Verbenalin alleviates acute lung injury induced by sepsis and IgG immune complex through GPR18 receptor.

Acute lung injury is significantly associated with the aberrant activation and pyroptosis of alveolar macrophages. Targeting the GPR18 receptor presents a potential therapeutic approach to mitigate inflammation. Verbenalin, a prominent component of Verbena in Xuanfeibaidu (XFBD) granules, is recommended for treating COVID-19. In this study, we demonstrate the therapeutic effect of verbenalin on lung injury through direct binding to the GPR18 receptor. Verbenalin inhibits the activation of inflammatory signaling pathways induced by lipopolysaccharide (LPS) and IgG immune complex (IgG IC) via GPR18 receptor activation. The structural basis for verbenalin's effect on GPR18 activation is elucidated through molecular docking and molecular dynamics simulations. Furthermore, we establish that IgG IC induces macrophage pyroptosis by upregulating the expression of GSDME and GSDMD through CEBP-δ activation, while verbenalin inhibits this process. Additionally, we provide the first evidence that IgG IC promotes the formation of neutrophil extracellular traps (NETs), and verbenalin suppresses NETs formation. Collectively, our findings indicate that verbenalin functions as a "phytoresolvin" to promote inflammation regression and suggests that targeting the C/EBP-δ/GSDMD/GSDME axis to inhibit macrophage pyroptosis may represent a novel strategy for treating acute lung injury and sepsis.

E-cigarette-Induced Pulmonary Inflammation and Dysregulated Repair are Mediated by nAChR α7 Receptor: Role of nAChR α7 in ACE2 Covid-19 receptor regulation.

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanism that mediate, toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChR α7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lungs tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased the inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased ACE2 Covid-19 receptor, whereas nAChR α7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8, and MMP9 were altered both at the protein and mRNA transcript levels in female and male, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChR α7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin significantly in a sex-dependent manner, but without the direct role of nAChR α7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChR α7 in a sex-dependent manner.

Potential Impact of the COVID-19 Pandemic on Public Perception of Water Pipes on Reddit: Observational Study

Background Socializing is one of the main motivations for water pipe smoking. Restrictions on social gatherings during the COVID-19 pandemic might have influenced water pipe smokers' behaviors. As one of the most popular social media platforms, Reddit has been used to study public opinions and user experiences. Objective In this study, we aimed to examine the influence of the COVID-19 pandemic on public perception and discussion of water pipe tobacco smoking using Reddit data. Methods We collected Reddit posts between December 1, 2018, and June 30, 2021, from a Reddit archive (PushShift) using keywords such as "waterpipe,” "hookah,” and "shisha.” We examined the temporal trend in Reddit posts mentioning water pipes and different locations (such as homes and lounges or bars). The temporal trend was further tested using interrupted time series analysis. Sentiment analysis was performed to study the change in sentiment of water pipe–related posts before and during the pandemic. Topic modeling using latent Dirichlet allocation (LDA) was used to examine major topics discussed in water pipe–related posts before and during the pandemic. Results A total of 45,765 nonpromotion water pipe–related Reddit posts were collected and used for data analysis. We found that the weekly number of Reddit posts mentioning water pipes significantly increased at the beginning of the COVID-19 pandemic (P<.001), and gradually decreased afterward (P<.001). In contrast, Reddit posts mentioning water pipes and lounges or bars showed an opposite trend. Compared to the period before the COVID-19 pandemic, the average number of Reddit posts mentioning lounges or bars was lower at the beginning of the pandemic but gradually increased afterward, while the average number of Reddit posts mentioning the word "home” remained similar during the COVID-19 pandemic (P=.29). While water pipe–related posts with a positive sentiment were dominant (12,526/21,182, 59.14% before the pandemic;14,686/24,583, 59.74% after the pandemic), there was no change in the proportion of water pipe–related posts with different sentiments before and during the pandemic (P=.19, P=.26, and P=.65 for positive, negative, and neutral posts, respectively). Most topics related to water pipes on Reddit were similar before and during the pandemic. There were more discussions about the opening and closing of hookah lounges or bars during the pandemic. Conclusions This study provides a first evaluation of the possible impact of the COVID-19 pandemic on public perceptions of and discussions about water pipes on Reddit.

Characteristics of and User Engagement With Antivaping Posts on Instagram: Observational Study.

BACKGROUND: Although government agencies acknowledge that messages about the adverse health effects of e-cigarette use should be promoted on social media, effectively delivering those health messages is challenging. Instagram is one of the most popular social media platforms among US youth and young adults, and it has been used to educate the public about the potential harm of vaping through antivaping posts. OBJECTIVE: We aim to analyze the characteristics of and user engagement with antivaping posts on Instagram to inform future message development and information delivery. METHODS: A total of 11,322 Instagram posts were collected from November 18, 2019, to January 2, 2020, by using antivaping hashtags including #novape, #novaping, #stopvaping, #dontvape, #antivaping, #quitvaping, #antivape, #stopjuuling, #dontvapeonthepizza, and #escapethevape. Among those posts, 1025 posts were randomly selected and 500 antivaping posts were further identified by hand coding. The image type, image content, and account type of antivaping posts were hand coded, the text information in the caption was explored by topic modeling, and the user engagement of each category was compared. RESULTS: Analyses found that antivaping images of the educational/warning type were the most common (253/500; 50.6%). The average likes of the educational/warning type (15 likes/post) were significantly lower than the catchphrase image type (these emphasized a slogan such as "athletesdontvape" in the image; 32.5 likes/post; P<.001). The majority of the antivaping posts contained the image content element text (n=332, 66.4%), followed by the image content element people/person (n=110, 22%). The images containing people/person elements (32.8 likes/post) had more likes than the images containing other elements (13.8-21.1 likes/post). The captions of the antivaping Instagram posts covered topics including "lung health," "teen vaping," "stop vaping," and "vaping death cases." Among the 500 antivaping Instagram posts, while most posts were from the antivaping community (n=177, 35.4%) and personal account types (n=182, 36.4%), the antivaping community account type had the highest average number of posts (1.69 posts/account). However, there was no difference in the number of likes among different account types. CONCLUSIONS: Multiple features of antivaping Instagram posts may be related to user engagement and perception. This study identified the critical elements associated with high user engagement, which could be used to design antivaping posts to deliver health-related information more efficiently.

Electronic Cigarette Users' Perspective on the COVID-19 Pandemic: Observational Study Using Twitter Data.

BACKGROUND: Previous studies have shown that electronic cigarette (e-cigarette) users might be more vulnerable to COVID-19 infection and could develop more severe symptoms if they contract the disease owing to their impaired immune responses to viral infections. Social media platforms such as Twitter have been widely used by individuals worldwide to express their responses to the current COVID-19 pandemic. OBJECTIVE: In this study, we aimed to examine the longitudinal changes in the attitudes of Twitter users who used e-cigarettes toward the COVID-19 pandemic, as well as compare differences in attitudes between e-cigarette users and nonusers based on Twitter data. METHODS: The study dataset containing COVID-19-related Twitter posts (tweets) posted between March 5 and April 3, 2020, was collected using a Twitter streaming application programming interface with COVID-19-related keywords. Twitter users were classified into two groups: Ecig group, including users who did not have commercial accounts but posted e-cigarette-related tweets between May 2019 and August 2019, and non-Ecig group, including users who did not post any e-cigarette-related tweets. Sentiment analysis was performed to compare sentiment scores towards the COVID-19 pandemic between both groups and determine whether the sentiment expressed was positive, negative, or neutral. Topic modeling was performed to compare the main topics discussed between the groups. RESULTS: The US COVID-19 dataset consisted of 4,500,248 COVID-19-related tweets collected from 187,399 unique Twitter users in the Ecig group and 11,479,773 COVID-19-related tweets collected from 2,511,659 unique Twitter users in the non-Ecig group. Sentiment analysis showed that Ecig group users had more negative sentiment scores than non-Ecig group users. Results from topic modeling indicated that Ecig group users had more concerns about deaths due to COVID-19, whereas non-Ecig group users cared more about the government's responses to the COVID-19 pandemic. CONCLUSIONS: Our findings show that Twitter users who tweeted about e-cigarettes had more concerns about the COVID-19 pandemic. These findings can inform public health practitioners to use social media platforms such as Twitter for timely monitoring of public responses to the COVID-19 pandemic and educating and encouraging current e-cigarette users to quit vaping to minimize the risks associated with COVID-19.

The COVID-19 Pandemic and Mental Health Concerns on Twitter in the United States

Background During the COVID-19 pandemic, mental health concerns (such as fear and loneliness) have been actively discussed on social media. We aim to examine mental health discussions on Twitter during the COVID-19 pandemic in the US and infer the demographic composition of Twitter users who had mental health concerns. Methods COVID-19-related tweets from March 5th, 2020, to January 31st, 2021, were collected through Twitter streaming API using keywords (i.e., “corona,” “covid19,” and “covid”). By further filtering using keywords (i.e., “depress,” “failure,” and “hopeless”), we extracted mental health-related tweets from the US. Topic modeling using the Latent Dirichlet Allocation model was conducted to monitor users' discussions surrounding mental health concerns. Deep learning algorithms were performed to infer the demographic composition of Twitter users who had mental health concerns during the pandemic. Results We observed a positive correlation between mental health concerns on Twitter and the COVID-19 pandemic in the US. Topic modeling showed that “stay-at-home,” “death poll,” and “politics and policy” were the most popular topics in COVID-19 mental health tweets. Among Twitter users who had mental health concerns during the pandemic, Males, White, and 30-49 age group people were more likely to express mental health concerns. In addition, Twitter users from the east and west coast had more mental health concerns. Conclusions The COVID-19 pandemic has a significant impact on mental health concerns on Twitter in the US. Certain groups of people (such as Males and White) were more likely to have mental health concerns during the COVID-19 pandemic.

Salivary and serum IgA and IgG responses to SARS-CoV-2-spike protein following SARS-CoV-2 infection and after immunization with COVID-19 vaccines.

Background: Secretory immunoglobulin A (sIgA) plays an important role in antiviral protective immunity. Although salivary testing has been used for many viral infections, including severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS), its use has not yet been well established with the SARS coronavirus 2 (SARS-CoV-2). Quantification of salivary IgA and IgG antibodies can elucidate mucosal and systemic immune responses after natural infection or vaccination. Here, we report the development and validation of a rapid enzyme-linked immunosorbent assay (ELISA) for anti-SARS-CoV-2 salivary IgA and serum IgG antibodies, and present quantitative results for immunized subjects both prior to or following COVID-19 infections. Objective: Total and serum SARS-CoV-2 spike-specific IgG responses were compared with salivary spike-specific IgA and IgG responses in samples obtained from patients recently infected with SARS-CoV-2 and from subjects recently immunized with COVID-19 vaccines. Methods: A total of 52 paired saliva and serum samples were collected from 26 study participants: 7 subjects after COVID-19 infection and 19 subjects who were uninfected. The ELISA results from these samples were compared with five prepandemic control serum samples. Total IgG and SARS-CoV-2 spike-specific IgG in the serum samples from the subjects who were infected and vaccinated were also measured in a commercial laboratory with an enzyme immunoassay. Results: A wide variation in antibody responses was seen in salivary and serum samples measured by both methods. Three groups of serum total and IgG spike-specific SARS-CoV-2 antibody responses were observed: (1) low, (2) intermediate, and (3) high antibody responders. A correlational analysis of salivary IgA (sIgA) responses with serum IgG concentrations showed a statistical correlation in the low and intermediate antibody responder groups but not in the high group (which we believe was a result of saturation). Conclusion: These preliminary findings suggest measuring salivary and serum IgG and IgA merit further investigation as markers of current or recent SARS-CoV-2 infections.

Broad Cross-Reactive IgA and IgG against Human Coronaviruses in Milk Induced by COVID-19 Vaccination and Infection.

It is currently unclear if SARS-CoV-2 infection or mRNA vaccination can also induce IgG and IgA against common human coronaviruses (HCoVs) in lactating parents. Here we prospectively analyzed human milk (HM) and blood samples from lactating parents to measure the temporal patterns of anti-SARS-CoV-2 specific and anti-HCoV cross-reactive IgA and IgG responses. Two cohorts were analyzed: a vaccination cohort (n = 30) who received mRNA-based vaccines for COVID-19 (mRNA-1273 or BNT162b2), and an infection cohort (n = 45) with COVID-19 disease. Longitudinal HM and fingerstick blood samples were collected pre- and post-vaccination or, for infected subjects, at 5 time-points 14-28 days after confirmed diagnosis. The anti-spike(S) and anti-nucleocapsid(N) IgA and IgG antibody levels against SARS-CoV-2 and HCoVs were measured by multiplex immunoassay (mPlex-CoV). We found that vaccination significantly increased the anti-S IgA and IgG levels in HM. In contrast, while IgG levels increased after a second vaccine dose, blood and HM IgA started to decrease. Moreover, HM and blood anti-S IgG levels were significantly correlated, but anti-S IgA levels were not. SARS2 acute infection elicited anti-S IgG and IgA that showed much higher correlations between HM and blood compared to vaccination. Vaccination and infection were able to significantly increase the broadly cross-reactive IgG recognizing HCoVs in HM and blood than the IgA antibodies in HM and blood. In addition, the broader cross-reactivity of IgG in HM versus blood indicates that COVID-19 vaccination and infection might provide passive immunity through HM for the breastfed infants not only against SARS-CoV-2 but also against common cold coronaviruses.

Research on the Differences in the Value Correlation of Accounting Data Under the Background of COVID-19: Comparative Evidence From China and Thailand

In today's highly developed world of financial globalization, international capital flows in my country and the entire Asia-Pacific region are gradually increasing. The stock market is an important part of the capital market. The stock market has gradually improved its capital liquidity. With the improvement of the investment environment in the international capital market and the gradual relaxation of capital controls, with the development of the "Belt and Road" development concept, Thailand has gradually chosen to buy and sell shares of Chinese investors. What investors need to consider is how to achieve capital appreciation. Investors need to consider how to achieve capital appreciation. However, a sudden new crown pneumonia epidemic broke the peace and excitement that the New Year should have, and also brought a great impact on the stock market. Of course, the stock market is affected by many factors. There are some problems here, such as the experience of the Chinese stock market.

Emotional or rational? The congruence effect of message appeals and country stereotype on tourists' international travel intentions

Advertising can be used to promote tourism recovery post-COVID-19 pandemic. However, the effectiveness of such advertising in the pandemic context remains uncertain. This study shows that when a country is associated with a warmth stereotype, advertisements with emotional appeals increase visit intention, whereas advertisements with rational appeals are more effective when the country is associated with a competence stereotype. These relationships are mediated by processing fluency and strengthened when the perceived health risk at a destination is low. Our study enriches tourism research by revealing that the effectiveness of destination advertising depends on a combination of tourists' pre-established country stereotypes, destination marketing organizations' advertising messages, and the pandemic environment. It also introduces metacognition as a new mechanism underlying travel decisions.

Both Baicalein and Gallocatechin Gallate Effectively Inhibit SARS-CoV-2 Replication by Targeting Mpro and Sepsis in Mice.

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than - 6. Then, ( -)-gallocatechin gallate, ( +)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 µM, 13.14 ± 2.081 µM and 5.158 ± 0.928 µM respectively by FRET assay. Molecular docking results also showed that ( -)-gallocatechin gallate, ( +)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of ( -)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. ( -)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, ( -)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19.

IgG Against Human Betacoronavirus Spike Proteins Correlates With SARS-CoV-2 Anti-Spike IgG Responses and COVID-19 Disease Severity.

BACKGROUND: A protective antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to decrease morbidity and mortality from severe coronavirus disease 2019 (COVID-19) disease. The effects of preexisting anti-human coronavirus (HCoV) antibodies on the SARS-CoV-2-specific immunoglobulin G (IgG) responses and severity of disease are currently unclear. METHODS: We profiled anti-spike (S), S1, S2, and receptor-binding domain IgG antibodies against SARS-CoV-2 and 6 HCoVs using a multiplex assay (mPLEX-CoV) with serum samples from SARS-CoV-2 infected (n = 155) and pre-COVID-19 (n = 188) cohorts. RESULTS: COVID-19 subjects showed significantly increased anti-S SARS-CoV-2 IgG levels that were highly correlated with IgG antibodies against OC43 and HKU1 S proteins. However, OC43 and HKU1 anti-S antibodies in pre-COVID-19 era sera did not cross-react with SARS-CoV-2. Unidirectional cross-reactive antibodies elicited by SARS-CoV-2 infection were distinct from the bidirectional cross-reactive antibodies recognizing homologous strains RaTG13 and SARS-CoV-1. High anti-OC43 and anti-S2 antibody levels were associated with both a rapid anti-SARS-CoV-2 antibody response and increased disease severity. Subjects with increased sequential organ failure assessment (SOFA) scores developed a higher ratio of S2- to S1-reactive antibodies. CONCLUSIONS: Early and rapid emergence of OC43 S- and S2-reactive IgG after SARS-CoV-2 infection correlates with COVID-19 disease severity.

Evaluating Population Invariance of Test Equating During the COVID-19 Pandemic

Population invariance is a desirable property of test equating which might not hold when significant changes occur in the test population, such as those brought about by the COVID-19 pandemic. This research aims to investigate whether equating functions are reasonably invariant when the test population is impacted by the pandemic. Based on pseudo-test forms constructed from an operational form administered in the springs of 2019, 2020, and 2021, this study conducted preequating and postequating using different data collection designs and different sample sizes based on each year's data. Raw-to-scale score conversion tables from each equating and the group means after applying these conversions were compared with those from a criterion equating, that is, single group design postequating based on the 2019 data. Within each design and sample size condition, the magnitude of the differences between the 2021 equating and the criterion equating was mostly similar to the magnitude of differences between the 2020 equating and the criterion, indicating a reasonable extent of invariance in equating results. Nevertheless, some equating designs showed slightly less invariance than others.

Antibody Mediated Immunity to SARS-CoV-2 and Human Coronaviruses: Multiplex Beads Assay and Volumetric Absorptive Microsampling to Generate Immune Repertoire Cartography.

The COVID-19 pandemic is caused by SARS-CoV-2, a novel zoonotic coronavirus. Emerging evidence indicates that preexisting humoral immunity against other seasonal human coronaviruses (HCoVs) plays a critical role in the specific antibody response to SARS-CoV-2. However, current work to assess the effects of preexisting and cross-reactive anti-HCoVs antibodies has been limited. To address this issue, we have adapted our previously reported multiplex assay to simultaneously and quantitatively measure anti-HCoV antibodies. The full mPlex-CoV panel covers the spike (S) and nucleocapsid (N) proteins of three highly pathogenic HCoVs (SARS-CoV-1, SARS-CoV-2, MERS) and four human seasonal strains (OC43, HKU1, NL63, 229E). Combining this assay with volumetric absorptive microsampling (VAMS), we measured the anti-HCoV IgG, IgA, and IgM antibodies in fingerstick blood samples. The results demonstrate that the mPlex-CoV assay has high specificity and sensitivity. It can detect strain-specific anti-HCoV antibodies down to 0.1 ng/ml with 4 log assay range and with low intra- and inter-assay coefficients of variation (%CV). We also estimate multiple strain HCoVs IgG, IgA and IgM concentration in VAMS samples in three categories of subjects: pre-COVID-19 (n=21), post-COVID-19 convalescents (n=19), and COVID-19 vaccine recipients (n=14). Using metric multidimensional scaling (MDS) analysis, HCoVs IgG concentrations in fingerstick blood samples were well separated between the pre-COVID-19, post-COVID-19 convalescents, and COVID-19 vaccine recipients. In addition, we demonstrate how multi-dimensional scaling analysis can be used to visualize IgG mediated antibody immunity against multiple human coronaviruses. We conclude that the combination of VAMS and the mPlex-Cov assay is well suited to performing remote study sample collection under pandemic conditions to monitor HCoVs antibody responses in population studies.

Effect of dihydromyricetin on SARS-CoV-2 viral replication and pulmonary inflammation and fibrosis.

BACKGROUND: COVID-19 (Coronavirus Disease-2019) has spread widely around the world and impacted human health for millions. The lack of effective targeted drugs and vaccines forces scientific world to search for new effective antiviral therapeutic drugs. It has reported that flavonoids have potential inhibitory activity on SARS-CoV-2 Mpro and anti-inflammatory properties. Dihydromyricetin, as a flavonol, also has antiviral and anti-inflammatory potential. However, the inhibition of dihydromyricetin on SARS-CoV-2 Mpro and the protective effect of dihydromyricetin on pulmonary inflammation and fibrosis have not been proved and explained. PURPOSE: The coronavirus main protease (Mpro) is essential for SARS-CoV-2 replication and to be recognized as an attractive drug target, we expect to find the inhibitor of Mpro. Novel coronavirus infection can cause severe inflammation and even sequelae of pulmonary fibrosis in critically ill patients. We hope to find a drug that can not only inhibit virus replication but also alleviate inflammation and pulmonary fibrosis in patients. METHODS: FRET-based enzymatic assay was used to evaluate the inhibit activity of dihydromyricetin on SARS-CoV-2 Mpro. Molecular docking was used to identify the binding pose of dihydromyricetin with SARS-CoV-2 Mpro. The protective effects of dihydromyricetin against BLM-induced pulmonary inflammation and fibrosis were investigated in C57BL6 mice. BALF and lung tissue were collected for inflammation cells count, ELISA, masson and HE staining, western blotting and immunohistochemistry to analyze the effects of dihydromyricetin on pulmonary inflammation and fibrosis. MTT, western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and wound healing were used to analyze the effects of dihydromyricetin on lung fibrosis mechanisms in Mlg cells. RESULTS: In this study, we found that dihydromyricetin is a potent inhibitor targeting the SARS-CoV-2 Mpro with a half-maximum inhibitory concentration (IC50) of 1.716 ± 0.419 µM, using molecular docking and the FRET-based enzymatic assay. The binding pose of dihydromyricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the dihydrochromone ring of dihydromyricetin interact with the imidazole side chain of His163 through π-π stacking. The 1-oxygen of dihydromyricetin forms a hydrogen bond with the backbone nitrogen of Glu166. The 3-, 7-, 3'- and 4'-hydroxyl of dihydromyricetin interact with Gln189, Leu141, Arg188 and Thr190 through hydrogen bonds. Moreover, our results showed that dihydromyricetin can significantly alleviate BLM-induced pulmonary inflammation by inhibiting the infiltration of inflammation cells and the secretion of inflammation factors in the early process and also ameliorate pulmonary fibrosis by improving pulmonary function and down-regulate the expression of α-SMA and fibronectin in vivo. Our results also showed that dihydromyricetin inhibits the migration and activation of myofibroblasts and extracellular matrix production via transforming growth factor (TGF)-ß1/Smad signaling pathways. CONCLUSION: Dihydromyricetin is an effective inhibitor for SARS-CoV-2 Mpro and it prevents BLM-induced pulmonary inflammation and fibrosis in mice. Dihydromyricetin will be a potential medicine for the treatment of COVID-19 and its sequelae.

1,10/1,11-Cyclization catalyzed by diverged plant sesquiterpene synthases is dependent on a single residue.

The exquisite chemodiversity of terpenoids is the product of the large diverse terpene synthase (TPS) superfamily. Here, by using structural and phylogenetic analyses and site-directed mutagenesis, we identified a residue (Cys440 in Nicotiana tabacum 5-epi-aristolochene synthase) proximal to an ion-binding motif common to all TPSs and named the preNSE/DTE residue, which determines the product specificity of sesquiterpene synthases from different plant species. In sesquiterpene synthases catalyzing 1,10-cyclization (1,10-cyclases) of farnesyl diphosphate, mutation of the residue in both specific and promiscuous 1,10-cyclases from different lineages leads to the accumulation of monocyclic germacrene A-11-ol, which is "short-circuited" from complex cyclization cascades, suggesting a key role of this residue in generating the first common intermediate of 1,10-cyclization. Altering this residue in a specific 1,11-cyclase results in alternative 1,10-cyclization products. Moreover, the preNSE/DTE residue can be harnessed to engineer highly specific sesquiterpene synthases for an improved proportion of high-value terpenoids, such as patchoulol, a main constituent of several traditional Chinese medicines that could treat SARS-CoV-2.

E-cigarette-induced pulmonary inflammation and dysregulated repair are mediated by nAChR α7 receptor: role of nAChR α7 in SARS-CoV-2 Covid-19 ACE2 receptor regulation.

Electronic cigarette (e-cig) vaping is increasing rapidly in the United States, as e-cigs are considered less harmful than combustible cigarettes. However, limited research has been conducted to understand the possible mechanisms that mediate toxicity and pulmonary health effects of e-cigs. We hypothesized that sub-chronic e-cig exposure induces inflammatory response and dysregulated repair/extracellular matrix (ECM) remodeling, which occur through the α7 nicotinic acetylcholine receptor (nAChRα7). Adult wild-type (WT), nAChRα7 knockout (KO), and lung epithelial cell-specific KO (nAChRα7 CreCC10) mice were exposed to e-cig aerosol containing propylene glycol (PG) with or without nicotine. Bronchoalveolar lavage fluids (BALF) and lung tissues were collected to determine e-cig induced inflammatory response and ECM remodeling, respectively. Sub-chronic e-cig exposure with nicotine increased inflammatory cellular influx of macrophages and T-lymphocytes including increased pro-inflammatory cytokines in BALF and increased SARS-Cov-2 Covid-19 ACE2 receptor, whereas nAChRα7 KO mice show reduced inflammatory responses associated with decreased ACE2 receptor. Interestingly, matrix metalloproteinases (MMPs), such as MMP2, MMP8 and MMP9, were altered both at the protein and mRNA transcript levels in female and male KO mice, but WT mice exposed to PG alone showed a sex-dependent phenotype. Moreover, MMP12 was increased significantly in male mice exposed to PG with or without nicotine in a nAChRα7-dependent manner. Additionally, sub-chronic e-cig exposure with or without nicotine altered the abundance of ECM proteins, such as collagen and fibronectin, significantly in a sex-dependent manner, but without the direct role of nAChRα7 gene. Overall, sub-chronic e-cig exposure with or without nicotine affected lung inflammation and repair responses/ECM remodeling, which were mediated by nAChRα7 in a sex-dependent manner.

Myricetin Inhibits SARS-CoV-2 Viral Replication by Targeting Mpro and Ameliorates Pulmonary Inflammation.

The coronavirus disease 2019 (COVID-19) has spread widely around the world and has seriously affected the human health of tens of millions of people. In view of lacking anti-virus drugs target to SARS-CoV-2, there is an urgent need to develop effective new drugs. In this study, we reported our discovery of SARS-CoV-2 Mpro inhibitors. We selected 15 natural compounds, including 7 flavonoids, 3 coumarins, 2 terpenoids, one henolic, one aldehyde and one steroid compound for molecular docking and enzymatic screening. Myricetin were identified to have potent inhibit activity with IC50 3.684 ± 0.076 µM in the enzyme assay. The binding pose of Myricetin with SARS-CoV-2 Mpro was identified using molecular docking method. In the binding pocket of SARS-CoV-2 Mpro, the chromone ring of Myricetin interacts with His41 through π-π stacking, and the 3'-, 4'- and 7-hydroxyl of Myricetin interact with Phe140, Glu166and Asp187 through hydrogen bonds. Significantly, our results showed that Myricetin has potent effect on bleomycin-induced pulmonary inflammation by inhibiting the infiltration of inflammatory cells and the secretion of inflammatory cytokines IL-6, IL-1α, TNF-α and IFN-γ. Overall, Myricetin may be a potential drug for anti-virus and symptomatic treatment of COVID-19.

Potential Impact of a Paper About COVID-19 and Smoking on Twitter Users' Attitudes Toward Smoking: Observational Study.

BACKGROUND: A cross-sectional study (Miyara et al, 2020) conducted by French researchers showed that the rate of current daily smoking was significantly lower in patients with COVID-19 than in the French general population, implying a potentially protective effect of smoking. OBJECTIVE: We aimed to examine the dissemination of the Miyara et al study among Twitter users and whether a shift in their attitudes toward smoking occurred after its publication as preprint on April 21, 2020. METHODS: Twitter posts were crawled between April 14 and May 4, 2020, by the Tweepy stream application programming interface, using a COVID-19-related keyword query. After filtering, the final 1929 tweets were classified into three groups: (1) tweets that were not related to the Miyara et al study before it was published, (2) tweets that were not related to Miyara et al study after it was published, and (3) tweets that were related to Miyara et al study after it was published. The attitudes toward smoking, as expressed in the tweets, were compared among the above three groups using multinomial logistic regression models in the statistical analysis software R (The R Foundation). RESULTS: Temporal analysis showed a peak in the number of tweets discussing the results from the Miyara et al study right after its publication. Multinomial logistic regression models on sentiment scores showed that the proportion of negative attitudes toward smoking in tweets related to the Miyara et al study after it was published (17.07%) was significantly lower than the proportion in tweets that were not related to the Miyara et al study, either before (44/126, 34.9%; P<.001) or after the Miyara et al study was published (68/198, 34.3%; P<.001). CONCLUSIONS: The public's attitude toward smoking shifted in a positive direction after the Miyara et al study found a lower incidence of COVID-19 cases among daily smokers.