Low level light therapy/photobiomodulation for diabetic peripheral neuropathy: protocol of a systematic review and meta-analysis.

INTRODUCTION: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes that strongly impact the patients' quality of life and working ability. Evidence indicated that low level light therapy (LLLT)/photobiomodulation might be effective for neuropathy. However, the effect of LLLT for DPN is not clear. The objective of this systematic review and meta-analysis is to determine the effects and safety of LLLT/photobiomodulation for DPN, in comparison with other methods such as sham light, no treatment, other active treatment and LLLT as an additional treatment compared with another treatment alone. METHODS AND ANALYSIS: We will search eight databases from their inception to the date before the review submission. Randomised controlled trials (RCTs) will be included. Two reviewers will independently extract data using a structured data extraction method and assess the risk of bias in the included studies. Data will be synthesised using standardised mean difference or risk ratio with 95% CIs for continuous and dichotomous data, respectively. The primary outcome will be change in pain and secondary outcomes will include global symptom improvement, functional impairment and disability, impairment of sensation, quality of life, nerve conduction, and adverse events. Sensitivity and subgroup analysis will be employed to explore the influence of possible clinical and methodological characteristics. Publication bias will be assessed using funnel plot. We will conduct meta-analysis with RevMan V.5.4 and evaluate quality of the evidence using GRADE approach. ETHICS AND DISSEMINATION: This study does not require ethics approval. Our findings will be disseminated in the peer-reviewed publications. PROSPERO REGISTRATION NUMBER: CRD42021276056.

Downregulation of microRNA-124-3p promotes subventricular zone neural stem cell activation by enhancing the function of BDNF downstream pathways after traumatic brain injury in adult rats.

AIMS: In this study, the effect of intracerebral ventricle injection with a miR-124-3p agomir or antagomir on prognosis and on subventricular zone (SVZ) neural stem cells (NSCs) in adult rats with moderate traumatic brain injury (TBI) was investigated. METHODS: Model rats with moderate controlled cortical impact (CCI) were established and verified as described previously. The dynamic changes in miR-124-3p and the status of NSCs in the SVZ were analyzed. To evaluate the effect of lateral ventricle injection with miR-124-3p analogs and inhibitors after TBI, modified neurological severity scores (mNSSs) and rotarod tests were used to assess motor function prognosis. The variation in SVZ NSC marker expression was also explored. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of predicted miR-124-3p targets was performed to infer miR-124-3p functions, and miR-124-3p effects on pivotal predicted targets were further explored. RESULTS: Administration of miR-124 inhibitors enhanced SVZ NSC proliferation and improved the motor function of TBI rats. Functional analysis of miR-124 targets revealed high correlations between miR-124 and neurotrophin signaling pathways, especially the TrkB downstream pathway. PI3K, Akt3, and Ras were found to be crucial miR-124 targets and to be involved in most predicted functional pathways. Interference with miR-124 expression in the lateral ventricle affected the PI3K/Akt3 and Ras pathways in the SVZ, and miR-124 inhibitors intensified the potency of brain-derived neurotrophic factor (BDNF) in SVZ NSC proliferation after TBI. CONCLUSION: Disrupting miR-124 expression through lateral ventricle injection has beneficial effects on neuroregeneration and TBI prognosis. Moreover, the combined use of BDNF and miR-124 inhibitors might lead to better outcomes in TBI than BDNF treatment alone.

[Phosphorylation of protein kinase C in cerebrospinal fluid-contacting nucleus modulates the inflammatory pain in rats].

The present study was aimed to investigate the role of cerebrospinal fluid-contacting nucleus (CSF-CN) neurons in modulation of inflammatory pain and underlying mechanism. The inflammatory pain model was made by subcutaneous injection of the complete Freund's adjuvant (CFA) into the left hind paw of rats. The phosphorylation level of PKC (p-PKC) was examined by Western blot. Thermal withdrawal latency (TWL) of the rats was measured to assess inflammatory pain. The results showed that, compared with the sham controls, the inflammatory pain model rats showed shortened TWL on day 1, 3, and 7 after CFA injection, as well as increased level of p-PKC in CSF-CN neurons at 24 h after CFA injection. The administration of GF109203X, a PKC inhibitor, into lateral ventricle decreased the level of p-PKC protein expression and increased TWL in the model rats. These results suggest that blocking the PKC pathway in CSF-CN neurons may be an effective way to reduce or eliminate the inflammatory pain.

MicroRNA Profiling Response to Acupuncture Therapy in Spontaneously Hypertensive Rats.

MicroRNAs (miRNAs) are a group of endogenous noncoding RNAs that play important roles in many biological processes. This study aimed to check if miRNAs were involved in the response to acupuncture in rats. Microarray analysis was performed to compare the miRNA expression profiles of medulla in spontaneously hypertensive rats (SHRs) treated with or without acupuncture. Our microarray analysis identified 222 differentially expressed miRNAs in the medulla of SHRs treated with acupuncture at taichong acupoint. Among these miRNAs, 23 miRNAs with a significant difference were found in acupuncture-treated SHRs compared to untreated rats. These 23 miRNAs could regulate 2963 target genes which were enriched in at least 14 pathways based on our bioinformatic analysis. miRNA-339, miR-223, and miR-145 were downregulated in the medulla of SHRs compared to normotensive rats. Notably, these miRNAs were upregulated to basal levels in the medulla of SHRs treated with acupuncture at taichong in comparison with SHRs receiving acupuncture at nonacupoint group or SHRs without any treatment. Our findings have revealed significant changes of a panel of selective miRNAs in hypertensive rats treated at taichong acupoint. These data provide insights into how acupuncture elicits beneficial effects on hypertension.

Acupuncture may exert its therapeutic effect through microRNA-339/Sirt2/NFκB/FOXO1 axis.

Recently, we have found that a number of microRNAs (miRNAs) and proteins are involved in the response to acupuncture therapy in hypertensive rats. Our bioinformatics study suggests an association between these miRNAs and proteins, which include miR-339 and sirtuin 2 (Sirt2). In this paper, we aimed to investigate whether Sirt2 was a direct target of miR-339 in neurons. In human SH-SY5Y cells, the luciferase assay implied that Sirt2 was likely a target of miRNA-339. Overexpression of miR-339 downregulated Sirt2 expression, while knockdown of miR-339 upregulated Sirt2 expression in human SH-SY5Y cells and rat PC12 cells. In addition, overexpression of miR-399 increased the acetylation of nuclear factor-κB (NF-κB) and forkhead box protein O1 (FOXO1) in SH-SY5Y cells, which are known targets of Sirt2. Our findings demonstrate that miR-339 regulates Sirt2 in human and rat neurons. Since Sirt2 plays a critical role in multiple important cellular functions, our data imply that acupuncture may act through epigenetic changes and subsequent action on their targets, such as miRNA-339/Sirt2/NF-κB/FOXO1 axis. Some physiological level changes of neurons after altering the miR-339 levels are needed to validate the suggested therapeutic role of miR-339/Sirt2/NF-κB/FOXO1 axis in response to acupuncture therapy in the future work.

Adenosine as a probing tool for the mechanistic study of acupuncture treatment.

To date, acupuncture has been widely used despite a lack of solid clinical evidence in the East and West. However, there are few validated in vitro models for the mechanistic studies of acupuncture. We hypothesized that adenosine could be used as a probing tool in the mechanistic studies of acupuncture because of its critical role in the action of acupuncture. Subsequently, we tested this hypothesis using both in vitro and in vivo experiments. First, we found that adenosine stimulation mimicked the effect of acupuncture on microRNA profiling (including miR-339, miR-145 and miR-451) and protein level (including Sirt2) in nerve growth factor-induced differentiated PC12 cells. These miRNA and proteins have been found to be regulated by acupuncture treatment in the brain of spontaneously hypertensive rats. Next, we found that adenosine stimulation downregulated miR-339 expression through adenosine A1 receptor-mediated pathway. Finally, we showed that the concentration of adenosine was actually decreased in the brain of spontaneously hypertensive rats after acupuncture treatment at Taichong acupoint. Taken together, these findings suggest that adenosine could be used as a useful probing tool for acupuncture mechanistic studies, while more validation studies are certainly warranted.

Extracellular signal-regulated kinase 5 in the cerebrospinal fluid-contacting nucleus contributes to morphine physical dependence in rats.

The cerebrospinal fluid-contacting nucleus (CSF-CN) may influence actual composition of the CSF for non-synaptic signal transmission via releasing or absorbing bioactive substances, which distributes and localizes in the ventral periaqueductal central gray of the brainstem. Previous studies demonstrated that CSF-CN was involved in neuropathic pain and morphine dependence. Thus, to identify whether extracellular signal-regulated kinase 5 (ERK5) distributed in the CSF-CN and its function on the formation and development of morphine physical dependence, morphine withdrawal-like behavioral test and immunofluorescent technique were used in this research. Morphine was subcutaneously injected by an intermittent and escalating procedure to induce physical dependence, which was measured by withdrawal symptoms. In this study, we found that horseradish peroxidase-conjugated toxin subunit B/p-ERK5 double-labeled neurons expressed in the CSF-CN of normal rats. ERK5 signaling pathway was remarkably activated by naloxone-precipitated withdrawal in the CSF-CN. Moreover, selective attenuation of p-ERK5 expression in the CSF-CN by lateral ventricle injection of BIX02188 could significantly relieve morphine withdrawal symptom. These findings confirmed that the activation of p-ERK5 in the CSF-CN might contribute to morphine physical dependence.

[Effect of moderate acupuncture-stimulation of "Taichong" (LR 3) on blood pressure and plasma endothelin-1 levels in spontaneous hypertension rats].

OBJECTIVE: To observe the effect of different strength of acupuncture stimulation on blood pressure and plasma endothelin (E)-1 in spontaneous hypertension rats (SHR) ,so as to seek a better acupuncture parameter for clinical treatment of hypertension. METHODS: Twenty-eight 9-week-old SHRs were randomized into mild-stimulation group, moderate-stimulation group, strong-stimulation group and model group (n = 7 in each group). Seven normotensive SD rats served as a normal control group. Acupuncture stimulation with mild, moderate and strong stimulation was applied to bilateral "Taichong" (LR 3) for 5 min, once daily for 7 days. Blood pressure (BP) was determined by using a non-invasive BP-6 detection system. Plasma ET-1 was assayed by radioimmunoassay. RESULTS: Compared with the model group, the systolic pressure of the moderate-stimulation group on the 6th and 7th day was decreased significantly after acupuncture of "Taichong" (LR 3) (P<0. 01), being significantly lower than that of the mild- and strong-stimulation groups (P<0. 01). In comparison with the normal control group, plasma ET-1 level in the model group was increased significantly (P<0.01), while compared with the model group, only that in the moderate-stimulation group was down-regulated considerably (P<0. 01). No significant differences were found between the mild-stimulation and model groups, between the strong-stimulation and model groups, and between the mild-stimulation and strong-stimulation groups in plasma ET-1 level (P>0. 05). CONCLUSION: Moderate-stimulation of "Taichong" (LR 3) can lower blood pressure and plasma EA-1 level in spontaneous hypertension rats. The reduced level of plasma ET-1 may be one of its mechanisms underlying improving hypertension.