Analysing the causal relationship between potentially protective and risk factors and cutaneous melanoma: A Mendelian randomization study.

BACKGROUND: Previous observational studies reported altered melanoma risks in relation to many potential factors, such as coffee intake, smoking habits and photodamage-related conditions. Considering the susceptibility of epidemiological studies to residual confounders, there remains uncertainty about the actual causal roles of these reported factors in melanoma aetiology. OBJECTIVES: This study aims to investigate the causal association between cutaneous melanoma (CM) and previously reported factors: coffee intake, alcohol consumption, lifetime smoking, socioeconomic status (SES), ease of skin tanning, childhood sunburn and facial ageing, providing insight into its underlying aetiology and preventative strategies. METHODS: We utilized a two-sample MR analysis on data from the largest meta-analysis summary statistics of confirmed cutaneous melanoma including 30,134 patients. Genetic instrumental variables were constructed by identifying single nucleotide polymorphisms (SNPs) that associate with corresponding factors. Inverse variance weighted (IVW) was the primary MR method. For sensitivity and heterogeneity, MR Egger, weighted median, simple mode, weighted mode and MR Egger intercept tests were examined. RESULTS: Cutaneous melanoma risks were found to be elevated in association with a predisposition towards ease of skin tanning (IVW: OR = 2.842, 95% CI 2.468-3.274, p < 0.001) and with childhood sunburn history (IVW: OR = 6.317, 95% CI 4.479-8.909, p < 0.001). Repeated MR after removing potential confounders and outliers demonstrated resolved horizontal pleiotropy and statistically significant results that closely mirrored the initial findings. Other potential factors, such as coffee intake, alcohol consumption, smoking and socioeconomic status (SES), indicated insignificant effects on melanoma risk in the analysis, and therefore, our Mendelian randomization study does not support their roles in modifying melanoma risks. CONCLUSIONS: Our extensive MR analysis provides strong evidence of the causative role of ease of skin tanning and childhood sunburn history in elevating melanoma risk. Curtailing ultraviolet radiation (UVR) exposure may be the single best preventative strategy to reduce melanoma risk.

Phenolic acids from Prunella vulgaris alleviate cardiac remodeling following myocardial infarction partially by suppressing NLRP3 activation.

Acute myocardial infarction (MI) is one of the leading causes of mortality around the world. Prunella vulgaris (Xia-Ku-Cao in Chinese) is used in traditional Chinese medicine practice for the treatment of cardiovascular diseases. However, its active ingredients and mechanisms of action on cardiac remodeling following MI remain unknown. In this study, we investigated the cardioprotective effect of P. vulgaris on MI rat models. MI rats were treated with aqueous extract of P. vulgaris or phenolic acids from P. vulgaris, including caffeic acid, ursolic acid or rosmarinic acid, 1 day after surgery and continued for the following 28 days. Then the cardioprotective effect, such as cardiac function, inflammatory status, and fibrosis areas were evaluated. RNA-sequencing (RNA-seq) analysis, real-time polymerase chain reaction (PCR), western blotting, and ELISA were used to explore the underlying mechanism. In addition, ultra-high performance liquid chromatography/mass spectrometer analysis was used to identify the chemicals from P. vulgaris. THP-1NLRP3-GFP cells were used to confirm the inhibitory effect of P. vulgaris and phenolic acids on the expression and activity of NLRP3. We found that P. vulgaris significantly improved cardiac function and reduced infarct size. Meanwhile, P. vulgaris protected cardiomyocyte against apoptosis, evidenced by increasing the expression of anti-apoptosis protein Bcl-2 in the heart and decreasing lactate dehydrogenase (LDH) levels in serum. Results from RNA-seq revealed that the therapeutic effect of P. vulgaris might relate to NLRP3-mediated inflammatory response. Results from real-time PCR and western blotting confirmed that P. vulgaris suppressed NLRP3 expression in MI heart. We also found that P. vulgaris suppressed NLRP3 expression and the secretion of HMGB1, IL-1ß, and IL-18 in THP-1NLRP3-GFP cells. Further studies indicated that the active components of P. vulgaris were three phenolic acids, those were caffeic acid, ursolic acid, and rosmarinic acid. These phenolic acids inhibited LPS-induced NLRP3 expression and activity in THP-1 cells, and improved cardiac function, suppressed inflammatory aggregation and fibrosis in MI rat models. In conclusion, our study demonstrated that P. vulgaris and phenolic acids from P. vulgaris, including caffeic acid, ursolic acid, and rosmarinic acid, could improve cardiac function and protect cardiomyocytes from ischemia injury during MI. The mechanism was partially related to inhibiting NLRP3 activation.

Suxiao Jiuxin Pill attenuates acute myocardial ischemia via regulation of coronary artery tone.

Suxiao Jiuxin Pill (SJP) is a well-known traditional Chinese medicine drug used to manage heart diseases. This study aimed at determining the pharmacological effects of SJP in acute myocardial infarction (AMI), and the molecular pathways its active compounds target to induce coronary artery vasorelaxation. Using the AMI rat model, SJP improved cardiac function and elevated ST segment. LC-MS and GC-MS detected twenty-eight non-volatile compounds and eleven volatile compounds in sera from SJP-treated rats. Network pharmacology analysis revealed eNOS and PTGS2 as the key drug targets. Indeed, SJP induced coronary artery relaxation via activation of the eNOS-NO pathway. Several of SJP's main compounds, like senkyunolide A, scopoletin, and borneol, caused concentration-dependent coronary artery relaxation. Senkyunolide A and scopoletin increased eNOS and Akt phosphorylation in human umbilical vein endothelial cells (HUVECs). Molecular docking and surface plasmon resonance (SPR) revealed an interaction between senkynolide A/scopoletin and Akt. Vasodilation caused by senkyunolide A and scopoletin was inhibited by uprosertib (Akt inhibitor) and eNOS/sGC/PKG axis inhibitors. This suggests that senkyunolide A and scopoletin relax coronary arteries through the Akt-eNOS-NO pathway. In addition, borneol induced endothelium-independent vasorelaxation of the coronary artery. The Kv channel inhibitor 4-AP, KCa2+ inhibitor TEA, and Kir inhibitor BaCl2 significantly inhibited the vasorelaxant effect of borneol in the coronary artery. In conclusion, the results show that Suxiao Jiuxin Pill protects the heart against acute myocardial infarction.

Antenatal mobile-delivered mindfulness-based intervention to reduce perinatal depression risk and improve obstetric and neonatal outcomes: A randomized controlled trial.

OBJECTIVES: One in five mothers will experience perinatal depression (PND) during pregnancy and within their first year following childbirth. Current evidence suggests the short-term efficacy of Mindfulness-based interventions (MBI) for perinatal women, but the extent to which this positive impact remains the early postpartum period is unclear. This study investigated the short- and maintenance efficacy of a mobile-delivered four-immeasurable MBI on PND, and obstetric and neonatal outcomes. METHODS: Seventy-five adult pregnant women suffering from heightened distress were randomized to receive a mobile-delivered four-immeasurable MBI (n = 38) or a web-based perinatal education program (n = 37). PND was measured by Edinburgh Postnatal Depression Scale at baseline, post-intervention, 37th-week gestation, and 4-6 weeks postpartum. Outcomes also included obstetric and neonatal outcomes, trait mindfulness, self-compassion, and positive affect. RESULTS: Participants reported an average age of 30.6 (SD = 3.1) years with a mean gestational age of 18.8 (SD = 4.6) weeks. In intention-to-treat analyses, women in the mindfulness group showed a significantly greater reduction in depression from baseline to post-intervention (adjusted mean change difference [ß] = -3.9; 95%CI = [-6.05, -1.81]; d = -0.6), and the reduction sustained until 4-6 weeks postpartum (ß = -6.3; 95%CI = [-8.43, -4.12]; d = -1.0), compared with control. They had a significantly reduced risk of emergent cesarean section (relative risk = 0.5) and gave birth to infants with higher Apgar scores (ß = 0.6;p = .03; d = 0.7). Depression reduction before giving birth significantly mediated the intervention effect on lowering the emergency cesarean risk. CONCLUSIONS: With a reasonably low dropout rate (13.2 %), the mobile-delivered MBI can be an acceptable and effective intervention for reducing depression throughout pregnancy and postpartum. Our study also suggests the potential benefits of early prevention for mitigating emergent cesarean section risk and enhancing neonatal health.

Buyang huanwu decoction inhibits diabetes-accelerated atherosclerosis via reduction of AMPK-Drp1-mitochondrial fission axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese drugs, including Buyang Huanwu decoction (BYHWD), have been used in traditional practice to manage cardiovascular and cerebrovascular diseases. However, the effect and mechanisms by which this decoction alleviates diabetes-accelerated atherosclerosis are unknown and require exploration. AIM OF THE STUDY: This study aims to investigate the pharmacological effects of BYHWD on preventing diabetes-accelerated atherosclerosis, and elucidate its underlying mechanism. MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic ApoE-/- mice were treated with BYHWD. Atherosclerotic aortic lesions, endothelial function, mitochondrial morphology, and mitochondrial dynamics-related proteins were evaluated in isolated aortas. High glucose-exposed human umbilical endothelial cells (HUVECs) were treated with BYHWD and its components. AMPK siRNA transfection, Drp1 molecular docking, Drp1 enzyme activity measurement, and so on were used to explore and verify the mechanism. RESULT: BYHWD treatment inhibited the worsening of diabetes-accelerated atherosclerosis by lessening atherosclerotic lesions in diabetic ApoE-/- mice, by impeding endothelial dysfunction under diabetic conditions, and by inhibiting mitochondrial fragmentation by lowering protein expression levels of Drp1 and mitochondrial fission-1 protein (Fis1) in diabetic aortic endothelium. In high glucose-exposed HUVECs, BYHWD treatment also downgraded reactive oxygen species, promoted nitric oxide levels, and abated mitochondrial fission by reducing protein expression levels of Drp1 and fis1, but not mitofusin-1 and optic atrophy-1. Interestingly, we found that BYHWD's protective effect against mitochondrial fission is mediated by AMPK activation-dependent reduction of Drp1 levels. The main serum chemical components of BYHWD, ferulic acid, and calycosin-7-glucoside, can reduce the expression of Drp1 by regulating AMPK, and can inhibit the activity of GTPase of Drp1. CONCLUSION: The above findings support the conclusion that BYHWD suppresses diabetes-accelerated atherosclerosis by reducing mitochondrial fission through modulation of the AMPK/Drp1 pathway.

Mindfulness-based intervention for clinical and subthreshold perinatal depression and anxiety: A systematic review and meta-analysis of randomized controlled trial.

OBJECTIVES: About one in four mothers will experience depression and anxiety during pregnancy and within their first year following childbirth. The meta-analysis aggregated the findings of randomized controlled trials (RCTs) evaluating the immediate post-intervention and maintenance effects of MBI on perinatal depression and anxiety. METHODS: A systematic search was conducted in PubMed, PsycINFO, Medline, Scopus, and Web of Science for English-language journal articles from the first available date until Oct 27th, 2022. RESULTS: Twenty-five published RCTs were identified and reviewed, with a total of 2495 perinatal women. MBI was superior to controls for clinical and subthreshold perinatal depression and anxiety. The benefit for depression reduction was stable over time and sustained to the postpartum period, but the maintenance effect on perinatal anxiety was less conclusive. Moreover, MBI's post-intervention effects on depression and anxiety were moderated by perinatal women's symptom severity. The post intervention effects were significantly greater among women in Low- and Middle-Income countries, where perinatal mental health care is less available and accessible. Greater improvement in mindfulness was also associated with a significantly larger post-intervention effect on perinatal depression. CONCLUSIONS: This meta-analysis suggests that MBIs may complement and extend the available range of effective interventions for clinical and subthreshold perinatal depression and anxiety.

Study protocol of guided mobile-based perinatal mindfulness intervention (GMBPMI) - a randomized controlled trial.

BACKGROUND: Psychological distress is a common occurrence among women during the perinatal period. Maternal psychological distress (MPS) can also have a negative influence on neonatal outcomes such as infant health, child development or mother-child interaction. Hence, interventions to improve mental wellbeing during this period are vital. Mindfulness based intervention (MBI) has been found to be effective in reducing psychological distress. Delivery of MBI via the internet, making it accessible and inexpensive, is showing a promising positive effect in reducing psychological distress. A randomized control trial with sufficient power is required to confirm its positive effect among pregnant women. The positive effects of MBI have been found to be associated with heart rate variability (HRV) biofeedback; however, the efficacy of MBI on HRV has been rarely studied among pregnant women. Also, the potential association of HRV with MBI and psychological wellbeing needs further examination. This research aims to test the effectiveness of guided mobile-based perinatal mindfulness intervention (GMBPMI) among pregnant women experiencing psychological distress during the pre- and post-natal period, as well as examining the efficacy of GMBPMI on HRV. METHOD: This study is a randomized controlled trial that follows a parallel design. Consenting pregnant women in their second trimester (between 12th and 20th week gestation) will be randomly assigned to an intervention group (GMBPMI) or a control group (psychoeducation). The intended sample size is 198, with 99 participants in each group. Three levels of outcomes will be measured at baseline, post intervention in both the intervention and control groups, and at 36-week gestation and five-week postpartum. The primary outcomes include maternal psychological stress, mindfulness and positive appraisal HRV. Secondary outcomes are psychological and physical wellbeing. Tertiary outcomes include obstetric and neonatal outcomes, and social support. Analyses will follow an intention-to-treat method and repeated measures MANOVA will be conducted to compare changes in primary and secondary outcomes. A series of mixed-effects models will be fitted to assess the mediation effects. DISCUSSION: This trial expects to increase understanding of GMBPMI on HRV and psychological wellbeing for pregnant women, with extended support in both pre-and post-natal periods. The study could also potentially provide evidence for delivery of cost-effective and accessible services to pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04876014, registered on 30 March 2021. Protocol Version 1.0., 10 May 2021.

Aristolone in Nardostachys jatamansi DC. induces mesenteric vasodilation and ameliorates hypertension via activation of the KATP channel and PDK1-Akt-eNOS pathway.

BACKGROUND: Nardostachys jatamansi DC. is a common medicinal herb used to treat cardiovascular diseases, particularly hypertension. Previously, our lab characterized the chemical compounds of N. jatamansi. However, the bioactive compounds of N. jatamansi and their mechanisms of action on blood pressure and blood vessels are unknown. PURPOSE: The vasorelaxant effects of the methanolic extract (MeOH ext.) of the roots and rhizomes of N. jatamansi, its main compounds, and their underlying mode of action, were investigated. METHODS: The main compounds of N. jatamansi were isolated and identified using UHPLC-TOF MS. The antihypertensive effect of N. jatamansi extracts and (-)-aristolone were determined using spontaneously hypertensive rats. The extracts, fractions, and compounds were also evaluated for their vasorelaxant effects on U46619 contractile responses in isolated thoracic aortic and mesenteric arterial rings. The endothelial-dependent relaxation, as well as the regulatory pathways and targets of (-)-aristolone, were studied in-vitro and ex-vivo. Molecular docking and biophysical characterization (Surface plasmon resonance) studies were utilized to investigate the molecular interaction between (-)-aristolone and the target protein. RESULTS: MeOH ext. (200 mg/kg) reduces the systolic and diastolic blood pressure in spontaneously hypertensive rats. MeOH ext. and its ethyl acetate fraction (EtOAc Fr.), but not the H2O fraction, had a significant relaxing effect on the thoracic aorta. (-)-aristolone and kanshone H from EtOAc Fr. induced vasorelaxation of the thoracic aorta and mesenteric artery. In human umbilical vein endothelial cells, (-)-aristolone treatment upregulated phosphorylation of Akt (T308) and eNOS. Molecular docking and surface plasmon resonance experiments revealed an interaction between (-)-aristolone and phosphoinositide-dependent protein kinase 1 (PDK1), an upstream protein kinase that phosphorylates Akt at T308. Treatment with PDK1 inhibitor PHT-427 and eNOS inhibitor L-NAME consistently inhibited (-)-aristolone-induced vasorelaxation. In addition, KATP channel inhibitor glibenclamide dramatically inhibited the vasorelaxant effects of (-)-aristolone and kanshone H in the endothelium-denuded thoracic aorta. Finally, (-)-aristolone lowers hypertensive rats' systolic and diastolic blood pressure. CONCLUSIONS: The extracts of N. jatamansi promote vasorelaxation and alleviate hypertension. The essential chemicals responsible for producing vasorelaxation effects are (-)-aristolone and kanshone H, which activate the PDK1-Akt-eNOS-NO relaxing pathway and stimulate the opening of the KATP channel. These findings point to N. jatamansi and aristolone as possible antihypertensive agents.

Objectification and ambiguity of body image in women with Polycystic Ovary Syndrome: A mixed-method study.

BACKGROUND: The manifestations of Polycystic Ovary Syndrome (PCOS), including acne, hirsutism, obesity, uncertain fertility, etc., can make women anxious, worried, or even depressed with their appearance and body. However, little relevant research has been conducted in the Chinese context. This mixed-method study aimed to understand how women with PCOS in China perceive their bodies and to examine the association between body image and depression. METHODS: First, 101 PCOS patients participated in a survey using the Body Surveillance subscale of the Objectified Body Consciousness Scale, the Short-form Mishel Uncertainty in Illness Scale, the Appearance Anxiety Scale, and the Beck Depression Inventory-II, which measured participants' self-objectification, illness ambiguity, appearance anxiety, and depression, respectively. Second, fifteen women joined face-to-face semi-structured in-depth interviews, investigating their illness ambiguity, objectified experience, and behaviors to pursue beauty. RESULTS: Results indicated a high level of self-objectification, illness ambiguity, appearance anxiety, and depression among women with PCOS in China and supported the significant associations among the outcomes. Qualitative findings presented a body image of the precarious body, indiscernible identity, and distraught mind. LIMITATIONS: A convenient sampling method was used. The generalization of the study results needs further validation. Future longitudinal studies are necessary to clarify the causal relationships among outcomes. CONCLUSIONS: This study presented women's body image with PCOS and found the negative impact of body image on their depression levels. This study was of both theoretical and practical significance. Appropriate mind-body therapies were suggested for them.

Major Depression in Chinese Medicine Outpatients with Stagnation Syndrome: Prevalence and the Impairments in Well-Being.

Stagnation syndrome, a diagnostic entity in traditional Chinese medicine (TCM), has been long regarded as the TCM counterpart of major depression in Western medicine. The study investigated the prevalence of major depression among stagnation syndrome patients and evaluated their well-being and functioning outcomes. In total, 117 patients diagnosed with stagnation syndrome were measured using Stagnation Scale, the Patient Health Questionnaire-9 (PHQ-9), and the Body-Mind-Spirit Well-Being Inventory. Results indicate major depression among stagnation syndrome patients was characterized by a high co-occurrence rate and worse physical, mental, and functional outcomes. More than one-quarter (26.5%) of the patients met the DSM-V diagnostic criteria for major depression and over half (53%) exceeded the PHQ-9 cutoff (score above 10) for moderate/severe depression symptoms. The wellness of the stagnation syndrome patients was worse (M = 298.2, SD = 66.5) than that of the general population (M = 360.9, SD = 79.9), with a large Cohen's d value of 0.9. The "wellness outlook" of the depressed stagnation syndrome patients appeared grimmer (M = 252.3, SD = 52.2). The correlation between stagnation and depression was higher for affective symptoms than somatic symptoms. Physical distress did not mediate the relationship between stagnation and daily functioning. These might suggest that stagnation syndrome and major depression may share some similar psychological mechanisms.