Ferroptosis and HMGB2 induced calreticulin translocation required for immunogenic cell death are controlled by the nuclear exporter XPO1.

Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the nucleus into the extracellular milieu. We previously showed that cisplatin mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is responsible for translocation of CRT to the plasma membrane. CT-HMGB2 is three orders of magnitude more potent than oxaliplatin at inducing CRT translocation. Inhibition of HMGB1 and HMGB2 secretion and/or their activation of nuclear factor-kappa B (NF-kB) has potential utility for treating cardiovascular, and neurodegenerative diseases; whereas CT-HMGB2 could augment therapeutic approaches to cancer treatment.

HMGB2-induced calreticulin translocation required for immunogenic cell death and ferroptosis of cancer cells are controlled by the nuclear exporter XPO1.

Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) protein from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the cell nucleus into the extracellular milieu. We previously showed that cisplatin-mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin-mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is required for the CRT translocation. Furthermore, CT-HMGB2 is three orders of magnitude more potent at inducing CRT translocation than oxaliplatin.

Efficacy of acupuncture (Jin's three-needle) on motor symptoms and anxiety in patients with Parkinson's disease: protocol for a multicentre, randomised, assessor-blinded clinical trial.

INTRODUCTION: Parkinson's disease (PD) has a significant impact on a substantial number of individuals in China. Notably, 31% of patients with PD also grapple with the additional burden of anxiety. This dual challenge of managing both PD and anxiety underscores the complexity of the condition and the diverse range of symptoms patients may experience. Considering the circumstances, the cost and potential drawbacks associated with traditional antiparkinsonian drugs become increasingly relevant. Acupuncture emerges as a significant non-pharmacological adjunct therapy. Offering a potentially safer and more cost-effective option, acupuncture addresses the pressing need for holistic and complementary treatments that may alleviate both the motor symptoms of PD and the accompanying anxiety. METHODS AND ANALYSIS: This is a multicentre, randomised controlled and assessor-blind trial. A total of 210 eligible patients with PD will be randomly assigned (1:1) to Jin's three-needle (JTN) acupuncture group or waitlist (WL) group. Patients in the JTN group will receive acupuncture therapy three times per week for 4 weeks. Patients in the WL group will maintain their original dosage of antiparkinsonian drugs and receive acupuncture therapy after the observation period. The primary outcome measure will be the Unified Parkinson's Disease Rating Scale score. The secondary outcome measures will be the scores of the Hoehn-Yahr Rating Scale, Unified Dyskinesia Rating Scale, Non-Motor Symptoms Scale, 39-item Parkinson's Disease Questionnaire, Parkinson Anxiety Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Zarit burden interview and the level of cortisol and adrenocorticotropic hormone. The evaluation will be executed at baseline, the end of the treatment and a follow-up period. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (K[2023]014). All patients have to provide written, informed consent. The study will be disseminated through presentations in peer-reviewed international journals and at national and international conferences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry; ChiCTR2300074675.

Acupuncture and Sleep Quality Among Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Poor sleep quality greatly impairs quality of life and accelerates deterioration in patients with Parkinson disease (PD), but current remedies remain limited. Acupuncture, used as an adjunctive therapy with anti-Parkinson medications, has shown positive effects in patients with PD. However, high-quality clinical evidence to support the effectiveness of acupuncture for patients with PD and poor sleep quality is lacking. Objective: To assess the safety and efficacy of real acupuncture (RA) vs sham acupuncture (SA) as an adjunctive therapy for patients with PD who have poor sleep quality. Design, Setting, and Participants: This single-center randomized clinical trial was performed at The First Affiliated Hospital of Guangzhou University of Chinese Medicine in China from February 18, 2022, to February 18, 2023. Patients with PD and sleep complaints were recruited and randomized (1:1) to receive RA or SA treatment for 4 weeks. Data analysis was performed from April 12 to August 17, 2023. Intervention: Treatment with RA or SA for 4 weeks. Main Outcomes and Measures: The main outcome was the change in Parkinson Disease Sleep Scale (PDSS) scores measured at baseline, after 4 weeks of treatment, and at 8 weeks of follow-up. Results: Of the 83 participants enrolled, 78 (94.0%) completed the intervention and were included in the analysis. Their mean (SD) age was 64.1 (7.9) years; 41 (52.6%) were men and 37 (47.4%) were women. A significant increase in PDSS scores from baseline was observed for both the RA group (29.65 [95% CI, 24.65-34.65]; P < .001) and the SA group (10.47 [95% CI, 5.35-15.60]; P < .001). Compared with the SA group, the RA group had a significant increase in PDSS scores after 4 weeks of treatment (19.75 [95% CI, 11.02-28.49]; P < .001) and at 8 weeks of follow-up (20.24 [95% CI, 11.51-28.98]; P < .001). Conclusions and Relevance: In this randomized clinical trial, acupuncture proved beneficial in improving sleep quality and quality of life among patients with PD. These findings suggest that the therapeutic effects of acupuncture could continue for up to 4 weeks. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200060655.

The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study.

Background: Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases. Methods: Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results. Results: The results show a significant decrease in risk of Parkinson's disease with GrimAge (OR = 0.8862, 95% CI 0.7914-0.9924, p = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056-1.1401, p = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk. Conclusion: The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases.

Efficacy of manual acupuncture vs. placebo acupuncture for generalized anxiety disorder (GAD) in perimenopausal women: a randomized, single-blinded controlled trial.

Background: Generalized anxiety disorder (GAD) is common among perimenopausal women. Acupuncture may be an effective treatment for GAD, but evidence is limited. The pathogenesis of GAD is not yet clear, but it is related to the hypothalamic-pituitary-adrenal axis and its excretion, cortisol (CORT), and the adrenocorticotropic hormone (ACTH). The objective of this study is to evaluate the efficacy of manual acupuncture (MA) vs. placebo acupuncture (PA) for perimenopausal women with GAD. Methods: This study is a single-center, randomized, single-blind clinical trial conducted in the First Affiliated Hospital of Guangzhou University of Chinese Medicine. A total of 112 eligible patients with GAD were randomly assigned (1:1) to receive MA (n = 56) or PA (n = 56) three times per week for 4 weeks. The primary outcome measure was the HAMA score. The secondary outcome measures were the GAD-7 and PSQI scores and the levels of CORT and ACTH. The evaluation will be executed at the baseline, 2 weeks, the end of the treatment, and a follow-up 3-month period. Results: Significant improvements in HAMA (p < 0.001, η2p = 0.465), GAD-7 (p < 0.001, η2p = 0.359) and ACTH (p = 0.050) values were found between T0 and T2 in the MA group compared to the PA group. No difference in PSQI (p = 0.613, η2p = 0.011) and CORT (p = 0.903) was found between T0 and T2 in the MA group compared to the PA group. Long-term improvements in HAMA (p < 0.001, p < 0.001) were found in the MA group and PA group. Conclusion: This study was the first completed study to evaluate the efficacy of acupuncture and placebo acupuncture for GAD in perimenopausal patients. Results suggested that placebo acupuncture has a therapeutic effect, however, acupuncture had a greater therapeutic effect than placebo acupuncture. This study supports the effectiveness of acupuncture and thereby contributes to extended treatment options for GAD.Clinical trial registration:http://www.chictr.org.cn, Chinese Clinical Trial Registry, ID: ChiCTR2100046604. Registered on 22 May 2021.

Qualitative and quantitative meta-analysis of acupuncture effects on the motor function of Parkinson's disease patients.

Objective: To explore the association between acupuncture sessions and its effects on the motor function of Parkinson's Disease (PD). Methods: Eight databases and two clinical trials registries were searched from inception to August 2022. Randomized controlled trials (RCTs) that compared acupuncture with sham acupuncture, or antiparkinsonian drugs, were included. After qualitative meta-analysis, a non-linear meta regression approach with restricted cubic spline was used to investigate the dose-response relationship between acupuncture sessions and their efficacy on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score. Subgroup meta-analysis was performed of the included studies according to the weekly acupuncture frequency. And finally, the included studies containing the determination of intermediate efficacy were compared. Results: Of the 268 citations screened, 16 studies (462 patients of PD) were included. The qualitative meta-analysis showed that the acupuncture group had better effect on UPDRS-III scores than the control group. And the quantitative meta-analysis suggested that acupuncture dose was correlated with the reduction of UPDRS-III score in PD patients with motor symptoms. In subgroup analysis, on the one hand, when the frequency of acupuncture was no more than 3 times a week, with the increase of acupuncture session, the changes of UPDRS-III score decreased and then increased (P = 0.000). On the other hand, when acupuncture for more than 3 times a week and the dose of acupuncture treatment was <60 times, the changes of UPDRS-III score increased with the increase of acupuncture dose, but the score stopped to decrease if the dose continued to increase (P = 0.020). The comparative analysis of two quantitative RCTs found that the score improvement was more significant at the higher weekly acupuncture frequency. Interpretation: This study found that when treating PD patients with motor symptoms, acupuncture treatment may need to reach a certain dose to obtain better therapeutic effect and excessive acupuncture stimulation may cause the body to develop a certain tolerance. However, the above results still need to be verified by more high-quality clinical studies. The protocol was registered on PROSPERO International Prospective Register of Systematic Reviews (CRD42022351428).

Acupuncture therapy for Parkinson's disease: a case report demonstrating symptomatic improvement without medication.

Background: Parkinson's disease (PD) often necessitates immediate medical intervention following diagnosis. In recent years, there has been a noticeable increase in clinical investigations assessing the efficacy of acupuncture in PD, with many studies reporting positive outcomes. Ethical guidelines commonly endorse pharmaceutical therapies for PD, leading ongoing research to combine acupuncture with standard drug-based treatments. At present, there is a conspicuous absence of dedicated clinical research exclusively examining the independent impact of acupuncture on PD treatment. Case: In a clinical observation, we documented a case involving a 75-year-old male displaying progressive, characteristic PD symptoms, including evident limb tremors, rigidity, bradykinesia, fatigue, and additional non-motor symptoms. The patient received a confirmed diagnosis of PD. Due to the refusal of the patient to take medication, we exclusively administered acupuncture therapy. The outcomes indicated a noteworthy enhancement in the clinical symptoms of the patient solely through acupuncture intervention. Conclusion: This case affirms that using acupuncture in isolation significantly improved both the motor and non-motor symptoms in the patient. Acupuncture could potentially serve as an alternative therapy for patients who decline or are intolerant to anti-Parkinson drugs. However, further studies are needed to assess its long-term efficacy. This case report obtained approval from the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (Ethics number: K-2023-127).

Efficacy of acupuncture for the treatment of Parkinson's disease-related constipation (PDC): A randomized controlled trial.

Objective: To evaluate the efficacy of acupuncture in treating Parkinson's disease-related constipation (PDC). Materials and methods: This was a randomized, controlled trial in which patients, outcome assessors, and statisticians were all blinded. Seventy-eight eligible patients were randomly assigned to either the manual acupuncture (MA) or sham acupuncture (SA) groups and received 12 sessions of treatment over a 4-week period. Following treatment, patients were monitored until the eighth week. The primary outcome was the change in weekly complete spontaneous bowel movements (CSBMs) from baseline after treatment and follow-up. The Constipation Symptom and Efficacy Assessment Scale (CSEAS), the Patient-Assessment of Constipation Quality of Life questionnaire (PAC-QOL), and the Unified Parkinson's Disease Rating Scale (UPDRS) were used as secondary outcomes. Results: In the intention-to-treat analysis, 78 patients with PDC were included, with 71 completing the 4-week intervention and 4-week follow-up. When compared to the SA group, weekly CSBMs were significantly increased after treatment with the MA group (P < 0.001). Weekly CSBMs in the MA group were 3.36 [standard deviation (SD) 1.44] at baseline and increased to 4.62 (SD, 1.84) after treatment (week 4). The SA group's weekly CSBMs were 3.10 (SD, 1.45) at baseline and 3.03 (SD, 1.25) after treatment, with no significant change from baseline. The effect on weekly CSBMs improvement in the MA group lasted through the follow-up period (P < 0.001). Conclusion: Acupuncture was found to be effective and safe in treating PDC in this study, and the treatment effect lasted up to 4 weeks. Clinical trial registration: http://www.chictr.org.cn/index.aspx, identifier ChiCTR2200059979.

[Effect of Daoqi Tongjing needling method on intra-uterine residue after drug abortion from the perspectives of Hegu (LI 4) and Sanyinjiao (SP 6)].

The paper introduces professor ZHUANG Li-xing's clinical experience in treatment of intra-uterine residue and lochia after drug abortion. Professor ZHUANG believes that this disorder is related to "dysfunction of the thoroughfare vessel and the conception vessel, qi deficiency and blood stagnation, and retention of turbid qi in the uterus" in pathogenesis. The treating principle should focus on "regulating the functions of the thoroughfare vessel and the conception vessel, tonifying qi and eliminating stasis, as well as promoting qi movement". Besides Hegu (LI 4) and Sanyinjiao (SP 6), the acupoints are added from the conception vessel. The Daoqi Tongjing needling technique (the specific technique for directing qi and preserving essence) is exerted flexibly instead of traditional reinforcing and reducing technique of acupuncture to tonify qi and remove stasis.

Electro-acupuncture on Vascular Parkinsonism with multiple sleep disorders: A Case Report.

Vascular Parkinsonism (VP) is a kind of rare secondary Parkinsonism caused by vascular lesions. Patients with VP experience not only movement disorders but also sleep disorders. But treatment options are limited and often associated with undesirable adverse effects. Electro-acupuncture (EA) is a safe, rapid work, easy operation, and convenient complementary replacement therapy. We report a case of a 51-year-old man who presented with VP and multiple sleep disorders. Based on clinical evaluation and nocturnal hospital-based polysomnography (PSG), the patient had severe PLMD (PSG showed severe periodic leg movements), excessive daytime sleepiness (EDS, the score of the ESS is 16), and probable rapid eye movement sleep disorder (RBD). Parkinson's disease sleep scale (PDSS) score, Pittsburgh sleep quality index (PSQI), and periodic leg movements index were 93, 11, and 135.2, respectively. After 8 weeks of EA treatment, the patient reported that the symptoms of subjective and objective sleep disturbance were significantly alleviated without any discomfort. This case report may provide a new alternative and complementary therapy for VP patients with sleep disturbance but more definitive and robust evidence is needed to support its efficacy.

Acupuncture for Parkinson's disease: From theory to practice.

Advances in molecular biology and biochemistry have improved the treatment of Parkinson's disease (PD). There has been extensive evidence on the benefit of standard treatment (e.g., deep brain stimulation, levodopa, and dopamine agonists) and acupuncture for PD. This article aims to distill the similarities and differences in the treatment concepts between Chinese and Western medicine from the perspective of reinforcing the deficiency and purging the excess, summarize the latest evidence on the benefits of acupuncture for PD from theory to practice, and propose prospective treatment options for PD.

Efficacy of Acupuncture for Parkinson's Disease Anxiety: Two-Stage Protocol for a Randomized Controlled Clinical Trial.

Parkinson's disease anxiety (PDA) is a nonmotor symptom of Parkinson's disease (PD) that is often neglected. PDA poses a far-reaching challenge to the treatment of PD. Acupuncture could be successful in the treatment of PDA. However, the evidence for this is still limited. We propose a two-stage clinical trial. In stage 1, a total of 70 volunteers with PDA will be randomly assigned to either acupuncture (manual acupuncture) or control group (sham acupuncture) in a 1 : 1 ratio. Treatments will be performed for four weeks. The change in the Hamilton Rating Scale for Anxiety (HAMA) score from baseline to week 4 and week 12 will be the primary outcome. The levels of adrenocorticotropic hormone (ACTH), cortisol (CORT), serotonin (5-HT), and corticotropin-releasing factor (CRH) in the patients' serum and the scores on the Hoehn-Yahr Rating Scale and the Unified Parkinson's Disease Rating Scale (UPDRS) will all be considered among the secondary outcomes. Participants will be followed up until week 12. In stage 2, a total of 82 volunteers with PDA will be randomly assigned to either an acupuncture (manual acupuncture) or a control group (anti-Parkinson drugs only) in a 1 : 1 ratio. HAMA score will be the primary outcome. Universality, feasibility and cost effectiveness, Hoehn-Yahr Rating Scale, UPDRS, and serological indicators will be secondary outcomes. Participants will be followed up until week 4. The statistical analysis will include all the allocated individuals. The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine's Research Ethical Committee authorized this procedure, and the trial is registered with ChiCTR2100047253.

Effect of electroacupuncture for Pisa syndrome in Parkinson's disease: A case report.

BACKGROUND: Pisa syndrome (PS) refers to marked lateral flexion of the trunk with a Cobb angle greater than 10°, which is typically mobile and can be resolved by lying down. PS is one of the most common postural deformities secondary to Parkinson's disease (PD) and can aggravate scoliosis in the advanced stages of PD. CASE SUMMARY: Here, we present the case of a 53-year-old woman who presented with lateral curvature for 6 mo. Full spine X-ray films in the correct position showed that the thoracolumbar spine was bent to the right without any rotation of the vertebrae. The patient was diagnosed with Pisa syndrome. After receiving a month's treatment with electroacupuncture, the Cobb angle decreased from 18.14° to 13.41°. CONCLUSION: This case demonstrates that electroacupuncture can effectively improve Pisa syndrome secondary to PD with few side effects and a low risk of recurrence. Additionally, early accurate diagnosis and timely intervention are meaningful for the prognosis of PS.

Effectiveness of Acupuncture for Anxiety Among Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: One of the ordinary manifestations of Parkinson disease (PD) is anxiety, which remains untreated. Anxiety is closely associated with the accelerated progression of PD. Efficacy of acupuncture for anxiety has been reported. However, to date, there are no data on acupuncture's effectiveness on anxiety for patients with PD. Objective: To investigate the effect of acupuncture vs sham acupuncture for treating anxiety in patients with PD. Design, Setting, and Participants: This is randomized, double-blinded, clinical trial enrolled patients between June 20, 2021, and February 26, 2022. Final follow-up was April 15, 2022. Patients with Parkinson disease and anxiety were allocated randomly (1:1) to receive acupuncture or sham acupuncture for 8 weeks. Acupuncture operators, outcome measures evaluators, and statistical analysts were blinded to the grouping of patients. Patients were blinded to their own grouping during the study. This study took place in the Parkinson clinic of a hospital in China. Interventions: Real acupuncture or sham acupuncture for 8 weeks. Main Outcomes and Measures: Primary outcome was Hamilton Anxiety Scale (HAM-A) score. Secondary outcomes were scores on the Unified Parkinson Disease Rating Scale (UPDRS), 39-item Parkinson Disease Questionnaire (PDQ-39), and serum levels of the adrenocorticotropic hormone (ACTH) and cortisol (CORT). Results: Seventy eligible patients were enrolled, including 34 women (48.5%) and 36 men (51.4%). Sixty-four patients (91%) completed the intervention and the 8-week follow-up, including 30 women (46.9%) and 34 men (53.1%) with a mean (SD) age of 61.84 (8.47) years. At the end of treatment, the variation of HAM-A score was 0.22 (95% CI, -0.63 to 1.07; P = .62) between the real acupuncture and sham acupuncture groups. At the end of follow-up, the real acupuncture group had a significant 7.03-point greater (95% CI, 6.18 to 7.88; P < .001) reduction in HAM-A score compared with the sham acupuncture group. Four mild adverse reactions occurred during the study. Conclusions and Relevance: This study found acupuncture to be an effective treatment for anxiety in patients with PD. These findings suggest that acupuncture may enhance the wellbeing of patients who have Parkinson disease and anxiety. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100047253.