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.

Background Increasing evidence has emerged for traditional, complementary and integrative medicine (TCIM) to treat COVID-19 which requires systematic summaries of the net benefits of interventions against standard care and one another. The study aims to conduct a systematic review and network meta-analysis (NMA) regarding TCIM therapies for treating mild/moderate acute COVID-19, potentially informing the WHO guideline development and clinical decision-making. Methods and analysis We will search Embase, MEDLINE, Virtual Health Library on Traditional Complementary and Integrative Medicine, Cochrane Central Register of Controlled Trials, WHO’s International Clinical Trials Registry Platform with additional searches of Chinese and Korean literature sources for randomised controlled trials comparing TCIM with placebo, standard care, no treatment or with an alternate type of TCIM to treat COVID-19. We will limit the search dates from 2020 to 28 March 2024. Reviewers will, in duplicate, screen eligible articles, extract data and evaluate the risk of bias. We will conduct frequentist network meta-analyses for network comparisons and each outcome. We will assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach and classify interventions from most to least effective or harmful. Ethics and dissemination This NMA is based on the existing trials and data which is not subject to ethical approval. We will publish the NMA in a peer-reviewed journal. This may provide methodological reference and clinical evidence for TCIM on future epidemic-prone diseases. PROSPERO registration number CRD42024517321.