Investigating causal relationships between extensive peripheral immune cell phenotypes and preeclampsia: A bi-directional Mendelian randomization analysis.

PROBLEM: Preeclampsia, a multifaceted condition during pregnancy characterized by hypertension and organ dysfunction, poses significant risks to both maternal and fetal health. This study aims to investigate the bidirectional causal relationship between peripheral immune cell phenotypes and preeclampsia using a two-sample Mendelian randomization (MR) approach. METHOD OF STUDY: Genetic data from two sizable cohorts were utilized: 3757 individuals from Sardinia, providing information on 731 immune traits, and 200 929 Finnish adult females, encompassing 6663 preeclampsia cases. Single-nucleotide polymorphisms served as instrumental variables. The MR analyses employed the inverse variance-weighted (IVW) method as the primary tool, supplemented by MR-Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy. RESULTS: Among the 731 immune cell phenotypes studied, 18 displayed a suggestive positive association (IVW p < .05) with heightened preeclampsia risk, while 20 exhibited a suggestive negative association linked to reduced risk. Following false discovery rate (FDR) adjustment, four immune phenotypes showed significant associations with decreased preeclampsia risk: CD27 on CD24+ CD27+ B cells (B-cell panel) (odds ratio [OR] = 0.927, PFDR = 0.061), CD33+ HLA DR+ CD14- absolute count (OR = 0.963, PFDR = 0.061), CD80 on plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061); and CD80 on CD62L+ plasmacytoid dendritic cells (OR = 0.923, PFDR = 0.061). In the reverse-direction MR analysis, no significant causal effects of preeclampsia on immune cell phenotypes were observed. CONCLUSIONS: This study provides quantifiable evidence linking specific immune cell phenotypes to the risk of developing preeclampsia. This novel understanding of the immunological aspects underlying preeclampsia's pathogenesis could lead to innovative therapeutic strategies centered on immune modulation.

Advancing breastfeeding promotion: leveraging integrative natural galactagogues and unveiling their potential roles-Insights from a 19-year Taiwan nationwide registry to address lactation insufficiency in postpartum women.

Background: Lactation insufficiency is a prevalent challenge for nursing mothers globally. There is a growing interest in the use of herbal galactagogues for enhancing lactation, but their therapeutic efficacy and underlying mechanisms need thorough investigation. This study aims to investigate the efficacy and mechanisms of action of herbal galactagogues in addressing lactation insufficiency by utilizing real-world data and employing a network analysis approach. Methods: Our retrospective study used Taiwan's Longitudinal Health Insurance Database 2000 (LHID2000) to identify 490 patients diagnosed with lactation insufficiency from 2000 to 2018. We analyzed demographic characteristics, co-existing diseases, and prescription patterns for both users and non-users of Chinese herbal products (CHP). Additionally, we utilized a network analysis approach to explore potential compounds and targets in the most frequently used CHP, the Wang Bu Liu Xing and Lu Lu Tong herb pair (WLHP) combination. Results: Out of 490 patients, 81% were CHP users. There were no significant differences in demographic characteristics between CHP users and non-users, but we observed a notable divergence in the prevalence of co-existing diseases. A detailed examination of CHP prescriptions revealed the predominance of WLHP, prompting further investigation. Comprehensive analysis identified 29 major compounds in WLHP, which were associated with 215 unique targets. Intersection analysis revealed 101 overlapping targets between WLHP and lactation, suggesting their potential as therapeutic targets for lactation insufficiency treatment. Topological analysis of the protein-protein interaction (PPI) network identified 13 hub genes potentially crucial for the therapeutic effect of WLHP. Functional enrichment analysis showed that these targets were involved in critical lactation regulation pathways, including the PI3K-Akt signaling pathway, prolactin signaling pathway, estrogen signaling pathway, and AMPK signaling pathway. Discussion: This study emphasizes the potential of CHP, specifically the WLHP combination, in managing lactation insufficiency. The multi-compound, multi-target approach of WLHP and its interaction with key biological processes and signaling pathways offer valuable insights into the underlying mechanisms of its therapeutic effects. These findings warrant further experimental validation and can guide future research and clinical applications of CHP in lactation insufficiency treatment.

Integrated Chinese and Western Medicine for Coronary Heart Disease Prevention in Polycystic Ovary Syndrome: A 19-Year Nationwide Cohort Study.

Background: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Chinese herbal medicine (CHM), a major branch of traditional Chinese medicine, has been reported to exert beneficial effects on PCOS symptoms. However, the relationship between CHM use and the risk of coronary heart disease (CHD) in patients with PCOS remains unclear. The study aimed to investigate the potential protective role of CHM on CHD incidence in patients with PCOS and to understand CHM prescription patterns for PCOS treatment. Methods: This retrospective cohort study was performed using data from Taiwan's Longitudinal Health Insurance Database 2000 (LHID2000). Patients with PCOS were identified, and data on their demographic characteristics, comorbidities, and medication use were extracted. The patients were then divided into CHM and non-CHM users. Results: Propensity score matching yielded two balanced cohorts of 2913 individuals each. CHM users demonstrated a 94% reduced risk of CHD compared to non-CHM users (adjusted hazard ratio, 0.06; 95% confidence interval, 0.04-0.1) during the 19-year follow-up period. Stratified analysis confirmed the benefits of CHM treatment on the incidence of CHD across various subgroups. The key elements identified in the CHM prescription patterns associated with reduced CHD risk were Xiang Fu, Yi Mu Cao, Jia Wei Xiao Yao San, and Gui Zhi Fu Ling Wan. Conclusion: This study provides evidence that CHM may protect against CHD development in patients with PCOS. It is also highlight the most frequently prescribed CHM for mitigating CHD risk among patients with PCOS. These findings lay the groundwork for future studies to confirm and elucidate CHM's therapeutic mechanisms in PCOS-related CHD prevention, offering a significant contribution to the field.

Acupuncture Is Effective at Reducing the Risk of Stroke in Patients with Migraines: A Real-World, Large-Scale Cohort Study with 19-Years of Follow-Up.

Migraines are common headache disorders and risk factors for subsequent strokes. Acupuncture has been widely used in the treatment of migraines; however, few studies have examined whether its use reduces the risk of strokes in migraineurs. This study explored the long-term effects of acupuncture treatment on stroke risk in migraineurs using national real-world data. We collected new migraine patients from the Taiwan National Health Insurance Research Database (NHIRD) from 1 January 2000 to 31 December 2017. Using 1:1 propensity-score matching, we assigned patients to either an acupuncture or non-acupuncture cohort and followed up until the end of 2018. The incidence of stroke in the two cohorts was compared using the Cox proportional hazards regression analysis. Each cohort was composed of 1354 newly diagnosed migraineurs with similar baseline characteristics. Compared with the non-acupuncture cohort, the acupuncture cohort had a significantly reduced risk of stroke (adjusted hazard ratio, 0.4; 95% confidence interval, 0.35-0.46). The Kaplan-Meier model showed a significantly lower cumulative incidence of stroke in migraine patients who received acupuncture during the 19-year follow-up (log-rank test, p < 0.001). Acupuncture confers protective benefits on migraineurs by reducing the risk of stroke. Our results provide new insights for clinicians and public health experts.

The Effectiveness of Scutellaria baicalensis on Migraine: Implications from Clinical Use and Experimental Proof.

BACKGROUND: Scutellaria baicalensis (SB), a traditional Chinese medicine, is commonly used for the treatment of inflammatory and painful conditions. The purpose of the present study was to examine the effects of SB on migraine. MATERIALS AND METHODS: We examined the clinical applications of SB based on the data obtained from Taiwan's National Health Insurance Research Database and confirmed that it was frequently used in Taiwan for the treatment of headaches. An experimental migraine model was established in rats by an intraperitoneal injection of nitroglycerin (NTG, 10 mg/kg). Pretreatment with SB was given orally 30 min before NTG administration. The rats were subjected to migraine-related behaviour tests that were video-recorded and analysed using EthoVision XT 12.0 software. RESULTS: The frequency of exploratory and locomotor behaviour was comparatively lower in the NTG group than that in the control group, while the frequency of resting and grooming behaviour increased. These phenomena were ameliorated by pretreatment with 1.0 g/kg SB. The total time spent on the smooth surface was longer in the NTG group than that in the control group, but the time was shortened by pretreatment with 1.0 g/kg SB. CONCLUSIONS: Pretreatment with 1.0 g/kg SB relieved migraine-related behaviours in the experimental NTG-induced migraine model. The outcome therefore demonstrated that pretreatment with 1.0 g/kg SB is beneficial for migraine treatment.

Long-Term Beneficial Effects of Acupuncture with Reduced Risk of Depression Development Following Trigeminal Neuralgia: A Nationwide Population-Based Cohort Study.

BACKGROUND: Existing evidence has shown that patients with trigeminal neuralgia (TN) have a higher risk of developing depression than the normal population. Clinically, acupuncture has been widely used to alleviate pain in TN. However, few studies have explored the use of acupuncture to prevent depression in TN. Therefore, this study aimed to apply national real-world data to investigate the long-term effect of acupuncture on the risk of depression in patients with TN. METHODS: We recruited participants with newly diagnosed TN from the Taiwanese National Health Insurance Research Database between January 1, 2000 and December 31, 2010, and categorized them into either the acupuncture cohort or non-acupuncture cohort using the 1:1 propensity score-matched method. All patients in the two cohorts were followed up until the end of 2013. Cox proportional hazards regression analysis was used to compare the incidence of depression between the two cohorts. RESULTS: In total, 776 patients with newly diagnosed TN in each cohort with similar baseline characteristics were enrolled in the study. The acupuncture cohort had a reduced risk of depression compared to the non-acupuncture cohort (adjusted hazard ratio, 0.47; 95% confidence interval, 0.31-0.70). Kaplan-Meier analysis also revealed that the cumulative incidence of depression was significantly lower in the acupuncture cohort during the 13-year follow-up period (Log rank test, p < 0.001). In particular, the beneficial effect of acupuncture was a decrease in the risk of depression among TN patients aged 50-69 years who had also used carbamazepine. CONCLUSION: This study demonstrated that acupuncture is associated with a reduction in the risk of depression during long-term follow-up in patients with TN. The results provide new insights for clinical practitioners as well as for health resource allocation.

Use of Traditional Chinese Medicine for Patients Diagnosed with Postpartum Depression: A Nationwide Population-Based Study.

Postpartum depression (PPD) is one of most common postnatal complications, affecting approximately 10%-15% of women after childbirth annually. Traditional Chinese medicine (TCM) has been gaining popularity as the choice of treatment for PPD in Taiwan. Hence, our aim was to analyze the utilization of TCM among PPD patients in Taiwan. A cross-sectional study was conducted using a random sample of one million beneficiaries selected from the Taiwanese National Health Insurance Research Database. We identified patients with PPD who had received either TCM treatment or non-TCM treatment from the database during 2000-2012. Multivariate logistic regression analysis was used to identify the factors associated with the use of TCM. A total of 653 patients with PPD were enrolled. The majority of patients with PPD were 26-30 years old, lived in a highly urbanized area of Taipei, had a monthly income <20,000 NT$, and were private enterprise employees. Around 52.7% of PPD patients had the motivation to seek TCM services. Younger women, who resided in central and southern Taiwan and who had used TCM one year before PPD diagnosis, were more likely to use TCM services. PPD patients who underwent TCM treatment had a lower overall medical expenditure than non-TCM users. Most TCM users chose simple Chinese herbal medicine. The coexisting factors that made PPD patients to seek TCM services were respiratory or oral infections. We demonstrated the characteristics of those that seek TCM for PPD, which may provide useful insights to health care providers towards resource allocation.

Long-Term Effect of Acupuncture on the Medical Expenditure and Risk of Depression and Anxiety in Migraine Patients: A Retrospective Cohort Study.

Background: Migraine, a common neurological disorder, increases the risk of psychiatric disorders. Currently, the efficacy of conventional therapies is considered unsatisfactory. Acupuncture has been gaining popularity in treatment of neuropsychiatric disease. This study aimed to investigate the effect of acupuncture on medical expenditure and the risk of depression and anxiety in migraine patients. Methods: Patients with migraine were either selected for acupuncture treatment or no treatment based on the 1:1 propensity score-matched method from the Taiwanese National Health Insurance Research Database between 2000 and 2012 and followed up until the end of 2013. The observed outcome measures were comparison of medical expenditure and incidence of depression/anxiety in the two cohorts. Results: The acupuncture cohort had a lower medical expenditure within 1 year of the intervention than the non-acupuncture cohort (p < 0.001). The acupuncture cohort had a reduced risk of depression [adjusted hazard ratio [HR], 0.61, 95% confidence interval [CI], 0.39-0.95] and anxiety (adjusted HR, 0.51, 95% CI, 0.43-0.59) after adjusting for sex, age, monthly income, urbanization level, occupation category, baseline comorbidities, and medicines used. The Kaplan-Meier analysis revealed that the cumulative incidence of depression and anxiety was significantly lower in the acupuncture cohort than in the non-acupuncture cohort during the 13-year follow-up period (log-rank test, p < 0.001). Conclusions: Acupuncture could reduce medical expenditure and the risk of depression and anxiety during the long-term follow-up period in migraine patients. However, the regulatory effects and mechanisms should be assessed in further clinical research.

Anti-hypertensive and angiotensin-converting enzyme inhibitory effects of Radix Astragali and its bioactive peptide AM-1.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypertension is one of the common chronic health problems in the world. Astragalus membranaceus root (AM), also known as Huangqi, is a popular medicinal herb traditionally used to reinforce vital energy and modulate hypertension. AIM OF THE STUDY: This study was to reveal the anti-hypertensive activities and mechanisms of AM in spontaneously hypertensive rats (SHRs). Moreover, the presence of bioactive components in AM was further identified. MATERIALS AND METHODS: We analyzed the effects of aqueous extract of AM (AME) on the regulation of blood pressure and angiotensin converting enzyme (ACE), the major target of anti-hypertensive drugs. Proteomic, bioinformatics, and docking analyses were performed to identify the anti-hypertensive bioactive peptides in AME. RESULTS: Our data showed that AME inhibited ACE activities in a dose-dependent manner, with an IC50 of 1.85 ± 0.01 µg/ml. In comparison with mock, oral administration of AME reduced systolic blood pressure (SBP) levels in SHRs, and the level of SBP was decreased by 22.33 ± 3.61 mmHg at 200 mg/kg AME. Proteomic analysis identified that an abundant 152-amino-acid putative protein kinase fragment accounted for approximately 11.7% of protein spots in AME. AM-1 (LVPPHA), a gastrointestinal enzyme-resistant peptide cleaved from putative protein kinase fragment, inhibited ACE activities, with an IC50 value of 414.88 ± 41.88 µM. Moreover, oral administration of AM-1 significantly decreased SBP levels by 42 ± 2.65 mmHg at 10 µmol/kg. Docking analysis further showed that AM-1 docked into the active site channel of ACE and interacted with Ala-354 in the active site pocket of ACE. CONCLUSIONS: the ACE inhibitory effect of AM and the presence of ACE inhibitory phytopeptide in AME supported the ethnomedical use of AM on hypertension.

Regulation effect and mechanism of Sheng-Hua-Tang on female reproductive system: From experimental transcriptomic analysis to clinical applications.

ETHNOPHARMACOLOGICAL RELEVANCE: Sheng-Hua-Tang (SHT) is commonly used to treat female illnesses, especially postpartum conditioning. However, its effects and mechanisms on female reproductive system remain unclear. The aim of the present study was to investigate the effect of SHT on female brain-ovary-uterus axis from bench to clinic. MATERIALS AND METHODS: Mice were administrated SHT (200 mg/kg) orally for seven consecutive days. Brain, ovary, and uterus tissues were then collected for microarray analysis. A nationwide database analysis and a pilot randomized, open-label clinical trial were further applied to evaluate the clinical application and effects of SHT on postpartum women. RESULTS: Microarray analysis showed that oral administration of SHT induced a cascade reaction of gene expression, with 17, 883, and 1592 genes were significantly regulated by SHT in brain, ovary, and uterus, respectively. Population-based analysis of one million subjects in Taiwan's National Health Insurance Research Database between 1997 and 2013 showed that SHT was commonly used in menstrual disorders in female population, especially dysmenorrhea, abnormal uterine bleeding, and variation of menstrual cycle. Clinical trial on postpartum women showed that oral administration SHT for one week alleviated uterine contraction pain and breast swelling pain. Furthermore, Mmp2, Mmp3, Mmp9, Mmp11, Mmp15, Oxtr, Plrl, and Tph2 gene expression affected by SHT in mice were correlated with clinical effects of SHT in human subjects. CONCLUSION: This report provided the scientific evidences of mechanisms and clinical efficacies of SHT. Moreover, our findings might afford insights for clinical doctors in terms of SHT prescription.

Auricular Electrical Stimulation Alleviates Headache through CGRP/COX-2/TRPV1/TRPA1 Signaling Pathways in a Nitroglycerin-Induced Migraine Rat Model.

The study aimed to investigate effect of auricular electrical stimulation (ES) on migraine. Migraine was induced in rats by intraperitoneal administration of nitroglycerin (NTG, 10 mg/kg) three times. Auricular ES pretreatment was performed for five consecutive days. Migraine behaviors were observed by a video recording. Auricular ES pretreatment could reverse the decrease of the total time spent on exploratory (2619.0 ± 113.0 s vs 1581.7 ± 217.6 s, p=0.0029) and locomotor behaviors (271.3 ± 21.4 s vs 114.3 ± 19.7 s, p=0.0135) and also could reverse the increase of the total time spent on resting (19.0 ± 10.6 s vs 154.3 ± 46.5 s, p=0.0398) and grooming (369.9 ± 66.8 s vs 1302.0 ± 244.5 s, p=0.0324) behaviors. Auricular ES pretreatment could increase the frequency of rearing behaviors (38.0 ± 1.8 vs 7.7 ± 3.5, p < 0.0001) and total distance traveled (1372.0 ± 157.9 cm vs 285.3 ± 85.6 cm, p < 0.0001) and also could increase the percentage of inner zone time (6.0 ± 1.6% vs 0.4 ± 0.2%, p=0.0472). The CGRP, COX-2, TRPV1, and TRPA1 immunoreactive cells in the trigeminal ganglion increased in the NTG group compared with the control group (all p < 0.0001); this increase could, however, be reduced by auricular ES pretreatment (27.8 ± 2.6 vs 63.0 ± 4.2, p < 0.0001; 21.7 ± 1.2 vs 61.8 ± 4.0, p < 0.0001; 24.3 ± 1.0 vs 36.5 ± 1.7, p=0.0003; and 20.7 ± 1.9 vs 90.8 ± 6.5, p < 0.0001, respectively). Therefore, we suggest that auricular ES pretreatment is beneficial for the treatment of migraine and this effect is partly related to CGRP/COX-2/TRPV1/TRPA1 signaling pathways.

Effect of Paeonia lactiflora, a traditional Chinese herb, on migraines based on clinical application and animal behavior analyses.

BACKGROUND: Paeonia lactiflora (PL) was widely used for pain relief, but its effects on migraine headaches remain unclear. PURPOSE: The aim of the present study was to investigate the effects of PL on migraine headaches. METHODS: First, we found that PL was frequently used in Taiwan for headache treatment based on data from Taiwan's National Health Insurance Research Database. Migraine was induced through the intraperitoneal injection (i.p.) of nitroglycerin (NTG, 10 mg/kg) in rats. Pretreatment with PL was administered orally 30 min prior to the NTG i.p. Migraine headache behavior was observed by video-recordings. Finally, the rats were sacrificed and brain was removed for immunohistochemistry staining analysis. RESULTS: The frequency and total time spent rearing up and sniffing in exploratory behavior, and walking in locomotor behavior, were reduced in the NTG group compared with the control group (all p <  0.001). This reduction could be ameliorated by pretreatment with PL 1.0 g/kg (all p <  0.05). Total time spent in the light chamber was lower in the NTG group compared with the control group (p <  0.05); this could be ameliorated by pretreatment with 1.0 g/kg PL (p <  0.05). The rats in the NTG group spent longer time on the smooth surface than those in the control group (p <  0.001); this could be shortened by pretreatment with 0.5 and 1.0 g/kg PL (both p <  0.01). The traveling distance of rats in the NTG group was shorter than in the control group (p <  0.001); rats given 1.0 g/kg PL had a longer traveling distance than those in the NTG group (p <  0.01). Both c-fos and CGRP immunoreactive cells increased in the TNC in the NTG group compared with that of the control group (both p <  0.001); this increased could be reduced by pretreatment with PL 0.5 and 1.0 g/kg (both p <  0.05). CONCLUSION: Pretreatment with PL ameliorated migraine headache behaviors in the NTG-induced migraine rat model, suggesting pretreatment with PL is beneficial for migraine headache treatment. This effect of PL is related to the decrease of c-fos and CGRP in the TNC. However, still there are too many methodological limitations which need to be overcome in further experiments to support the data.

Vanillin-Ameliorated Development of Azoxymethane/Dextran Sodium Sulfate-Induced Murine Colorectal Cancer: The Involvement of Proteasome/Nuclear Factor-κB/Mitogen-Activated Protein Kinase Pathways.

Vanillin is a natural dietary flavoring widely used in the food industry. Colorectal cancer (CRC) is one of the common malignancies in the world. Chronic intestinal inflammation is a risk factor for the development of CRC. We have previously found that vanillin improves and prevents colitis in mice. Here we evaluated the inhibitory activities of vanillin on a mouse model of colitis-induced CRC. Mice were challenged intraperitoneally with azoxymethane (AOM) and orally with dextran sodium sulfate (DSS). Various dosages of vanillin were orally administered for 13 consecutive weeks. Vanillin alleviated the development of tumors in AOM/DSS-induced mice. The total number of tumors in 100 mg/kg vanillin group was significantly reduced by 57.14 ± 7.67%, compared with sham group. Gene expression analysis showed that vanillin downregulated the expression levels of proteasome genes in colon tissues. Moreover, vanillin at 10 mM significantly suppressed proteasome activities in HCT-116 cells by 41.27 ± 0.41%. Furthermore, vanillin diminished the phosphorylation of mitogen-activated protein kinases (MAPKs) and reduced the number of p65-positive cells, proliferating cells, and granulocytes in colon tissues with statistical significance. In conclusion, our data suggested that vanillin was a bioactive compound that ameliorated the development of AOM/DSS-induced colon cancer in mice. Moreover, the amelioration of vanillin might be associated with the downregulation of proteasome, nuclear factor-κB, and MAPK pathways.