From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

The Effects of Short-term Pm 2.5 Exposure on Pulmonary Function Among Children With Asthma——A Panel Study in Shanghai, China

BackgroundFine particulate matter with aerodynamic diameter ≤ 2.5 mm (PM2.5) has been reported to be an important risk factor for asthma. Our study was designed to evaluate the relationship between air PM2.5 and lung function among children with asthma in Shanghai, China. MethodsFrom 2016 to 2019, a total of 70 Chinese children aged 4 to 14 in Pudong, Shanghai were recruited for this panel study. Upon entry to the group, questionnaire was used to collect basic information, and the lung function covering forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF) were carried out for each child more than two times during follow-up. Meanwhile, the simultaneous daily air atmospheric pollutants and meteorological data were collected. The linear mixed effect (LME) model was used to assess the relationship between air pollutants and lung function adjusting other covariates like sex, age, season and so on. ResultsA significantly negative association was found between PM2.5 level and lung function in children with asthma. In the single-pollutant model, the largest effect of PM2.5 on lung function were found on lag 0-2, FVC and FEV1 decreased by 0.91% [95% confidence interval (CI): -1.75, -0.07] and 1.05% (95% CI: -2.09, 0.00) for every 10 mg/m3 increase of PM2.5. In the multi-pollution model (adjusted PM2.5+SO2+O3), the maximum effect of PM2.5 on FVC and FEV1 also appeared on lag 0-2, FVC and FEV1 decreased by 1.57% (95% CI: -2.69, -0.44) and 1.67% (95% CI: -3.05, -0.26) for every 10 mg/m3 increase of PM2.5, respectively. In the subgroup analysis, boys, children and hot season more were sensitive. ConclusionThe short-term exposure of ambient PM2.5 is a risk factor for the lung function of children with asthma, particularly in boys, preschoolers (<6 years old) and in the hot season.

Possible toxicity of chronic carbon dioxide exposure associated with mask use, particularly in pregnant women, children and adolescents – a scoping review

Literature was systematically reviewed regarding CO2 exposure and facemask use. Observational and experimental data are helpful for a risk-benefit assessment for masks as a popular non-pharmaceutical intervention against SARS-CoV2 in the populace. Masks impede breathing by increasing the resistance and dead space volume leading to a re-breathing of CO2 with every breath taken. Fresh air has around 0.04% CO2, while wearing masks more than 5 minutes bears a possible chronic exposure to carbon dioxide of 1.41–3.2% of the inhaled air. Although the buildup is usually within the short-term exposure limits, long-term consequences must be considered due to experimental data. US Navy toxicity experts set the exposure limits for submarines carrying female crews to 0.8% CO2 based on animal studies indicating an increased risk for stillbirths. Additionally, in mammals chronically exposed to 0.3% CO2 experimental data demonstrates teratogenicity with irreversible damage of neurons and reduced spatial learning caused by brainstem neuron apoptosis and a reduced blood level of the insulin-like growth factor 1. With significant impact on three readout parameters (morphological, functional, marker) this chronic 0.3% CO2 exposure has to be defined as being toxic. Additional data exists on the exposure of chronic 0.3% CO2 in adolescent mammals causing neuron destruction, which includes less activity, increased anxiety and impaired learning and memory. There is a possible negative impact risk by imposing extended mask mandates especially for vulnerable subgroups. Circumstantial evidence exists that extended mask use may be related to current observations of stillbirths and to reduced verbal motor and overall cognitive performance in children born during the pandemic. Extended masking in pregnant women, children and adolescents has not been thoroughly tested and studied. As a result of the animal experimental data available, a risk-benefit analysis is urgent and a need exists to rethink mask mandates, which provide appropriate warnings.

Corchorus olitorius L. Leaf Extract Protects Rats from Acrylamide-Induced Hepatic Injury

Acrylamide is a water-soluble compound that forms during the high-temperature cooking of starchy foods and has carcinogenic, neurotoxic, and genotoxic properties. Also, short-term exposure to acrylamide has been shown to cause significant hepatic injury in laboratory animals, along with disruption of antioxidant defense mechanisms due to excessive ROS production. Therefore, dietary antioxidants are believed to be useful in combating the negative effects of acrylamide. Corchorus olitoris L., also known as molokhia in Arabic, is a leafy vegetable which is shown to possess potent antioxidant and organoprotective properties. In this study, rats were administered with an aqueous extract of molokhia leaves to see if it could protect them against acrylamide-induced hepatic damage. Hepatic injury markers included serum total protein, total bilirubin, ALT, AST, and ALP, while oxidative stress markers included MDA, GSH, CAT, and SOD after dosing with three levels of extract (100, 250, and 500 mg/kg) for 21 days. Results indicated that the extracts substantially reduced elevated levels of bilirubin, ALT, AST, ALP, and MDA to normal levels at all doses. The extracts also brought serum protein, GSH, CAT, and SOD levels back to normal. Although the restoration of serum hepatic enzyme levels was dose dependent, no specific dose dependent relationship was found for serum proteins, MDA, GSH, CAT, or SOD activities. The study's findings show that molokhia leaves extract protects against acrylamide-induced hepatic damage by virtue of its good radical scavenging and anti-lipiperoxidative properties conferred by phenolics, flavonoids, and alkaloids.