Danyu Lin

Aims: We aimed to investigate the shared molecular pathways between Parkinson's disease (PD) and constipation using bioinformatics analysis. Methods: Differentially expressed genes (DEGs) were identified via the R limma package, and Weighted Gene Co‐Expression Network Analysis (WGCNA) was conducted to identify hub modules. Biological enrichment analysis clarified the biological processes involved. A gene–gene interaction (GGI) network was constructed to identify shared hub biomarkers. Validation of these biomarkers was done in vitro with α‐synuclein (α‐syn)‐treated SH‐SY5Y cells and in vivo through α‐syn‐induced PD mouse models, A53T transgenic mice, and loperamide‐induced constipation models. Results: Numerous DEGs were identified in both conditions, with 14 shared DEGs found through the intersection of core modules and upregulated DEGs. These DEGs are primarily involved in energy metabolism, protein modification, and mitochondrial function. Five key hub genes were identified using the GGI network and gene topological analysis. Notably, Serine hydroxymethyltransferase 2 (SHMT2) expression was significantly upregulated after α‐syn treatment in vitro. Immunohistochemical and immunofluorescence analyses revealed elevated SHMT2 expression in brain and colon tissues in PD mouse models ( p < 0.001), whereas in constipation models, SHMT2 was only elevated in the colon wall with no significant expression in the enteric nervous system. Conclusion: Our findings offer new views on the molecular link between PD and constipation, suggesting SHMT2 as a possible biomarker and therapeutic target for PD symptoms.

Background: Refractory chronic cluster headache (rCCH) is a severe form of trigeminal autonomic primary headache that often resists conventional pharmacological treatment, resulting in significant impairment in patients’ quality of life. Identifying effective strategies to reduce attack frequency and shorten cluster periods remains a crucial clinical challenge. Case presentation: Two cases of rCCH who had suffered from recurrent paroxysmal headaches for several decades were reported. Both had received multiple medications over the long term, with suboptimal response. Given that vasodilation is a key pathophysiological feature of rCCH, an extremely low dose norepinephrine was administered to two cases during acute phase of headache depending on the vasoconstrictive effect of norepinephrine. Their headaches were alleviated significantly through systematic and adjustable titration therapy of extremely low dose norepinephrine for 1–2 weeks. Following treatment, improvements were observed across multiple headache-related scales, including Cluster Headache Impact Questionnaire, Migraine-Specific Quality of Life Questionnaire, Migraine Disability Assessment Questionnaire, Health-Related Quality of Life, Hamilton Rating Scale for Depression and Hamilton Anxiety Scale. After the acute phase, both patients received preventive medications. At one-year follow-up, both patients remained attack-free under regular preventive therapy, had returned to normal daily activities, and maintained baseline scores on headache-related scales. Conclusion: The administration of norepinephrine in these two cases suggests that extremely low dose norepinephrine may be a potential adjunctive option for acute exacerbations in rCCH patients who are unresponsive to multiple medications. However, further studies are needed to confirm its efficacy and safety.

The aggregation of α-synuclein (α-syn) promotes neuroinflammation and neuronal apoptosis, which eventually contribute to the pathogenesis of Parkinson’s disease (PD). Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in α-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous α-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with α-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS/STAT3/HIF-1α axis. Our research revealed the relationships among α-synuclein, IL6ST, STAT3, and HIF-1α in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD.