The mechanism of Qingwen Gupi decoction on pulmonary fibrosis based on metabolomics and intestinal flora.

AIMS: To evaluate the effects of the Qingwen Gupi decoction (QGT) in a rat model of bleomycin-induced pulmonary fibrosis (PF), and explore the underlying mechanisms by integrating UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing of gut microbiota. METHODS AND RESULTS: The animals were randomly divided into the control, PF model, pirfenidone-treated, and low-, medium-, and high-dose QGT groups. The lung tissues were examined and the expression of TGF-ß, SMAD-3, and SMAD-7 mRNAs in the lung tissues were analyzed. Metabolomic profiles were analyzed by UPLC-QTOF/MS, and the intestinal flora were examined by prokaryotic 16 rDNA sequencing. Pathological examination and biochemical indices revealed that QGT treatment improved the symptoms of PF by varying degrees. Furthermore, QGT significantly downregulated TGF-ß1 and Smad-3 mRNAs and increased the expression levels of Smad-7. QGT-L in particular increased the levels of 18 key metabolic biomarkers that were associated with nine gut microbial species and may exert antifibrosis effects through arachidonic acid metabolism, glycerophospholipid metabolism, and phenylalanine metabolism. CONCLUSIONS: QGT alleviated PF in a rat model through its anti-inflammatory, antioxidant, and anti-fibrotic effects, and by reversing bleomycin-induced gut dysbiosis.This study lays the foundation for further research on the pathological mechanisms of PF and the development of new drug candidates.

Activation of Nurr1 with Amodiaquine Protected Neuron and Alleviated Neuroinflammation after Subarachnoid Hemorrhage in Rats

Background. Nurr1, a member of the nuclear receptor 4A family (NR4A), played a role in neuron protection, anti-inflammation, and antioxidative stress in multidiseases. We explored the role of Nurr1 on subarachnoid hemorrhage (SAH) progression and investigated the feasibility of its agonist (amodiaquine, AQ) as a treatment for SAH. Methods. SAH rat models were constructed by the endovascular perforation technique. AQ was administered intraperitoneally at 2 hours after SAH induction. SAH grade, mortality, weight loss, neurological performance tests, brain water content, western blot, immunofluorescence, Nissl staining, and qPCR were assessed post-SAH. In vitro, hemin was introduced into HT22 cells to develop a model of SAH. Results. Stimulation of Nurr1 with AQ improved the outcomes and attenuated brain edema. Nurr1 was mainly expressed in neuron, and administration of AQ alleviated neuron injury in vivo and enhanced the neuron viability and inhibited neuron apoptosis and necrosis in vitro. Besides, AQ reduced the amount of IL-1β+Iba-1+ cells and inhibited the mRNA level of proinflammatory cytokines (IL-1β and TNF-α) and the M1-like phenotype markers (CD68 and CD86). AQ inhibited the expression of MMP9 in HT22 cells. Furthermore, AQ reduced the expression of nuclear NF-κB and Nurr1 while increased cytoplasmic Nurr1 in vivo and in vitro. Conclusion. Pharmacological activation of Nurr1 with AQ alleviated the neuron injury and neuroinflammation. The mechanism of antineuroinflammation may be associated with the Nurr1/NF-κB/MMP9 pathway in the neuron. The data supported that AQ might be a promising treatment strategy for SAH.

Spatiotemporal spread pattern of the COVID-19 cases in China.

The COVID-19 pandemic is currently spreading widely around the world, causing huge threats to public safety and global society. This study analyzes the spatiotemporal pattern of the COVID-19 pandemic in China, reveals China's epicenters of the pandemic through spatial clustering, and delineates the substantial effect of distance to Wuhan on the pandemic spread. The results show that the daily new COVID-19 cases mostly occurred in and around Wuhan before March 6, and then moved to the Grand Bay Area (Shenzhen, Hong Kong and Macau). The total COVID-19 cases in China were mainly distributed in the east of the Huhuanyong Line, where the epicenters accounted for more than 60% of the country's total in/on 24 January and 7 February, half in/on 31 January, and more than 70% from 14 February. The total cases finally stabilized at approximately 84,000, and the inflection point for Wuhan was on 14 February, one week later than those of Hubei (outside Wuhan) and China (outside Hubei). The generalized additive model-based analysis shows that population density and distance to provincial cities were significantly associated with the total number of the cases, while distances to prefecture cities and intercity traffic stations, and population inflow from Wuhan after 24 January, had no strong relationships with the total number of cases. The results and findings should provide valuable insights for understanding the changes in the COVID-19 transmission as well as implications for controlling the global COVID-19 pandemic spread.

Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19.

The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019 (COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60-11.03] P<0.001), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50-7.47] P<0.001), CK (creatine phosphokinase)-MB was 4.86 ([95% CI, 3.33-7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18-6.36] P<0.001), and CK was 3.56 ([95% CI, 2.53-5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%-50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff values of these biomarkers might be much lower than the current reference standards. These findings can assist in better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of COVID-19-associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical trials.

Spontaneous pneumomediastinum in an elderly COVID-19 patient: A case report.

BACKGROUND: Spontaneous pneumomediastinum (SPM) is more common in young adults, usually caused by external factors like trauma. It causes symptoms such as chest pain or dyspnea, but it is rare to see elderly patients who develop SPM. Here we report the case of an elderly patient diagnosed with coronavirus disease 2019 (COVID-19) who neither got mechanical ventilation nor had chest trauma but were found to develop SPM for unknown reason. CASE SUMMARY: A 62-year-old man complained of a 14-d history of fever accompanied by dry cough, shortness of breath, wheezing, myalgia, nausea, and vomiting. Real-time fluorescence polymerase chain reaction confirmed the diagnosis of COVID-19. The patient was treated with supplementary oxygen by nasal cannula and gamma globulin. Other symptomatic treatments included antibacterial and antiviral treatments. On day 4 of hospitalization, he reported sudden onset of dyspnea. On day 6, he was somnolent. On day 12, the patient reported worsening right-sided chest pain which eventually progressed to bilateral chest pain. He was diagnosed with SPM, with no clear trigger found. Conservative treatment was administrated. During follow-up, the pneumomediastinum had resolved and the patient recovered without other complications. CONCLUSION: We presume that aging lung changes and bronchopulmonary infection play an important part in the onset of SPM in COVID-19, but severe acute respiratory syndrome may represent a separate pathophysiologic mechanism for pneumomediastinum. Although the incidence of SPM in elderly patients is low, clinicians should be alert to the possibility of SPM in those infected with severe acute respiratory syndrome coronavirus 2 for life-threatening complications such as cardiorespiratory arrest may occur.