Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation.

BACKGROUND: Silicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it's unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear. METHODS: To evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions. RESULTS: In vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-ß/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts. CONCLUSION: In summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Kynurenine acts as a signaling molecule to attenuate pulmonary fibrosis by enhancing the AHR-PTEN axis.

INTRODUCTION: Pulmonary fibrosis (PF) is a fatal fibrotic lung disease without any options to halt disease progression. Feasible evidence suggests that aberrant metabolism of amino acids may play a role in the pathoetiology of PF. However, the exact impact of kynurenine (Kyn), a metabolite derived from tryptophan (Trp) on PF is yet to be addressed. OBJECTIVES: This study aims to elucidate the role of kynurenine in both the onset and advancement of PF. METHODS: Liquid chromatography-tandem mass spectrometry was employed to assess Kyn levels in patients with idiopathic PF and PF associated with Sjögren's syndrome. Additionally, a mouse model of PF induced by bleomycin was utilized to study the impact of Kyn administration. Furthermore, cell models treated with TGF-ß1 were used to explore the mechanism by which Kyn inhibits fibroblast functions. RESULTS: We demonstrated that high levels of Kyn are a clinical feature in both idiopathic PF patients and primary Sjögren syndrome associated PF patients. Further studies illustrated that Kyn served as a braking molecule to suppress fibroblast functionality, thereby protecting mice from bleomycin-induced lung fibrosis. The protective effects depend on AHR, in which Kyn induces AHR nuclear translocation, where it upregulates PTEN expression to blunt TGF-ß mediated AKT/mTOR signaling in fibroblasts. However, in fibrotic microenviroment, the expression of AHR is repressed by methyl-CpG-binding domain 2 (MBD2), a reader interpreting the effect of DNA methylation, which results in a significantly reduced sensitivity of Kyn to fibroblasts. Therefore, exogenous administration of Kyn substantially reversed established PF. CONCLUSION: Our studies not only highlighted a critical role of Trp metabolism in PF pathogenesis, but also provided compelling evidence suggesting that Kyn could serve as a promising metabolite against PF.

3D hierarchical Ti3C2/TiO2 composite via in situ oxidation for improved lithium-ion storage.

To address the intrinsic limitations of both TiO2 and MXenes, we propose an effective strategy for the engineering of a 3D Ti3C2/TiO2 nanorod hybrid, where the in situ synthesized TiO2 nanorods are homogeneously decorated onto the surface of 3D Ti3C2 MXene via simple oxidation. As the LIB anode, it demonstrates exceptional long-term cycling stability with a specific capacity of 384.1 mA h g-1 after 600 cycles at 1.0 A g-1.

Salient object detection in low-light RGB-T scene via spatial-frequency cues mining.

Low-light conditions pose significant challenges to vision tasks, such as salient object detection (SOD), due to insufficient photons. Light-insensitive RGB-T SOD models mitigate the above problems to some extent, but they are limited in performance as they only focus on spatial feature fusion while ignoring the frequency discrepancy. To this end, we propose an RGB-T SOD model by mining spatial-frequency cues, called SFMNet, for low-light scenes. Our SFMNet consists of spatial-frequency feature exploration (SFFE) modules and spatial-frequency feature interaction (SFFI) modules. To be specific, the SFFE module aims to separate spatial-frequency features and adaptively extract high and low-frequency features. Moreover, the SFFI module integrates cross-modality and cross-domain information to capture effective feature representations. By deploying both modules in a top-down pathway, our method generates high-quality saliency predictions. Furthermore, we construct the first low-light RGB-T SOD dataset as a benchmark for evaluating performance. Extensive experiments demonstrate that our SFMNet can achieve higher accuracy than the existing models for low-light scenes.

Cellular and molecular mechanisms of fibrosis and resolution in bleomycin-induced pulmonary fibrosis mouse model revealed by spatial transcriptome analysis.

The bleomycin-induced pulmonary fibrosis mouse model is commonly used in idiopathic pulmonary fibrosis research, but its cellular and molecular changes and efficiency as a model at the molecular level are not fully understood. In this study, we used spatial transcriptome technology to investigate the cellular and molecular changes in the lungs of bleomycin-induced pulmonary fibrosis mouse models. Our analyses revealed cell dynamics during fibrosis in epithelial cells, mesenchymal cells, immunocytes, and erythrocytes with their spatial distribution available. We confirmed the differentiation of the alveolar type II (AT2) cell type expressing Krt8, and we inferred their trajectories from both the AT2 cells and club cells. In addition to the fibrosis process, we also noticed evidence of self-resolving, especially to identify possible self-resolving related genes, including Prkca. Our findings provide insights into the cellular and molecular mechanisms underlying fibrosis resolution and represent the first spatiotemporal transcriptome dataset of the bleomycin-induced fibrosis mouse model.

MBD2 facilitates tumor metastasis by mitigating DDB2 expression.

Despite past extensive studies, the pathoetiologies underlying tumor metastasis remain poorly understood, which renders its treatment largely unsuccessful. The methyl-CpG-binding domain 2 (MBD2), a "reader" to interpret DNA methylome-encoded information, has been noted to be involved in the development of certain types of tumors, while its exact impact on tumor metastasis remains elusive. Herein we demonstrated that patients with LUAD metastasis were highly correlated with enhanced MBD2 expression. Therefore, knockdown of MBD2 significantly attenuated the migration and invasion of LUAD cells (A549 and H1975 cell lines) coupled with attenuated epithelial-mesenchymal transition (EMT). Moreover, similar results were observed in other types of tumor cells (B16F10). Mechanistically, MBD2 selectively bound to the methylated CpG DNA within the DDB2 promoter, by which MBD2 repressed DDB2 expression to promote tumor metastasis. As a result, administration of MBD2 siRNA-loaded liposomes remarkably suppressed EMT along with attenuated tumor metastasis in the B16F10 tumor-bearing mice. Collectively, our study indicates that MBD2 could be a promising prognostic marker for tumor metastasis, while administration of MBD2 siRNA-loaded liposomes could be a viable therapeutic approach against tumor metastasis in clinical settings.

Clinical characteristics of COVID-19 patients with asthma in Wuhan, China: a retrospective cohort study.

OBJECTIVE: Although it is reported that patients with coronavirus disease 2019 (COVID-19) disease who have comorbidities are at higher risk to suffer adverse clinical outcomes, there are inadequate evidence to clarify the association between COVID-19 and asthma. On this ground, this study aims to systematically analyze the clinical characteristics of COVID-19 patients with asthma. METHODS: In this single-center, retrospective and observational cohort study, 21 COVID-19 patients with asthma and 100 non-asthma COVID-19 patients were statistically matched by propensity score based on age, sex and comorbidities. Meanwhile, a collection and comparison concerning demographic indicators, clinical and laboratory examinations, treatments and outcomes were conducted between two groups to specify their differences. RESULTS: Statistically, the COVID-19 patients with asthma had a higher proportion of ICU admission (14.3% [3/21] vs. 2.1% [2/96] p = 0.040) than those who do not have. On top this, a higher level of inflammatory responses, such as interleukin 6, interleukin 8, procalcitonin, leukocytes, neutrophils and CD4+ T cells was presented in asthma patients. Moreover, the increase of organ damage indices like D-dimer, lactate dehydrogenase and high-sensitivity cardiac troponin I, were more pronounced in COVID-19 patients with asthma. CONCLUSIONS: Exacerbated inflammatory responses and multiple organ damages were triggered in COVID-19 patients with asthma, which highlights more intensive surveillance and supportive treatment.

Isolated pulmonary mucormycosis in an immunocompetent patient: a case report and systematic review of the literature.

BACKGROUND: Pulmonary mucormycosis caused by Mucorales is a highly lethal invasive fungal infection usually found in immunocompromised patients. Isolated pulmonary mucormycosis in immunocompetent patients is very rare. Here, we present a case of a 32-year-old male who developed pulmonary mucormycosis without any known immunodeficiency. CASE PRESENTATION: The patient presented to our hospital because of cough and chest pain along with blood in the sputum. He was first treated for community-acquired pneumonia until bronchoalveolar lavage fluid culture confirmed the growth of Absidia. His symptoms were relieved with the use of amphotericin B, and he eventually recovered. We also provide a systematic review of relevant literature to summarize the characteristics of pulmonary mucormycosis in immunocompetent patients. CONCLUSIONS: Pulmonary mucormycosis has variable clinical presentations and is difficult to identify. Due to its high fatality rate, clinicians should make judgements regarding suspected cases correctly and in a timely manner to avoid misdiagnosis and delayed treatment.

MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program.

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.

Repurposed Tocilizumab in Patients with Severe COVID-19.

The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable morbidity and mortality. Tocilizumab, an inhibitor of IL-6, has been widely repurposed as a treatment of severely ill patients without robust evidence supporting its use. In this study, we aimed to systematically describe the effectiveness of treatment and prevention of the cytokine storms in COVID-19 patients with tocilizumab. In this multicentered retrospective and observational cohort study, 65 patients with COVID-19 receiving tocilizumab and 130 not receiving tocilizumab were propensity score matched at a ratio of 2:1 based on age, sex, and comorbidities from January 20, 2020 to March 18, 2020 in Wuhan, China. After adjusting for confounding, the detected risk for in-hospital death was lower in the tocilizumab group versus nontocilizumab group (hazard ratio = 0.47; 95% confidence interval = 0.25-0.90; p = 0.023). Moreover, use of tocilizumab was associated with a lower risk of acute respiratory distress syndrome (odds ratio = 0.23; 95% confidence interval = 0.11-0.45; p < 0.0001). Furthermore, patients had heightened inflammation and more dysregulated immune cells before treatment, which might aggravate disease progression. After tocilizumab administration, abnormally elevated IL-6, C-reactive protein, fibrinogen, and activated partial thromboplastin time decreased. Tocilizumab may be of value in prolonging survival in patients with severe COVID-19, which provided a novel strategy for COVID-19-induced cytokine release syndrome. Our findings could inform bedside decisions until data from randomized, controlled clinical trials become available.

The epidemiology and clinical characteristics of co-infection of SARS-CoV-2 and influenza viruses in patients during COVID-19 outbreak.

In this study, we performed a single-centered study of 307 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. It was found that co-infection of SARS-CoV-2 and influenza virus was common during COVID-19 outbreak. And patients coinfected with SARS-CoV-2 and influenza B virus have a higher risk of developing poor outcomes so a detection of both viruses was recommended during COVID-19 outbreak.

Outpatient strategies and the changing SARS-CoV-2 epidemic.

In response to the early outbreak of SARS-CoV-2, online fever clinics were set up. Then, an online face-to-face consultation was developed to solve the extreme difficulty of getting medical services to patients with chronic diseases. http://bit.ly/3cPppai.

Clinical characteristics of 54 medical staff with COVID-19: A retrospective study in a single center in Wuhan, China.

In December 2019, an outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection occurred in Wuhan, and rapidly spread to worldwide, which has attracted many people's concerns about the patients. However, studies on the infection status of medical personnel is still lacking. A total of 54 cases of SARS-Cov-2 infected medical staff from Tongji Hospital between 7 January and 11 February 2020 were analyzed in this retrospective study. Clinical and epidemiological characteristics were compared between different groups by statistical method. From 7 January to 11 February 2020, 54 medical staff of Tongji Hospital were hospitalized due to coronavirus disease 2019 (COVID-19). Most of them were from other clinical departments (72.2%) rather than emergency department (3.7%) or medical technology departments (18.5%). Among the 54 patients with COVID-19, the distribution of age had a significant difference between non-severe type and severe/critical cases (median age: 47 years vs 38 years; P = .0015). However, there was no statistical difference in terms of gender distribution and the first symptoms between theses two groups. Furthermore, we observed that the lesion regions in SARS-Cov-2 infected lungs with severe-/critical-type of medical staff were more likely to exhibit lesions in the right upper lobe (31.7% vs 0%; P = .028) and right lung (61% vs 18.2%; P = .012). Based on our findings with medical staff infection data, we suggest training for all hospital staff to prevent infection and preparation of sufficient protection and disinfection materials.

Blockade of JAK2 protects mice against hypoxia-induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation.

OBJECTIVES: Hypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH. METHODS: Smooth muscle cell (SMC)-specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2 ) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre-treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24-hour hypoxic exposure. RESULTS: Mice with hypoxia-induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia-induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia-induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG-101348, suppressed hypoxia-induced human PASMC proliferation. Upon hypoxia-induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation. CONCLUSIONS: Our studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.

Viral Infection Increases the Risk of Idiopathic Pulmonary Fibrosis: A Meta-Analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with a poor prognosis. Although many factors have been identified that possibly trigger or aggravate IPF, such as viral infection, the exact cause of IPF remains unclear. Until now, there has been no systematic review to assess the role of viral infection in IPF quantitatively. OBJECTIVE: This meta-analysis aims to present a collective view on the relationship between viral infection and IPF. METHODS: We searched studies reporting the effect of viral infection on IPF in the PubMed, Embase, Cochrane Library, Web of Science, and Wiley Online Library databases. We calculated ORs with 95% CIs to assess the risk of virus in IPF. We also estimated statistical heterogeneity by using I2 and Cochran Q tests and publication bias by using the funnel plot, Begg test, Egger test, and trim-and-fill methods. Regression, sensitivity, and subgroup analyses were performed to assess the effects of confounding factors, such as sex and age. RESULTS: We analyzed 20 case-control studies from 10 countries with 1,287 participants. The pooled OR of all viruses indicated that viral infection could increase the risk of IPF significantly (OR, 3.48; 95% CI, 1.61-7.52; P = .001), but not that of exacerbation of IPF (OR, 0.99; 95% CI, 0.47-2.12; P = .988). All analyzed viruses, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 7 (HHV-7), and human herpesvirus 8 (HHV-8), were associated with a significant elevation in the risk of IPF, except human herpesvirus 6 (HHV-6). CONCLUSIONS: The presence of persistent or chronic, but not acute, viral infections, including EBV, CMV, HHV-7, and HHV-8, significantly increases the risk of developing IPF, but not exacerbation of IPF. These findings imply that viral infection could be a potential risk factor for IPF.

A Regularized Weighted Smoothed L0 Norm Minimization Method for Underdetermined Blind Source Separation.

Compressed sensing (CS) theory has attracted widespread attention in recent years and has been widely used in signal and image processing, such as underdetermined blind source separation (UBSS), magnetic resonance imaging (MRI), etc. As the main link of CS, the goal of sparse signal reconstruction is how to recover accurately and effectively the original signal from an underdetermined linear system of equations (ULSE). For this problem, we propose a new algorithm called the weighted regularized smoothed L 0 -norm minimization algorithm (WReSL0). Under the framework of this algorithm, we have done three things: (1) proposed a new smoothed function called the compound inverse proportional function (CIPF); (2) proposed a new weighted function; and (3) a new regularization form is derived and constructed. In this algorithm, the weighted function and the new smoothed function are combined as the sparsity-promoting object, and a new regularization form is derived and constructed to enhance de-noising performance. Performance simulation experiments on both the real signal and real images show that the proposed WReSL0 algorithm outperforms other popular approaches, such as SL0, BPDN, NSL0, and L p -RLSand achieves better performances when it is used for UBSS.

Capability of cation exchange technology to remove proven N-nitrosodimethylamine precursors.

N-nitrosodimethylamine (NDMA) precursors consist of a positively charged dimethylamine group and a non-polar moiety, which inspired us to develop a targeted cation exchange technology to remove NDMA precursors. In this study, we tested the removal of two representative NDMA precursors, dimethylamine (DMA) and ranitidine (RNTD), by strong acidic cation exchange resin. The results showed that pH greatly affected the exchange efficiency, with high removal (DMA>78% and RNTD>94%) observed at pHMg2+>RNTD+>K+>DMA+>NH4+>Na+. The partition coefficient of DMA+ to Na+ was 1.41±0.26, while that of RNTD+ to Na+ was 12.1±1.9. The pseudo second-order equation fitted the cation exchange kinetics well. Bivalent inorganic cations such as Ca2+ were found to have a notable effect on NA precursor removal in softening column test. Besides DMA and RNTD, cation exchange process also worked well for removing other 7 model NDMA precursors. Overall, NDMA precursor removal can be an added benefit of making use of cation exchange water softening processes.