ABSTRACT
In recent years, owing to the miniaturization of the fluidic environment, microfluidic technology offers unique opportunities for the implementation of nano drug delivery systems (NDDSs) production processes. Compared with traditional methods, microfluidics improves the controllability and uniformity of NDDSs. The fast mixing and laminar flow properties achieved in the microchannels can tune the physicochemical properties of NDDSs, including particle size, distribution and morphology, resulting in narrow particle size distribution and high drug-loading capacity. The success of lipid nanoparticles encapsulated mRNA vaccines against coronavirus disease 2019 by microfluidics also confirmed its feasibility for scaling up the preparation of NDDSs via parallelization or numbering-up. In this review, we provide a comprehensive summary of microfluidics-based NDDSs, including the fundamentals of microfluidics, microfluidic synthesis of NDDSs, and their industrialization. The challenges of microfluidics-based NDDSs in the current status and the prospects for future development are also discussed. We believe that this review will provide good guidance for microfluidics-based NDDSs.
ABSTRACT
Background. Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease , attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor ( α7nAChR ) signal transduction, to prevent cytokine storm. Methods. The potential anti-inflammatory effects of famotidine and other H2R antagonists was assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Results. Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor α and interleukin-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. Conclusions. These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
Subject(s)
COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic conditions increased GP73 production and secretion. Secreted GP73 then trafficked to the liver and kidney to stimulate gluconeogenesis through the cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of the PKA kinase hub exerted by GP73. Notably, plasma GP73 levels were elevated and positively correlated with blood glucose in patients with COVID19 and diabetes. Neutralization of circulating GP73 in serum of individuals infected with SARS-CoV-2 or with diabetes reduced excessive gluconeogenesis in cultured hepatocytes, and lowered blood glucose levels in animal models of diabetes. Ablation of GP73 from whole animals has a profound glucose-lowering effect secondary to reduced gluconeogenesis. Thus, GP73 is a key glucogenic hormone contributing to SARS-CoV-2-induced glucose abnormality.
Subject(s)
COVID-19ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic condition increased the cellular secretion of GP73. Secreted GP73 trafficked to the liver and kidney to stimulate gluconeogenesis through cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of PKA kinase hub exerted by GP73. Notably, COVID-19 patients showed pathologically elevated plasma GP73, and neutralization of the secreted GP73 inhibited enhanced PKA signaling and glucose production associated with SARS-CoV-2 infection. GP73 blockade also reduced gluconeogenesis and lowered hyperglycemia in type 2 (T2D) diabetic mice. Therefore, our findings provide novel insight into the roles of GP73 as a key glucogenic hormone and mechanistic clues underlying the development of SARS-CoV-induced glucose abnormalities.
Subject(s)
Diabetes Mellitus , Severe Acute Respiratory Syndrome , COVID-19 , HyperglycemiaABSTRACT
Background: More evidence in understanding the heterogeneity of COVID-19-associated acute respiratory distress syndrome (ARDS) and in improving strategy to increase the survival from the critical patients intubated is always needed. The study aimed to comprehensively explore the features of COVID-19-associated ARDS and the features and outcomes between the early and late intubation groups. Methods: This retrospective cohort included 65 adult COVID-19 inpatients with ARDS at two hospitals in Hubei, China. The ARDS in these patients was diagnosed according to the Berlin criteria. We defined intubation within 7 days of ARDS diagnosis as ‘early’ intubation and that performed from the eighth day as ‘late’ intubation based on literatures. The outcomes were invasive mechanical ventilation and in-hospital death. The log-binomial regression models were used to explore the risk factors and the Kaplan-Meier statistic was used to estimate the risk of mortality. Results: The median number of days from symptom onset to ARDS diagnosis was 11.0 (IQR, 8.0–13.0). Up to 84.1% COVID-19-related ARDS patients demonstrated multiple organ injuries. The mortality rates were 41.9% and 85.7% in moderate and severe ARDS. The early intubation and the late intubation had the differences in days from symptom onset/hospital admission/ARDS diagnosis to intubation (P = 0.023, P = 0.011, P < 0.001). Compared with the early-intubation group, the late-intubation group showed less severity at admission (median oxygenation index 159.0 95% CI 134.0-203.0 vs. 133.9 95% CI 98.3-183.2), but required more aggressive therapies (ICU 80% vs. 70%, CRRT 50% vs. 10%, prone-position 50% vs. 30%, and ECMO 50% vs. 10%) and had higher risk to die at hospital (RR, 3.18; 95% CI 1.98-5.12). Conclusion: The ARDS caused by COVID-19 was not typical ARDS due to prolonged onset time, multiple organ injuries, and higher mortalities. The late-intubation group showed less severity at admission but higher risk of in-hospital death than the early-intubation group.
Subject(s)
COVID-19 , Respiratory Distress SyndromeABSTRACT
Background: Novel coronavirus disease 2019 (COVID-19) is a global public health emergency. Here, we developed and validated a practical model based on the data from a multi-center cohort in China for early identification and prediction of which patients will be admitted to the intensive care unit (ICU). Methods: Data of 1087 patients with laboratory-confirmed COVID-19 were collected from 49 sites between January 2 and February 28, 2020, in Sichuan and Wuhan. Patients were randomly categorized into the training and validation cohorts (7:3). The least absolute shrinkage and selection operator and logistic regression analyzes were used to develop the nomogram. The performance of the nomogram was evaluated for the C-index, calibration, discrimination, and clinical usefulness. Further, the nomogram was externally validated in a different cohort. Results: The individualized prediction nomogram included 6 predictors: age, respiratory rate, systolic blood pressure, smoking status, fever, and chronic kidney disease. The model demonstrated a high discriminative ability in the training cohort (C-index = 0.829), which was confirmed in the external validation cohort (C-index = 0.776). In addition, the calibration plots confirmed good concordance for predicting the risk of ICU admission. Decision curve analysis revealed that the prediction nomogram was clinically useful. Conclusion: We established an early prediction model incorporating clinical characteristics that could be quickly obtained on hospital admission, even in community health centers. This model can be conveniently used to predict the individual risk for ICU admission of patients with COVID-19 and optimize the use of limited resources.
Subject(s)
COVID-19 , Kidney Diseases , FeverABSTRACT
The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.
Subject(s)
COVID-19ABSTRACT
With the relatively serious global epidemic outbreak of SARS-CoV-2 infection, public concerns focus on not only clinical therapeutic measures and public quarantine for this disease but also the development of vaccines. The technical design of our SARS-CoV-2 inactivated vaccine provides a viral antigen that enables the exposure of more than one structural protein based upon the antibody composition of COVID-19 patients convalescent serum. This design led to valid immunity with increasing neutralizing antibody titers and a CTL response detected post-immunization of this vaccine by two injections in rhesus macaques. Further, this elicited immunoprotection in macaques enables not only to restrain completely viral replication in tissues of immunized animals, compared to the adjuvant control and those immunized by an RBD peptide vaccine, but also to significantly alleviate inflammatory lesion in lung tissues in histo-pathologic detection, compared to the adjuvant control with developed interstitial pneumonia. The data obtained from these macaques immunized with the inactivated vaccine or RBD peptide vaccine suggest that immunity with a clinically protective effect against SARS-CoV-2 infection should include not only specific neutralizing antibodies but also specific CTL responses against at least the S and N antigens.
Subject(s)
COVID-19 , Lung Diseases, InterstitialABSTRACT
Background The novel coronavirus disease 2019 (Covid-19) has been a worldwide pandemic with more than 300,000 deaths. Corticosteroids have been used in some patients with severe Covid-19 in order to control the systemic inflammation or cytokine storm, however, their effects and safety have not yet been elucidated.Methods Patients with confirmed Covid-19 were retrospectively included from both the epicentre and out of the epicentre. Patients were classified into two groups according to the use of systemic corticosteroids, and the mortality and the rate of virus clearance were compared between the two groups. In addition, independent factors associated with death after corticosteroids treatment were also identified.Results A total of 775 patients were included in our final analysis, of which 238 (30.7%) patients received systemic corticosteroids treatment. Compared with patients without corticosteroids treatment, patients with corticosteroids treatment had significantly higher mortality (19.3% vs. 3.7%, P < 0.001) and lower rate of virus clearance (43.2% vs. 66.7%, P < 0.001) although along with increase of SpO2/FiO2 and blood lymphocytes in patients with severe Covid-19. Corticosteroids treatment was associated with longer hospital length of stays and delayed virus clearance time. In patients with corticosteroids treatment, blood lymphocytes (odds ratio (OR) 0.792, 95% confidence interval (CI) 0.672–0.932, P = 0.005) and creatine kinase (CK) (OR 1.006, 95%CI 1.000-1.012, P = 0.038) were independent risk factors associated with death, with a sensitivity of 90.91% and 44.44% and a specificity of 70.75% and 94.05%, respectively.Conclusions In patients with Covid-19, corticosteroids treatment is associated with increased mortality and reduced rate of virus clearance.
Subject(s)
COVID-19 , Inflammation , DeathABSTRACT
Abstract The recently emerged pathogenic SARS-coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global pandemic. In this study, we show that SARS-CoV-2 infection was associated with clinically significant lower level of HDL cholesterol (HDL-C), which can be used as indicators of disease severity and poor prognosis. Importantly, we found the spike protein of SARS-CoV-2 (SARS-2-S) bound to HDL. Antagonists of HDL receptor-Scavenger receptor class B type I (SR-B1), strongly inhibited SARS-CoV-2 infection. Notably, the lipids transfer function of SR-B1 was indispensable for this inhibition, offering explanations for the reduced serum HDL level observed in COVID-19 patients. Basing on findings here, we speculate that SR-B1-mediated pulmonary HDL-vitamin E uptake could participate in mediating SARS-CoV-2 infection of lung cells, and the unique expression profile of SR-B1 may also affect SARS-CoV-2 cell and tissue tropism. These findings might help to provide further insights into viral transmission, pathological characteristics and reveal therapeutic targets.
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
Objects: To investigate the impact of COVID-19 epidemic on adult myasthenia gravis (MG) patients, in order to provide better medical advice for special patient population during the quarantine period.Methods: Adult MG patients were randomly recruited to participate. The survey consisted of self-designed questionnaires and the revised 15-item Myasthenia Gravis Quality of Life Questionnaire (MGQOL15r). Participation was strictly voluntary and remained anonymous.Results: A total of 214 adult MG patients (84 males and 130 females) gave valid replies. There were 49.53% patients reported they had the fear of COVID-19 outbreak at different levels. And female patients had a significant higher level of fear to COVID outbreak (p=0.009). It was found that the adult MG patients are more likely to be influenced by the COVID-19 epidemic compared to the general population. During the COVID-19 outbreak, 36.45% patients reported they got an improvement of MG disease severity. 57.01% patients reported they felt no change. 6.54% patients reported their condition got worse. The average of MGQOL15r score was 7.38±6.22. The higher level of the fear of COVID-19 outbreak, the higher score of MGQOL15r (p=0.029), the poorer quality of life. 96.73% patients hoped the specialist physicians could provide online consult. In addition, 64.95% patients would go to the tertiary hospital without hesitation if the Outpatients Department was opened even during the COVID-19 epidemic.Conclusions: The COVID-19 epidemic has significant impact on the quality of life and psychological status in the adult MG patients. Compared to the general population, the adult MG patients are more likely to be influenced by the COVID-19 epidemic. Hence, it is important for health care organizations to provide professional therapeutic advice and psychosocial support in time.*, Contributed to this work equally.