Cytotoxic, antitumour-promoting and inhibition of protein denaturation effects of flavonoids, isolated from <i>Potentilla evestita</i> Th. Wolf

<div><p>This study was designed to evaluate the isolated flavonoids (chrysin <b>1</b>, and umbelliferone <b>2</b>) from <i>Potentilla evestita</i> for cytotoxic, antitumour-promoting and inhibition of protein denaturation activities. The results showed marked cytotoxic effect of compounds <b>1</b> and <b>2</b> in brine shrimp cytotoxic assay at various concentrations with LD₅₀ of 34.5 and 31.8 mg/mL, respectively. In Epstein–Barr-virus early antigen activation assay, both compounds <b>1</b> and <b>2</b> illustrated significant antitumour-promoting effect with IC₅₀ values of 462 and 308 mol ratio/32 pmol TPA, respectively. The cytotoxic and antitumour-promoting effects of compounds were strongly supported by inhibition of protein denaturation activity with IC₅₀ of 119 and 112 μg/mL, respectively. In conclusion, both compounds possess strong cytotoxic, antitumour-promoting and inhibition of protein denaturation activities.</p></div

<i>In vivo</i> antinociceptive and anti-inflammatory activities of umbelliferone isolated from <i>Potentilla evestita</i>

<div><p>This study was designed to evaluate the antinociceptive and anti-inflammatory activities of a compound, umbelliferone, isolated from the chloroform fraction of <i>Potentilla evestita</i> in animal models. When tested against acetic acid-induced noxious stimulus, it significantly prolonged pain threshold and provided 38.38% and 60.95% reduction in abdominal constriction at 5 and 10 mg/kg i.p., respectively. Post-umbelliferone injection evoked significant dose-dependent reduction in noxious stimulation with 33.65% and 58.89% pain attenuation at 5 and 10 mg/kg i.p., respectively, in the initial phase. In the late phase, it illustrated more dominant effect with 37.65% and 63.79% blockade of painful sensation. Similarly, it exhibited significant anti-inflammatory activity during various assessment times (1–5 h) with 46.28% and 66.13% amelioration after 4th of administration against induced oedema. In conclusion, umbelliferone possessed strong antinociceptive and anti-inflammatory activities by inhibiting both peripheral and centrally acting pain mediators.</p></div

Forest plots with pooled RR and 95% CIs for depression in women with and without history of (a) miscarriage or (b) stillbirth.

Forest plots with pooled RR and 95% CIs for depression in women with and without history of (a) miscarriage or (b) stillbirth.</p

Supporting information.

Fig A in S1 Appendix: Key Word Strategy. Fig B in S1 Appendix: Quality assessment of cohort studies using Adapted Newcastle Ottawa Scale. Fig C in S1 Appendix: Quality assessment of case-controlled studies using Adapted Newcastle Ottawa Scale. Fig D in S1 Appendix: Quality assessment of cross-sectional studies using Adapted Newcastle Ottawa Scale. Fig E in S1 Appendix: Funnel plots of the association of miscarriage and (a) ischaemic heart disease and (b) breast cancer. Fig F in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) ischaemic heart disease, (b) cerebrovascular disease and (c) circulatory diseases for the miscarriage arm using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig G in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) type 2 diabetes mellitus and (b) depression for the miscarriage arm using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig H in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) breast cancer, (b) ovarian cancer, and (c) uterine malignancies for the miscarriage arm using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig I in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) ischaemic heart disease, (b) cerebrovascular disease, (c) breast cancer, and (d) ovarian cancer for recurrent vs. single miscarriage using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig J in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) ischaemic heart disease, (b) cerebrovascular disease, and (c) breast cancer for recurrent vs. no miscarriage using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig K in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) ischaemic heart disease, (b) cerebrovascular disease, (c) breast cancer, and (d) ovarian cancer for recurrent vs. single miscarriage using the Generic inverse variance random effects model meta-analysis. Fig L in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) ischaemic heart disease, (b) cerebrovascular disease, and (c) breast cancer for recurrent vs. no miscarriage using the Generic inverse variance random effects model with dichotomous data in meta-analysis. Fig M in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) ischaemic heart disease, (b) cerebrovascular disease, and (c) circulatory disease for stillbirth arm using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig N in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) breast cancer, (b) female malignancies, and (c) all malignancies for stillbirth arm using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Fig O in S1 Appendix: Forrest plots presenting pooled RRs for development of (a) type 2 diabetes, (b) renal disease, (c) depression for stillbirth arm using the Mantel–Haenszel random effects model with dichotomous data in meta-analysis. Table A in S1 Appendix: Outcome definitions of the miscarriage arm of the meta-analysis. Table B in S1 Appendix: Outcome definitions of the stillbirth arm of the meta-analysis. Table C in S1 Appendix: Covariate/Confounding variables the researchers adjusted for in the studies of miscarriage. Table D in S1 Appendix: Covariate/Confounding variables the researchers adjusted for in the studies of stillbirth. (DOCX)</p

Characteristics of all studies examining the effect of stillbirth in long-term maternal morbidity and mortality included in the systematic review.

Characteristics of all studies examining the effect of stillbirth in long-term maternal morbidity and mortality included in the systematic review.</p

Characteristics of all studies examining the effect of miscarriage in long-term maternal morbidity and mortality included in the systematic review.

Characteristics of all studies examining the effect of miscarriage in long-term maternal morbidity and mortality included in the systematic review.</p

PRISMA checklist.

BackgroundEvidence suggests common pathways between pregnancy losses and subsequent long-term maternal morbidity, rendering pregnancy complications an early chronic disease marker. There is a plethora of studies exploring associations between miscarriage and stillbirth with long-term adverse maternal health; however, these data are inconclusive.Methods and findingsWe systematically searched MEDLINE, EMBASE, AMED, BNI, CINAHL, and the Cochrane Library with relevant keywords and MeSH terms from inception to June 2023 (no language restrictions). We included studies exploring associations between stillbirth or miscarriage and incidence of cardiovascular, malignancy, mental health, other morbidities, and all-cause mortality in women without previous pregnancy loss. Studies reporting short-term morbidity (within a year of loss), case reports, letters, and animal studies were excluded. Study selection and data extraction were performed by 2 independent reviewers. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) and publication bias with funnel plots. Subgroup analysis explored the effect of recurrent losses on adverse outcomes. Statistical analysis was performed using an inverse variance random effects model and results are reported as risk ratios (RRs) with 95% confidence intervals (CIs) and prediction intervals (PIs) by combining the most adjusted RR, odds ratios (ORs) and hazard ratios (HRs) under the rare outcome assumption. We included 56 observational studies, including 45 in meta-analysis. There were 1,119,815 women who experienced pregnancy loss of whom 951,258 had a miscarriage and 168,557 stillbirth, compared with 11,965,574 women without previous loss. Women with a history of stillbirth had a greater risk of ischaemic heart disease (IHD) RR 1.56, 95% CI [1.30, 1.88]; p p p = 0.05, 95% PI [0.74, 4.10]) compared with women without pregnancy loss. There was no evidence of increased risk of cardiovascular disease (IHD: RR 1.11, 95% CI [0.98, 1.27], 95% PI [0.46, 2.76] or cerebrovascular: RR 1.01, 95% CI [0.85, 1.21]) in women experiencing a miscarriage. Only women with a previous stillbirth were more likely to develop type 2 diabetes mellitus (T2DM) (RR: 1.16, 95% CI [1.07 to 2.26]; p p ConclusionsOur results suggest that women with a history of stillbirth have a greater risk of future cardiovascular disease, T2DM, and renal morbidities. Women experiencing miscarriages, single or multiple, do not seem to have an altered risk.</div

PRISMA Flowchart of study inclusion and exclusion.

AMED; Allied and Complementary Medicine, BNI; British Nursing Index, CINAHL; Cumulative Index to Nursing and Allied Health Literature.</p

Forest plots with pooled RR and 95% CIs for outcomes in women with and without history of miscarriage or stillbirth.

(a) T2DM in women with miscarriage vs. no miscarriage, (b) T2DM in women with stillbirth vs. no stillbirth, and (c) renal disease in women with stillbirth vs. no stillbirth. CI, confidence interval; RR, risk ratio; T2DM, type 2 diabetes mellitus.</p

Forest plot with pooled RR and 95% CIs for cardiovascular morbidity outcomes in women with and without history of miscarriage or stillbirth.

(a) IHD in women with miscarriage vs. no miscarriage, (b) IHD in women with stillbirth vs. no history of stillbirth, (c) cerebrovascular disease in women with miscarriage vs. no miscarriage, (d) cerebrovascular in women with stillbirths vs. no stillbirth, (e) overall circulatory disease in women with stillbirth vs. no stillbirth. CI, confidence interval; IHD, ischaemic heart disease; RR, risk ratio.</p