.12), neck/shoulder (OR = 1.12, 95% CI: 1.07-1.16), back (OR = 1.12, 95% CI: 1.07-1.18) and hip (OR = 1.08, 95% CI: 1.05-1.10). Reversely, headache (OR = 1.14, 95% CI: 1.05-1.24), neck/shoulder pain (OR = 1.95, 95% CI: 1.03-3.68), back pain (OR = 1.40, 95% CI: 1.22-1.60), and hip pain (OR = 2.29, 95% CI: 1.18-4.45) promote the genetic liability of insomnia. Depression is strongly associated with the predisposition of multisite pain including headache (OR = 1.28, 95% CI: 1.08-1.52), neck/shoulder pain (OR = 1.32, 95% CI: 1.16-1.50), back pain (OR = 1.35, 95% CI: 1.10-1.66) and stomach/abdominal pain (OR = 1.14, 95% CI: 1.05-1.25), while headache (OR = 1.06, 95% CI: 1.03-1.08), neck/shoulder (OR = 1.09, 95% CI: 1.01-1.17), back (OR = 1.08, 95% CI: 1.03-1.14), and stomach/abdominal pain (OR = 1.19, 95% CI: 1.11-1.26) are predisposing factors for depression. Additionally, insomnia is associated with the predisposition of facial, stomach/abdominal, and knee pain, anxiety was associated with the predisposition of neck/shoulder and back pain, while the susceptibilities of hip and facial pain are influenced by depression, but these associations were unidirectional. CONCLUSIONS: Our results enhance the understanding of the complex interplay between pain and mental health and highlight the importance of a holistic approach to pain management that addresses both physical and psychological factors.

Krüppel-like factors in tumors: Key regulators and therapeutic avenues.

Krüppel-like factors (KLFs) are a group of DNA-binding transcriptional regulators with multiple essential functions in various cellular processes, including proliferation, migration, inflammation, and angiogenesis. The aberrant expression of KLFs is often found in tumor tissues and is essential for tumor development. At the molecular level, KLFs regulate multiple signaling pathways and mediate crosstalk among them. Some KLFs may also be molecular switches for specific biological signals, driving their transition from tumor suppressors to promoters. At the histological level, the abnormal expression of KLFs is closely associated with tumor cell stemness, proliferation, apoptosis, and alterations in the tumor microenvironment. Notably, the role of each KLF in tumors varies according to tumor type and different stages of tumor development rather than being invariant. In this review, we focus on the advances in the molecular biology of KLFs, particularly the regulations of several classical signaling pathways by these factors, and the critical role of KLFs in tumor development. We also highlight their strong potential as molecular targets in tumor therapy and suggest potential directions for clinical translational research.

Yijinjing Qigong intervention shows strong evidence on clinical effectiveness and electroencephalography signal features for early poststroke depression: A randomized, controlled trial.

Objective: Although Traditional Chinese Yijinjing Qigong Exercise (YJJQE) as mind-body intervention is popularly used among adults to ameliorate depressive symptoms in China, no randomized controlled trials (RCTs) are available to evaluate the effects of YJJQE in patients with poststroke depression (PSD). This study aims to explore the clinical efficacy and the neurological and psychiatric mechanism in brain network functional connectivity underlying electroencephalography (EEG). Materials and methods: A total of 60 patients, diagnosed with mild PSD, were randomly (1:1) assigned to YJJQE group (n = 30) and control group of routine segmental rehabilitation training group (n = 30) for a 60-min exercise session once a day for 3 weeks. All outcome measures were collected at baseline and 3-weeks ending intervention. The primary outcome was the 24-item Hamilton Depression Scale (HAMD-24) score, evaluation at more time points for 1 month of follow-up. The secondary outcomes were EEG data in four frequency domains (δ, θ, α, and ß), global efficiency (GE), local efficiency (LE), GE/LE curve [areas under the curve (AUC)], Phase Lag Index (PLI), (HAMD-24) Score and EEG correlation analysis. Results: All patients showed no significant differences in baseline data. After 3 weeks and 1 month of follow-up, the YJJQE group demonstrated significant decreasing changes compared to the control group on the HAMD-24 scores (p < 0.001). Furthermore, the YJJQE group also showed a significant reduction in θ wave, and an increase in both GE and LE. Compared to the control group, the YJJQE Qigong group showed significantly greater functional connectivity in the δ, θ, and ß frequency bands in the brain network of the degree of phase synchronization (p < 0.001). HAMD-24 Score and EEG correlation analysis negative correlation in the Qigong group θ wave (p < 0.001). Conclusion: Our findings demonstrated that YJJQE is estimated to effectively alleviate the depressed mood of patients with PSD by promoting the efficiency in information transmission of network functional connectivity and its integration ability in different brain regions. Therefore, the YJJQE would be useful as a non-pharmacological treatment to prevent PSD. Clinical trial registration: [http://www.chictr.org.cn/showproj.aspx?proj=55789], identifier [ChiCTR2000035588].

Transcriptome profiling of microRNAs reveals potential mechanisms of manual therapy alleviating neuropathic pain through microRNA-547-3p-mediated Map4k4/NF-κb signaling pathway.

BACKGROUND: Local neuroinflammation secondary to spinal nerve compression in lumbar disk herniation (LDH) is a key driver contributing to neuropathic pain. Manual therapy (MT), a widely used nonsurgical therapy, can relieve LDH-mediated pain by reducing inflammation. MT has attracted extensive attention; however, its mechanism remains poorly understood. MicroRNAs (miRNAs) are important regulators of pain signaling transduction, but are rarely reported in the chronic compression of dorsal root ganglia (CCD) model, and further investigation is needed to decipher whether they mediate anti-inflammatory and analgesic effects of MT. METHODS: We used a combination of in vivo behavioral and molecular techniques to study MT intervention mechanisms. Neuropathic pain was induced in a CCD rat model and MT intervention was performed according to standard procedures. Enzyme-linked immunosorbent assay (ELISA) was used to detect inflammatory cytokine levels in dorsal root ganglia (DRG). Small RNA sequencing, immunofluorescence, Western blot, and qRT-PCR were performed to screen miRNAs and their target genes and determine core factors in the pathway possibly regulated by miRNA-mediated target gene in DRG of MT-treated CCD rats. RESULTS: Compared with naive rats, small RNA sequencing detected 22 differentially expressed miRNAs in DRG of CCD rats, and compared with CCD rats, MT-treated rats presented 19 differentially expressed miRNAs, which were functionally associated with nerve injury and inflammation. Among these, miR-547-3p was screened as a key miRNA mediating neuroinflammation and participating in neuropathic pain. We confirmed in vitro that its function is achieved by directly regulating its target gene Map4k4. Intrathecal injection of miR-547-3p agomir or MT intervention significantly reduced Map4k4 expression and the expression and phosphorylation of IκBα and p65 in the NF-κB pathway, thus reducing the inflammatory cytokine levels and exerting an analgesic effect, whereas intrathecal injection of miR-547-3p antagomir led to opposite effects. CONCLUSIONS: In rats, CCD-induced neuropathic pain leads to variation in miRNA expression in DRG, and MT can intervene the transcription and translation of inflammation-related genes through miRNAs to improve neuroinflammation and alleviate neuropathic pain. MiR-547-3p may be a key target of MT for anti-inflammatory and analgesia effects, which is achieved by mediating the Map4k4/NF-κB pathway to regulate downstream inflammatory cytokines.

Effectiveness and functional magnetic resonance imaging outcomes of Tuina therapy in patients with post-stroke depression: A randomized controlled trial.

Objective: To investigate the effectiveness and functional magnetic resonance imaging (fMRI) outcomes of Tuina therapy in patients with post-stroke depression (PSD). Methods: This was a single-center, randomized, two-armed, controlled trial. Eighty-four patients with PSD were selected and randomly assigned to a Tuina therapy group or a routine rehabilitation control group. The patients underwent five 20-min treatment sessions per week over a period of 2 weeks. The primary outcome measure was change in Hamilton Depression Rating Scale (HAMD) score over the 2 weeks of intervention, whereas the secondary outcome measures were changes in Fugl-Meyer Assessment (FMA) score, Modified Barthel index (MBI), and Mini Mental State Examination (MMSE) score. Results: The Tuina group showed significantly improved HAMD scores compared to the routine rehabilitation control group (5.85, [2.54, 9.16]). For the secondary outcomes, the Tuina group showed better MMSE scores than the routine rehabilitation group (1.97, [1.19, 2.76]); however, there were no significant differences between the other secondary outcomes of both groups (P > 0.05). After 2 weeks, both groups showed a significant decrease in HAMD score compared to baseline. In addition, the Tuina group showed a significant decrease in MMSE score compared to baseline (2.35, [1.8, 2.9]); however, there were no significant differences in the MBI and FMA scores of the two group after the intervention (P > 0.05). Regarding fMRI results, the zALFF values of the right caudate nucleus, right putamen, right insula, left superior temporal gyrus, right parahippocampal gyrus, right hippocampus, left middle temporal gyrus, left angular gyrus, and left thalamus were higher in the Tuina group. In the Tuina group, the functional connectivity between the hippocampus and thalamus, and the thalamus and caudate nucleus, were significantly different (P <0.01). In addition, the zALFF value of the hippocampus was significantly negatively correlated with HAMD score. No serious adverse events were observed in both groups. Conclusion: Tuina therapy administered 10 times within 2 weeks is safe and can effectively relieve depression and improve cognitive function in patients with PSD. This finding may be closely related to the effect of Tuina therapy on the activation and functional connectivity of the hippocampus. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=55151, identifier ChiCTR200003388.

Manual therapy regulates oxidative stress in aging rat lumbar intervertebral discs through the SIRT1/FOXO1 pathway.

With the increasing burden of a globally aging population, low back pain has become one of the most common musculoskeletal disorders, caused mainly by intervertebral disc (IVD) degeneration. There are currently several clinical methods to alleviate back pain, but there is scarce attention paid as to whether they can improve age-related IVD degeneration. It is therefore difficult to conduct an in-depth evaluation of these methods. A large number of clinical studies have shown that manual therapy (MT), a widely used comprehensive alternative method, has effects on pain, the mechanisms of which require further study. In this study, MT was performed on aging rats for 6 months, and their behaviors were compared with those of a non-intervention group of aging and young rats. After the intervention, all rats were examined by X-ray to observe lumbar spine degeneration, and the IVD tissues were dissected for detection, including pathological staining, immunofluorescence, Western bolt, etc. This study demonstrated the possibility that MT intervention delay the lumbar IVD degeneration in aging rats, specifically improving the motor function and regulating senescence-associated ß-galactosidase, p53, p21, p16, and telomerase activity to retard the senescence of cells in IVDs. Moreover, MT intervention can modify oxidative stress, increase the expression of SIRT1 and FOXO1 in IVDs and decrease ac-FOXO1 expression, suggesting that MT can reduce oxidative stress through the SIRT1/FOXO1 pathway, thereby playing a role in delaying the aging of IVDs. This study shows that drug-free, non-invasive mechanical interventions could be of major significance in improving the physical function of the elderly.

Clinical Evidence for the Effects of Manual Therapy on Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis aimed to evaluate the effects of manual therapy (MT) on cancer pain, so as to provide clinical evidence for application. METHODS: Five English and Chinese databases were searched until February 29, 2020, for randomized controlled trials (RCTs) of MT for cancer pain. Articles published in the English or Chinese language were included. Two authors independently reviewed all articles and extracted the data, and any disagreements in the above process were discussed with other reviewers until the authors reached consensus. Review Manager 5.3 was used to calculate the effect size and 95% confidence intervals. This review was registered in PROSPERO, number CRD42020172053. RESULTS: The intensity of cancer pain is our primary outcome measure, and compared with standard care, MT can significantly relieve the pain of patients with cancer (SMD, 0.63; 95% CI [0.18, 1.08]; P=0.006 < 0.01); the effects of MT plus active activity were significantly different from AT alone (SMD, 0.79; 95% CI [0.28, 1.30]; P=0.002 < 0.01); there was no statistical difference in the efficacy of MT and AT alone (SMD, -0.24; 95% CI [-1.09, 0.62]; P=0.53 > 0.05). In other related symptoms, the above evidence cannot support that MT had a good effect on fatigue (SMD, 0.77; 95% CI [-0.09, 1.63]; P=0.08 > 0.05), nausea (SMD, 0.24; 95% CI [-0.00, 0.48]; P=0.05), anxiety (SMD, 0.76; 95 % CI [-0.32, 1.84]; P=0.17 > 0.05), and depression (SMD, 0.67; 95 % CI [-0.28, 1.62]; P=0.17 > 0.05); however, MT intervention can improve physical function (n = 271; SMD, 0.35; 95 % CI [-0.04, 0.74]; P=0.04 < 0.05) and global well-being (SMD, 0.50; 95 % CI [0.02, 0.98]; P=0.04 < 0.05). In addition, MT had a significant effect on pain relief (SMD, 0.52; 95% CI [0.03, 1.01]; P=0.04 < 0.05) and improvement of physical function (SMD, 0.28; 95% CI [0.02, 0.53]; P=0.03 < 0.05) even after a period of time after treatment. CONCLUSION: MT was an effective intervention, which may have immediate effect on cancer pain and may improve physical function and global well-being. In the view of follow-up effects, MT had good effects for the reduction of pain and the recovery of physical function. However, because of limitations, the seemingly promising results should be interpreted with caution.

Effects of Wuqinxi in the Patients with Chronic Low Back Pain: A Randomized Controlled Trial.

Low back pain (LBP) is one of the major concerns of the current health care. The guidelines for chronic LBP recommend traditional Chinese exercise as an effective treatment. As one of the representatives of traditional Chinese exercise, Wuqinxi has been famous in China for its effects on improving health and treating chronic diseases for thousands of years. The objectives of the study were to assess the effects of Wuqinxi in the patients with chronic LBP on pain intensity, trunk muscle strength, and quality of life. The primary outcome measure was assessed by the Short-Form McGill Pain Questionnaire (SF-MPQ), including the Visual Analog Scale (VAS) and Present Pain Intensity (PPI) as the subtables. The effects of Wuqinxi on the quality of life were also assessed by the Short-Form Health Survey (SF-36) and the Pittsburgh Sleep Quality Index (PSQI) from physical component summary (PCS), mental component summary (MCS), and sleep quality. Besides, the electrical activities of the rectus abdominis (RA), obliquus externus abdominis (OEA), lumbar erector spinae (ES), and multifidus (MF) were assessed by integrated electromyogram (iEMG) after the end of the intervention. Both the groups showed statistically significant improvement in SF-MPQ, SF-36, PSQI, and iEMG at 12 weeks and 24 weeks when compared with baseline (P < 0.05). However, Wuqinxi demonstrated better effects in SF-MPQ and MCS after 24 weeks of intervention compared with the general exercise (P < 0.05). The patients in the Wuqinxi group (WQXG) also showed a significantly higher iEMG on OEA than the general exercise group (GEG) in 30°/s and 90°/s (P < 0.05). Our results showed that Wuqinxi had better effects on chronic LBP for a long time compared with general exercise, including pain intensity and quality of life. Thus, Wuqinxi should be recognized as a possible standalone therapy and self-management skill in chronic LBP, which is suitable for long-term practice.

Effect of Moxibustion on Testosterone Secretion and Apoptosis of Spermatogenic Cells in Aging Rats.

Analysis of androgen secretion and sperm production was conducted in the testis to investigate the efficacy of moxibustion on testicular function in aging rats. Male Sprague-Dawley rats were randomly divided into the aging group (N = 8), the mild-warm moxibustion group (N = 8), and the youth control group (N = 8). Rats in the mild-warm moxibustion group (MWMG) were exposed to mild-warm moxibustion at the Zusanli (ST36) and Shenshu (BL23) acupuncture points daily, from the age of 12 months until the age of 24 months. After the intervention, testicular tissue was harvested from all rats across groups. Changes in testicular structure were examined by hematoxylin and eosin (H&E) stain. Detection of the apoptosis of spermatogenic cells was performed by the TUNEL assay. Testosterone level in the testis was analyzed by the ELISA assay, and the expression of Bax, Bcl-2, and androgen receptor (AR) in the testis was evaluated by immunohistochemistry. AR expression analysis was subsequently performed by the western blotting assay, and the detection of telomerase activity of the testis and the expression of Bax, Bcl-2, and AR mRNA were performed by real-time PCR. Compared with the youth controls, telomerase activity in the testis, testosterone levels, expression of AR, and expression of antiapoptosis factor Bcl-2 protein and mRNA were significantly decreased (P < 0.01) in the aging group. Spermatogenic cell apoptosis (P < 0.01) and proapoptotic factor Bax expression were significantly increased (P < 0.01) in the aging rats compared with the youth control group. The MWMG exhibited significant increases in testicular telomerase activity, testosterone level, AR expression, and antiapoptosis factor Bcl-2 expression (P < 0.05 or P < 0.01) compared with the aging group. In this experimental group, spermatogenic apoptosis was inhibited (P < 0.01) and proapoptotic factor Bax expression significantly reduced (P < 0.01). Mild-warm moxibustion can inhibit reproductive senescence by improving telomerase activity, improving AR expression, restoring testosterone, and inhibiting spermatogenic apoptosis via regulation of Bcl-2/Bax.

[Mechanisms of the three pathways regulating the apoptosis of testicular germ cells].

Cell apoptosis is an active process of the self-destruction of biological cells, which is an important mechanism of multicellular organisms regulating the development of the body, controlling cell senescence, and maintaining the stability of the internal and external environment of the body. As a basic biological process of keeping the balance in the body, cell apoptosis also plays an important role in cell differentiation and sperm maturation and survival in the testis. In spermatogenesis, any change may affect cell apoptosis and consequently upset the balance between the survival and death of germ cells. Current studies have shown that the mitochondrial pathway, cell death receptor pathway and endoplasmic reticulum pathway are essential for the apoptosis of germ cells in the testis and the factors in the three pathways interact with one another, forming a complex network for the regulation of cell apoptosis. This review focuses on the mechanisms of the three pathways regulating the apoptosis of testicular germ cells.