Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Subthalamic nucleus-deep brain stimulation improves autonomic dysfunctions in Parkinson's disease.

BACKGROUND: To study the effects of subthalamic nucleus-deep brain stimulation (STN-DBS) on autonomic dysfunctions in Parkinson's disease (PD) patients. METHODS: A total of 57 PD patients who underwent bilateral STN-DBS from March to December 2018, were retrospectively analyzed. Preplanned assessments at baseline and postoperatively at 1, 3, and 6 months also included the Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-Aut), the Unified Parkinson's Disease Rating Scale (UPDRS) III score, levodopa equivalent day dose (LEDD), Parkinson's Disease Quality of Life Scale (PDQ-39), the Hamilton Anxiety Rating Scale (HAMA), and the Hamilton Depression Rating Scale (HAMD). RESULTS: The SCOPA-Aut scores improved significantly [14.59% (18.32%), 24.00% (27.05%), 22.16% (27.07%), all P < 0.001] at 1 month, 3 months, and 6 months of STN-DBS, respectively. Analysis of the SCOPA-Aut sub-items showed significant improvements only in urine and thermoregulation sub-items at 6 months after surgery (P < 0.001). There was no significant correlation between improvements of SCOPA-Aut scores and improvements of PDQ-39 scores (P > 0.05) at 6 months after surgery. SCOPA-Aut scores were positively correlated with age (r = 0.428, P = 0.001); the improvements of SCCOPA-Aut scores were positively correlated with improvements of HAMA and HAMD scores (HAMA: r = 0.325, P = 0.015; HAMD: r = 0.265, P = 0.049) at 6 months after surgery. CONCLUSION: STN-DBS improved autonomic dysfunction symptoms of PD patients, and urinary and thermoregulatory sub-items of autonomic dysfunction were improved in the short-term after surgery. There was a close relationship between improved autonomic symptoms and improved anxiety and depression 6 months after surgery. We should therefore direct more attention to autonomic dysfunctions in PD involving detailed preoperative evaluations and postoperative follow-ups, to improve the quality of life of patients.

Correlation between Electrode Location and Anxiety Depression of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease.

Objectives: our group explored the correlation between postoperative coordinates of the electrode contacts, VTA, and anxiety and depression symptoms in Parkinson's disease (PD) patients after subthalamic nucleus deep brain stimulation (STN-DBS). Methods: STN-DBS was conducted on PD patients (n = 57) for six months with follow-up. Clinical outcomes were explored using the unified Parkinson's disease rating scale Part III (UPDRS-III), the Hamilton Anxiety Rating Scale (HAM-A), and the Hamilton Depression Rating Scale (HAM-D) before and after surgery. At the Montreal Neurological Institute (MNI), the location of active contacts and the volume of tissue activated (VTA) were calculated. Results: patient evaluations took place preoperatively and follow-ups took place at 1 month, 3 months, and 6 months. The average patient improvement rates for HAM-A and HAM-D scores at the 6-month follow-up were 41.7% [interquartile range (IQR) 34.9%] and 37.5% (IQR 33.4%), respectively (both p < 0.001). In medication-off, there were negative correlations between the HAM-A improvement rate and the Z-axis coordinate of the active contact (left side: r = −0.308, p = 0.020; right side: r = −0.390, p = 0.003), and negative correlations between the HAM-D improvement rate and the Z-axis coordinate of the active contact (left side: r = −0.345, p = 0.009; right side: r = −0.521, p = 0.001). There were positive correlations between the HAM-A and HAM-D scores improvement rate at 6 months after surgery and bilateral VTA in the right STN limbic subregion (HAM-A: r = 0.314, p = 0.018; HAM-D: r = 0.321, p = 0.015). Conclusion: bilateral STN-DBS can improve anxiety and depression symptoms in PD patients. The closer the stimulation to the ventral limbic region of the STN, the more significant the improvement in anxiety and depression symptoms of PD patients.

Electromyography Biomarkers for Quantifying the Intraoperative Efficacy of Deep Brain Stimulation in Parkinson's Patients With Resting Tremor.

Introduction: Deep brain stimulation (DBS) is an effective therapy for resting tremor in Parkinson's disease (PD). However, quick and objective biomarkers for quantifying the efficacy of DBS intraoperatively are lacking. Therefore, we aimed to study how DBS modulates the intraoperative neuromuscular pattern of resting tremor in PD patients and to find predictive surface electromyography (sEMG) biomarkers for quantifying the intraoperative efficacy of DBS. Methods: Intraoperative sEMG of 39 PD patients with resting tremor was measured with the DBS on and off, respectively, during the intraoperative DBS testing stage. Twelve signal features (time and frequency domains) were extracted from the intraoperative sEMG data. These sEMG features were associated with the clinical outcome to evaluate the efficacy of intraoperative DBS. Also, an sEMG-based prediction model was established to predict the clinical improvement rate (IR) of resting tremor with DBS therapy. Results: A typical resting tremor with a peak frequency of 4.93 ± 0.98 Hz (mean ± SD) was measured. Compared to the baseline, DBS modulated significant neuromuscular pattern changes in most features except for the peak frequency, by decreasing the motor unit firing rate, amplitude, or power and by changing the regularity pattern. Three sEMG features were detected with significant associations with the clinical improvement rate (IR) of the tremor scale: peak frequency power (R = 0.37, p = 0.03), weighted root mean square (R = 0.42, p = 0.01), and modified mean amplitude power (R = 0.48, p = 0.003). These were adopted to train a Gaussian process regression model with a leave-one-out cross-validation procedure. The prediction values from the trained sEMG prediction model (1,000 permutations, p = 0.003) showed a good correlation (r = 0.47, p = 0.0043) with the true IR of the tremor scale. Conclusion: DBS acutely modulated the intraoperative resting tremor, mainly by suppressing the amplitude and motor unit firing rate and by changing the regularity pattern, but not by modifying the frequency pattern. Three features showed strong robustness and could be used as quick intraoperative biomarkers to quantify and predict the efficacy of DBS in PD patients with resting tremor.

Pallidal versus subthalamic nucleus deep brain stimulation for levodopa-induced dyskinesia.

OBJECTIVE: To compare the efficacy of subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) on reducing levodopa-induced dyskinesia (LID) in Parkinson's disease, and to explore the potential underlying mechanisms. METHODS: We retrospectively assessed clinical outcomes in 43 patients with preoperative LID who underwent DBS targeting the STN (20/43) or GPi (23/43). The primary clinical outcome was the change from baseline in the Unified Dyskinesia Rating Scale (UDysRS) and secondary outcomes included changes in the total daily levodopa equivalent dose, the drug-off Unified Parkinson Disease Rating Scale Part Ⅲ at the last follow-up (median, 18 months), adverse effects, and programming settings. Correlation analysis was used to find potential associated factors that could be used to predict the efficacy of DBS for dyskinesia management. RESULTS: Compared to baseline, both the STN group and the GPi group showed significant improvement in LID with 60.73 ± 40.29% (mean ± standard deviation) and 93.78 ± 14.15% improvement, respectively, according to the UDysRS score. Furthermore, GPi-DBS provided greater clinical benefit in the improvement of dyskinesia (P < 0.05) compared to the STN. Compared to the GPi group, the levodopa equivalent dose reduction was greater in the STN group at the last follow-up (43.81% vs. 13.29%, P < 0.05). For the correlation analysis, the improvement in the UDysRS outcomes were significantly associated with a reduction in levodopa equivalent dose in the STN group (r = 0.543, P = 0.013), but not in the GPi group (r = -0.056, P = 0.801). INTERPRETATION: Both STN and GPi-DBS have a beneficial effect on LID but GPi-DBS provided greater anti-dyskinetic effects. Dyskinesia suppression for STN-DBS may depend on the reduction of levodopa equivalent dose. Unlike the STN, GPi-DBS might exert a direct and independent anti-dyskinesia effect.

Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc-MKRN2-42:1 in the pathogenesis of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common movement disorder for which diagnosis mainly depends on the medical history and clinical symptoms. Exosomes are now considered an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids, and genetic material. Long noncoding (lnc) RNA in exosomes plays a critical role in many diseases, including neurodegenerative disease. AIM: To study expression differences for lncRNAs in peripheral blood exosomes of PD patients compared with healthy individuals and to look for lncRNAs that might be related to the pathogenesis of PD. MATERIALS AND METHODS: We recruited PD patients along with age- and sex-matched healthy individuals as healthy controls and evaluated levels of lncRNAs extracted from exosomes in plasma samples via next-generation sequencing and real-time quantitative PCR. Correlation analysis was conducted for the clinical characteristics of PD patients and the expression of selected lncRNAs. RESULTS: We found 15 upregulated and 24 downregulated exosomal lncRNAs in the PD group. According to bioinformatics analyses, we chose lnc-MKRN2-42:1 for further study. Interestingly, lnc-MKRN2-42:1 was positively correlated with the MDS-UPDRS III score for PD patients. CONCLUSION: Our study suggested that lnc-MKRN2-42:1 may be involved in the occurrence and development of PD.

Integrated transcriptome expression profiling reveals a novel lncRNA associated with L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.

Levodopa-induced dyskinesia (LID) is a common complication of chronic dopamine replacement therapy in the treatment of Parkinson's disease (PD). Long noncoding RNAs regulate gene expression and participate in many biological processes. However, the role of long noncoding RNAs in LID is not well understood. In the present study, we examined the lncRNA transcriptome profile of a rat model of PD and LID by RNA sequence and got a subset of lncRNAs, which were gradually decreased during the development of PD and LID. We further identified a previously uncharacterized long noncoding RNA, NONRATT023402.2, and its target genes glutathione S-transferase omega (Gsto)2 and prostaglandin E receptor (Ptger)3. All of them were decreased in the PD and LID rats as shown by quantitative real-time PCR, fluorescence in situ hybridization and western blotting. Pearson's correlation analysis showed that their expression was positively correlated with the dyskinesia score of LID rats. In vitro experiments by small interfering RNA confirmed that slicing NONRATT023402 inhibited Gsto2 and Ptger3 and promoted the inflammatory response. These results demonstrate that NONRATT023402.2 may have inhibitive effects on the development of PD and LID.