Effects of Cadmium Exposure on Oxidative Stress in Atherosclerotic Rats by Downregulating TopBP1 Expression to Induce Mitochondrial DNA Damage.

Objective: To explore the mechanism of the effect of cadmium exposure on TopBP1-induced mitochondrial DNA damage in atherosclerotic rats to affect oxidative stress. Methods: 50 rats were established atherosclerotic model, and they were divided into model control group (MC group), low-dose cadmium exposure group (LD group), medium-dose cadmium exposure group (MD group), high-dose cadmium exposure group (HD group), and positive control group, with 10 rats in each group. Rats in the LD group, MD group, and HD group were intraperitoneally injected with different doses of cadmium acetate solution for intervention, rats in the PC group were intraperitoneally injected with oxidized banking solution, and those in the MC group were injected with normal saline. 10 rats were taken as the normal control group (NC group). Human umbilical vein endothelial cells were taken for cell experiments, normal saline was added as the blank control group (group A), cadmium acetate solution was added (group B), oxidized bankning solution was added (Group C), and oxidized bankning solution and cadmium acetate solution were added (Group D). Western blot and fluorescence quantitative PCR were used to detect the protein and mRNA expressions respectively. ROS, MDA, and SOD were detected by ELISA, apoptosis of endothelial cells was detected by flow cytometry, and arterial plaque damage was observed by oil red O staining. Results: The relative expressions of TopBP, Bax, and Bcl-2 proteins in rat aortic tissues in each group were significantly different (all P < .05). The relative expressions of TopBP1 and Bcl-2 proteins in the aortic tissues of rats in NC group, MC group, LD group, MD group, HD group, and PC group decreased (all P < .05), while the relative expressions of Bax protein in those groups were increased (all P < .05). Similarly, the relative expression levels of Topbp1mRNA, BaxmRNA, and Bcl-2mRNA in the aortic tissues of rats in each group were significantly different (all P < .05). There were statistically significant differences in the expression levels of ROS, MDA, SOD, and mtDNA expression levels in the aortic tissues of rats in each group. There were statistically significant differences in TopBP1, Topbp1mRNA, and mtDNA among groups (all P < .05); while the relative expression of TopBP1 and Topbp1mRNA in groups A, B, C, and D decreased (all P < .05), the expression levels of mtDNA in those group increased (all P < .05), and the apoptosis rates of endothelial cells were also increased (all P < .05). Conclusion: Cadmium exposure can down-regulate the expression of TopBP1 in atherosclerotic rats, aggravate mitochondrial DNA damage, promote oxidative stress response, and then induce the development of atherosclerosis.

The perceived effectiveness and hidden inequity of postpandemic fiscal stimuli.

The world has committed trillions in fiscal expenditures to reboot the economy in the post­COVID-19 era. However, the effectiveness and the equity impacts of current fiscal stimuli are not fully understood. Using an extended adaptive regional input­output model, we assess the short-term impacts (2020 through 2022) of feasible stimuli on the global economy and the labor market. Our findings show that the stimuli pledged by 26 countries, i.e., 2.4 trillion euros in total, are effective in keeping the recession short and shallow by saving 53 million to 57 million jobs (compared to the no-stimulus scenario). However, the stimuli exacerbate income inequity at the global scale if we define "equity" as those who suffer more from the pandemic should receive more assistance. Low-skilled workers in these countries, who suffer more from the pandemic than high-skilled workers, benefit 38 to 41% less from the job-creation effects of the current fiscal stimuli. As an alternative, low-carbon stimuli can achieve a balance between effectiveness and equity at the global level. Low-carbon stimuli save 55 million to 58 million jobs and decrease income inequality by 2 to 3% globally compared to the currently pledged stimuli. Country-level situations are more complicated, as modifying the current stimuli to achieve more "greenness" brings win­win in effectiveness and equity in some countries, while in the others, more greenness and equity are at the expense of less job savings. Our findings underscore the need to consider the overlooked trade-offs between effectiveness, equity, and greenness, both globally and nationally, when designing further postpandemic fiscal stimuli.

Association Between Longitudinal Change in Abnormal Fasting Blood Glucose Levels and Outcome of COVID-19 Patients Without Previous Diagnosis of Diabetes.

This retrospective study examined changes in fasting blood glucose (FBG) levels during hospitalization and their effect on risk of death for Coronavirus disease 2019 (COVID-19) patients without previously diagnosed diabetes. A model with low- and high-stable pattern trajectories was established based on a longitudinal change in FBG levels. We analyzed FBG trajectory-associated clinical features and risk factors for death due to COVID-19. Of the 230 enrolled patients, 44 died and 87.83% had a low-stable pattern (average FBG range: 6.63-7.54 mmol/L), and 12.17% had a high-stable pattern (average FBG range: 12.59-14.02 mmol/L). There were statistical differences in laboratory findings and case fatality between the two FBG patterns. Multivariable logistic regression analysis showed that increased neutrophil count (odds ratio [OR], 25.43; 95% confidence interval [CI]: 2.07, 313.03), elevated direct bilirubin (OR, 5.80; 95%CI: 1.72, 19.58), elevated creatinine (OR, 26.69; 95% CI: 5.82, 122.29), lymphopenia (OR, 8.07; 95% CI: 2.70, 24.14), and high-stable FBG pattern (OR, 8.79; 95% CI: 2.39, 32.29) were independent risk factors for higher case fatality in patients with COVID-19 and hyperglycemia but no history of diabetes. FBG trajectories were significantly associated with death risk in patients with COVID-19 and no diabetes.

The role of extracorporeal membrane oxygenation in critically ill patients with COVID-19: a narrative review.

Extracorporeal life support treatments such as extracorporeal membrane oxygenation (ECMO) have been recommended for the treatment of severe acute respiratory distress syndrome (ARDS) patients with coronavirus disease 2019 (COVID-19). To date, many countries, including China, have adopted ECMO as a treatment for severe COVID-19. However, marked differences in patient survival rates have been reported, and the underlying reasons are unclear. This study aimed to summarize the experience of using ECMO to treat severe COVID-19 and provide suggestions for improving ECMO management. The effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the pathophysiology of COVID-19 and the effects of ECMO on the clinical outcomes in patients with severe cases of COVID-19 were reviewed. Recent data from frontline workers involved in the use of ECMO in Wuhan, China, and those experienced in the implementation of artificial heart and lung support strategies were analysed. There is evidence that ECMO may complicate the pathophysiological state in COVID-19 patients. However, many studies have shown that the appropriate application of ECMO improves the prognosis of such patients. To expand our understanding of the benefits of ECMO for critically ill patients with COVID-19, further prospective, multicentre clinical trials are needed.

Individualism and nationally determined contributions to climate change.

Ratcheting up the Nationally Determined Contributions (NDCs) to achieve the Paris Agreement goals requires a better understanding of the enablers and barriers behind NDC formulation. However, existing quantitative analyses on the drivers of NDCs from an anthropological perspective are elusive. This study proposes both a conceptual framework and empirical analysis of how cultural values link with the pledged NDCs. The findings show that individualism (IDV) is a significant and robust predictor for the mitigation levels of NDCs, after controlling for affluence level, renewable energy proportion, democracy and other socioeconomic factors. For every 10-point increase in the IDV score (say from the score of Canada to Australia or from the score of Vietnam to Mexico), the committed per-capita emission in 2030 relative to 1990 levels decrease by 14%-22%. However, such a correlation is absent when assessing the mitigation ambitions using various fair benchmarks. This study underscores the necessity of considering more cultural context and nuances in tackling common climate problems, and advocates for developing tailored climate communication strategies to enhance the NDCs.

Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study.

AIMS/HYPOTHESIS: Hyperglycaemia is associated with an elevated risk of mortality in community-acquired pneumonia, stroke, acute myocardial infarction, trauma and surgery, among other conditions. In this study, we examined the relationship between fasting blood glucose (FBG) and 28-day mortality in coronavirus disease 2019 (COVID-19) patients not previously diagnosed as having diabetes. METHODS: We conducted a retrospective study involving all consecutive COVID-19 patients with a definitive 28-day outcome and FBG measurement at admission from 24 January 2020 to 10 February 2020 in two hospitals based in Wuhan, China. Demographic and clinical data, 28-day outcomes, in-hospital complications and CRB-65 scores of COVID-19 patients in the two hospitals were analysed. CRB-65 is an effective measure for assessing the severity of pneumonia and is based on four indicators, i.e. confusion, respiratory rate (>30/min), systolic blood pressure (≤90 mmHg) or diastolic blood pressure (≤60 mmHg), and age (≥65 years). RESULTS: Six hundred and five COVID-19 patients were enrolled, including 114 who died in hospital. Multivariable Cox regression analysis showed that age (HR 1.02 [95% CI 1.00, 1.04]), male sex (HR 1.75 [95% CI 1.17, 2.60]), CRB-65 score 1-2 (HR 2.68 [95% CI 1.56, 4.59]), CRB-65 score 3-4 (HR 5.25 [95% CI 2.05, 13.43]) and FBG ≥7.0 mmol/l (HR 2.30 [95% CI 1.49, 3.55]) were independent predictors for 28-day mortality. The OR for 28-day in-hospital complications in those with FBG ≥7.0 mmol/l and 6.1-6.9 mmol/l vs <6.1 mmol/l was 3.99 (95% CI 2.71, 5.88) or 2.61 (95% CI 1.64, 4.41), respectively. CONCLUSIONS/INTERPRETATION: FBG ≥7.0 mmol/l at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes. Glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes, as most COVID-19 patients are prone to glucose metabolic disorders. Graphical abstract.

Transport characteristics of isorhamnetin across intestinal Caco-2 cell monolayers and the effects of transporters on it.

Flavonoid isorhamnetin occurs in various plants and herbs, and demonstrates various biological effects in humans. This work will clarify the isorhamnetin absorption mechanism using the Caco-2 monolayer cell model. The isorhamnetin transport characteristics at different concentrations, pHs, temperatures, tight junctions and potential transporters were systemically investigated. Isorhamnetin was poorly absorbed by both passive diffusion and active transport mechanisms. Both trans- and paracellular pathways were involved during isorhamnetin transport. Active transport under an ATP-dependent transport mechanism was mediated by the organic anion transporting peptide (OATP); isorhamnetin's permeability from the apical to the basolateral side significantly decreased after estrone-3-sulfate was added (p<0.01). Efflux transporters, P-glycoproteins (P-gp), breast cancer resistance proteins (BCRP) and multidrug resistance proteins (MRPs) participated in the isorhamnetin transport process. Among them, the MRPs (especially MRP2) were the main efflux transporters for isorhamnetin; transport from the apical to the basolateral side increased 10.8-fold after adding an MRP inhibitor (MK571). This study details isorhamnetin's cellular transport and elaborates isorhamnetin's absorption mechanisms to provide a foundation for further studies.

Phytic acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total flavones of Hippophae rhamnoides L.

AIM: Total flavones of Hippophae rhamnoides L. (TFH) have a clinical use in the treatment of cardiac disease. The pharmacological effects of TFH are attributed to its major flavonoid components, isorhamnetin, kaempferol, and quercetin. However, poor oral bioavailability of these flavonoids limits the clinical applications of TFH. This study explores phytic acid (IP6) enhancement of the oral absorption in rats of isorhamnetin, kaempferol, and quercetin in TFH. METHODS: In vitro Caco-2 cell experiments and in vivo pharmacokinetic studies were performed to investigate the effects of IP6. The aqueous solubility and lipophilicity of isorhamnetin, quercetin, and kaempferol were determined with and without IP6, and mucosal epithelial damage resulting from IP6 addition was evaluated by MTT assays and morphology observations. RESULTS: The Papp of isorhamnetin, kaempferol, and quercetin was improved 2.03-, 1.69-, and 2.11-fold in the presence of 333 µg/mL of IP6, respectively. Water solubility was increased 22.75-, 15.15-, and 12.86-fold for isorhamnetin, kaempferol, and quercetin, respectively, in the presence of 20mg/mL IP6. The lipophilicity of the three flavonoids was slightly decreased, but their hydrophilicity was increased after the addition of IP6 in the water phase as the logP values of isorhamnetin, kaempferol, and quercetin decreased from 2.38±0.12 to 1.64±0.02, from 2.57±0.20 to 2.01±0.04, and from 2.39±0.12 to 1.15±0.01, respectively. The absorption enhancement ratios were 3.21 for isorhamnetin, 2.98 for kaempferol, and 1.64 for quercetin with co-administration of IP6 (200 mg/kg) in rats. In addition, IP6 (200 mg/kg, oral) caused neither significant irritation to the rat intestines nor cytotoxicity (400 µg/mL) in Caco-2 cells. CONCLUSIONS: The oral bioavailability of isorhamnetin, kaempferol, and quercetin in TFH was enhanced by the co-administration of IP6. The main mechanisms are related to their enhanced aqueous solubility and permeability in the presence of IP6. In summary, IP6 is a potential absorption enhancer for pharmaceutical formulations that is both effective and safe.

Effects of solid dispersion and self-emulsifying formulations on the solubility, dissolution, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in total flavones of Hippophae rhamnoides L.

The aim of this study was to investigate the effects of solid dispersions (SD) and self-emulsifying (SE) formulations on the solubility and absorption properties of active components in total flavones of Hippophae rhamnoides L. (TFH). The solubility, dissolution rate, permeability and pharmacokinetics of isorhamnetin, quercetin and kaempferol in TFH SD/SE formulations and TFH were compared. The results showed that the solubility and dissolution rate of isorhamnetin, quercetin and kaempferol in SD/SE formulations were significantly enhanced compared to those in TFH, however, their intestinal permeability was comparable. The bioavailability of isorhamnetin, quercetin and kaempferol in rats remarkably increased after oral administration of TFH SD formulations compared to TFH, but there was no significant increase after oral administration of TFH SE formulations. The results of this study indicated the SD formulations on the improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH were much better than those of SE formulations. The improvement of pharmacokinetic properties of isorhamnetin, quercetin and kaempferol in TFH by SD formulations was probably ascribed to the enhancement of the solubility and dissolution of the three components, but was not relevant to the intestinal permeability. Therefore, as for herb extracts containing multiple components, especially for their major components with poor water solubility, solid dispersion formulations might have the better potential to enhance their bioavailability.