RESUMO
Introduction: Cannabis is a widely used substance in pregnancy, yet there is a paucity of literature addressing the neuro-behavioural consequences for prenatally exposed children. Our systematic review synthesizes currently available data for the impact of prenatal cannabis use on offspring intelligence and cognitive functioning. Methods: MEDLINE, EMBASE, PsychINFO, CINAHL, and Clinicaltrials.gov were searched. Observational studies comparing prenatal cannabis use to controls were included. Offspring neuro-behavioural outcomes were grouped in prespecified domains of (1) intelligence and (2) cognitive functioning. Random-effect models were performed for meta-analyses when at least three studies reported the same outcome. All others were summarized qualitatively. GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework was used to assess evidence certainty. Results: Of the 1982 reviewed studies (n = 523,107 patients), 28 were included. Significant heterogeneity and cohort redundancy limited meta-analysis. Very low-quality evidence from pooled analyses showed no significant associations between prenatal cannabis exposure and attention [standardized mean difference = -0.27 (95% CI = -0.60 to 0.07)], global intelligence quotient [-0.16 (-0.42 to 0.10)], reading [-0.05 (-0.29 to 0.20)], written comprehension [-0.09 (-0.40 to 0.22)], spelling [-0.04 (-0.26 to 0.17)], and mathematics [-0.01 (-0.15 to 0.13)]. No significant associations were found between prenatal cannabis exposure for all other outcomes. Individual studies reported significant differences between the heavy use groups and non-exposed, although this did not prove to be significant when outcomes were pooled. Conclusions: The current review did not find a clear association between prenatal cannabis use and offspring neuro-behavioural outcomes. However, evidence was low quality and heterogenous. Further prospective investigation is needed to elucidate any potential association between prenatal cannabis use and long-term neuro-developmental outcomes.
RESUMO
Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Cigarette smoke heightens oxidative stress and impairs autophagy, advancing COPD progression. Andrographolide is a bioactive diterpenoid lactone isolated from the plant Andrographis paniculata which has been a traditional medicinal herb for respiratory diseases. As airway epithelial cells form the first interface to be exposed to cigarette smoke, this study aimed to explore the modulatory effects of andrographolide on oxidative stress and autophagy in human bronchial epithelial BEAS-2B cells exposed to cigarette smoke extract (CSE). CSE (2%) exposure increased autophagic markers p62 and LC3B-II levels in BEAS-2B cells. Andrographolide alone increased p62 and p-p62 (S349) but not LC3B-II in BEAS-2B cells. However, in the presence of CSE, andrographolide was able to simultaneously increase LC3B-II level and enhance antioxidant defense by decreasing oxidative stress and increasing total antioxidant capacity, through upregulation of nuclear Nrf2 via the p62-Nrf2 positive feedback loop. Using RFP-GFP-LC3B transfected BEAS-2B cells exposed to CSE, andrographolide was found to impair autophagosome fusion with lysosome, which may account for the moderate increase in activated caspase 3/7 and annexin V levels. Our findings revealed for the first time that andrographolide simultaneously upregulated antioxidant defense through the p62-Nrf2 loop and moderately induced apoptosis through impairment of autophagic flux in CSE-exposed bronchial epithelium. Andrographolide facilitated cigarette smoke-induced apoptosis may be a potential toxicological outcome or may protect against chronic inflammation and aberrant DNA repair. Validation of these in-vitro findings in an experimental COPD model by andrographolide is warranted.