There is no effective treatment for peripheral nerve injury-induced chronic neuropathic pain (NP), which profoundly impacts the quality of life of those affected. Transmembraneprotein100 (TMEM100) is considered to be a pain regulatory protein and is expressed in the dorsal root ganglion (DRG) of rats. However, the mechanism of pain regulation and the expression of TMEM100 following various peripheral nerve injuries are unclear. In this study, we constructed two pain models of peripheral nerve injury: tibial nerve injury (TNI) and chronic constriction injury (CCI). This study found that the Paw Withdrawal Mechanical Threshold (PWMT) and Paw Withdraw Thermal Latency (PWTL) of the rats in the two pain models decreased significantly, and the expression of TMEM100 in the DRG of two groups also decreased significantly. Furthermore, the decrease in the CCI group was more obvious than in the TNI group. There was no significant statistical significance (P > 0.05). We constructed an adeno-associated virus 6 (AAV6) vector expressing recombinant fluorescent TMEM100 protein and injected it into the sciatic nerve (SN) of two pain models: CCI and TNI. PWMT and PWTL were significantly increased in the two groups, along with the expression of TMEM100 in the spinal cord and DRG. It also significantly inhibited the activation of microglia, astrocytes, and several inflammatory mediators (TNF- α, IL-1 β, and IL-6). In summary, the results of this study suggested that TMEM100 might be a promising molecular strategy for the treatment of NP, and its anti-inflammatory effects might play an important role in pain relief.

Background It is well established that discogenic low back pain (DLBP) is often caused by the inflammatory response during intervertebral disc degeneration (IDD). However, it remains unclear how inflammatory mediators such as Interleukin-6 (IL-6) are involved in discogenic pain caused by degeneration and intervertebral disc (IVD) metabolism. The purpose of this study is to study the relationship between IL-6 and Transmembrane protein 100 (TMEM100), and to analyze the different metabolites and metabolic pathways in various rat intervertebral discs by metabonomics. Methods We established a rat model of IDD-DLBP by disc punctures and PBS infusion to examine the rat pain behaviors. Intervertebral disc tissues were harvested for molecular biology experiments to explore the relationship between IL-6 and TMEM100. High-resolution mass spectrometry (HRMS) was performed for untargeted metabolomics, and nuclear magnetic resonance spectroscopy metabolomics (MRS) for differential metabolites and metabolic pathways. Results The results showed a significant decrease in vonFrey test, hot plate test and acetone test (P < 0.05). The expression of IL-6 and TMEM100 in DLBP model was significantly higher than that in sham control group and IDD discs without PBS infusion group (P < 0.05). There were 15 major contributing metabolites identified in the DLBP intervertebral discs through metabolomic studies, involving 6 major metabolic pathways. The main differential metabolites included nitric oxide (NO), ammonia, and lactic acid as the metabolic endpoints; and the differential metabolic pathways included the glycine-serine-threonine (Gly-Ser-Thr), which is gradually weakened with the progression of inflammation. Conclusion The change of TMEM100 expression mediated by il-6 is related to the Gly-Ser-Thr metabolic axis and plays an important role in the relief of discogenic pain.

Rheumatoid arthritis (RA) causes irreversible joint damage, but the pathogenesis is unknown. Therefore, it is crucial to identify diagnostic biomarkers of RA metabolism-related genes (MRGs). This study obtained transcriptome data from healthy individuals (HC) and RA patients from the GEO database. Weighted gene correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and random forest (RF) algorithms were adopted to identify the diagnostic feature biomarker for RA. In addition, biomarkers were verified by qRT-PCR and Western blot analysis. We established a mouse model of collagen-induced arthritis (CIA), which was confirmed by HE staining and bone structure micro-CT analysis, and then further verified the biomarkers by immunofluorescence. In vitro NMR analysis was used to analyze and identify possible metabolites. The correlation of diagnostic feature biomarkers and immune cells was performed using the Spearman-rank correlation algorithm. In this study, a total of 434 DE-MRGs were identified. GO and KEGG enrichment analysis indicated that the DE-MRGs were significantly enriched in small molecules, catabolic process, purine metabolism, carbon metabolism, and inositol phosphate metabolism. AKR1C3, MCEE, POLE4, and PFKM were identified through WGCNA, LASSO, and RF algorithms. The nomogram result should have a significant diagnostic capacity of four biomarkers in RA. Immune infiltration landscape analysis revealed a significant difference in immune cells between HC and RA groups. Our findings suggest that AKR1C3, MCEE, POLE4, and PFKM were identified as potential diagnostic feature biomarkers associated with RA’s immune cell infiltrations, providing a new perspective for future research and clinical management of RA.

There is no effective treatment for peripheral nerve injury-induced chronic neuropathic pain (NP), which profoundly impacts the quality of life of those affected. Transmembraneprotein100 (TMEM100) is considered to be a pain regulatory protein and is expressed in the dorsal root ganglion (DRG) of rats. However, the mechanism of pain regulation and the expression of TMEM100 following various peripheral nerve injuries are unclear. In this study, we constructed two pain models of peripheral nerve injury: tibial nerve injury (TNI) and chronic constriction injury (CCI). This study found that the Paw Withdrawal Mechanical Threshold (PWMT) and Paw Withdraw Thermal Latency (PWTL) of the rats in the two pain models decreased significantly, and the expression of TMEM100 in the DRG of two groups also decreased significantly. Furthermore, the decrease in the CCI group was more obvious than in the TNI group. There was no significant statistical significance ( P > 0.05 ). We constructed an adeno-associated virus 6 (AAV6) vector expressing recombinant fluorescent TMEM100 protein and injected it into the sciatic nerve (SN) of two pain models: CCI and TNI. PWMT and PWTL were significantly increased in the two groups, along with the expression of TMEM100 in the spinal cord and DRG. It also significantly inhibited the activation of microglia, astrocytes, and several inflammatory mediators (TNF- α, IL-1 β, and IL-6). In summary, the results of this study suggested that TMEM100 might be a promising molecular strategy for the treatment of NP, and its anti-inflammatory effects might play an important role in pain relief.