Aloperine protects pulmonary hypertension via triggering PPARγ signaling and inhibiting calcium regulatory pathway in pulmonary arterial smooth muscle cells.

Previous studies have reported the beneficial role of Aloperine (ALO), an active vasodilator purified from the seeds and leaves of the herbal plant Sophora alopecuroides L., on experimental pulmonary hypertension (PH); however, detailed mechanisms remain unclear. In this study, monocrotaline-induced PH (MCT-PH) rat model and primarily cultured rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to investigate the mechanisms of ALO on experimental PH, pulmonary vascular remodeling, and excessive proliferation of PASMCs. Results showed that first, ALO significantly prevented the disease development of MCT-PH by inhibiting right ventricular systolic pressure (RVSP) and right ventricular hypertrophy indexed by the Fulton Index, normalizing the pulmonary arterials (PAs) remodeling and improving the right ventricular function indexed by transthoracic echocardiography. ALO inhibited the excessive proliferation of both PAs and PASMCs. Then, isometric tension measurements showed vasodilation of ALO on precontracted PAs isolated from both control and MCT-PH rats via activating the KCNQ channel, which was blocked by specific KCNQ potassium channel inhibitor linopirdine. Moreover, by using immunofluorescence staining and nuclear/cytosol fractionation, we further observed that ALO significantly enhanced the PPARγ nuclear translocation and activation in PASMCs. Transcriptome analyses also revealed activated PPARγ signaling and suppressed calcium regulatory pathway in lungs from MCT-PH rats treated with ALO. In summary, ALO could attenuate MCT-PH through both transient vasodilation of PAs and chronic activation of PPARγ signaling pathway, which exerted antiproliferative roles on PASMCs and remodeled PAs.NEW & NOTEWORTHY Aloperine attenuates monocrotaline-induced pulmonary hypertension (MCT-PH) in rats by inhibiting the pulmonary vascular remodeling and proliferation of pulmonary arterial smooth muscle cells (PASMCs). In mechanism, Aloperine not only exerts a transient KCNQ-dependent vasodilation in precontracted pulmonary arteries (PAs) from both control and MCT-PH rats but also activates PPARγ nuclear translocation and signaling transduction in PASMCs, which chronically inhibits the calcium regulatory pathway and proliferation of PASMCs.

Echocardiographic evaluation of right heart failure which might be associated with DNA damage response in SU5416-hypoxia induced pulmonary hypertension rat model.

Right heart failure is the leading cause of death in pulmonary hypertension (PH), and echocardiography is a commonly used tool for evaluating the risk hierarchy of PH. However, few studies have explored the dynamic changes in the structural and functional changes of the right heart during the process of PH. Previous studies have found that pulmonary circulation coupling right ventricular adaptation depends on the degree of pressure overload and other factors. In this study, we performed a time-dependent evaluation of right heart functional changes using transthoracic echocardiography in a SU5416 plus hypoxia (SuHx)-induced PH rat model. Rats were examined in 1-, 2-, 4-, and 6-week using right-heart catheterization, cardiac echocardiography, and harvested heart tissue. Our study found that echocardiographic measures of the right ventricle (RV) gradually worsened with the increase of right ventricular systolic pressure, and right heart hypofunction occurred at an earlier stage than pulmonary artery thickening during the development of PH. Furthermore, sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2), a marker of myocardial damage, was highly expressed in week 2 of SuHx-induced PH and had higher levels of expression of γ-H2AX at all timepoints, as well as higher levels of DDR-related proteins p-ATM and p53/p-p53 and p21 in week 4 and week 6. Our study demonstrates that the structure and function of the RV begin to deteriorate with DNA damage and cellular senescence during the early stages of PH development.

SARS-CoV-2 spike protein receptor-binding domain perturbates intracellular calcium homeostasis and impairs pulmonary vascular endothelial cells.

Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium. Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis. These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+]i. Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD. In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+]i through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+]i axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases.

Microbiome and metabolome dysbiosis of the gut-lung axis in pulmonary hypertension.

Previous studies have suggested that dysbiosis of the gut microbiota is associated with the development of pulmonary hypertension (PH). In this study, we established a left pulmonary artery ligation (LPAL)-induced PH rat model due to high flow and hemodynamic stress and investigated the association between gut microbiota composition and host metabolome signatures (in both gut and lung tissues) by using multiomics and correlation analysis. The results showed that LPAL successfully induced PH, characterized by increased right ventricular systolic pressure, right ventricular hypertrophy and pulmonary vascular remodelling. Moreover, gut pathological abnormalities were observed in association with dramatic alterations in the gut microbiome and metabolome as well as the lung metabolome. The increased bacterial genus Sporobacter and decreased genera Eubacterium, Eubacteriaceae, Deltaproteobacteria and Desulfovibrio featured the altered gut microbiome in LPAL-PH versus SHAM rats. Moreover, imbalanced abundance of protective metabolites (e.g., butyrate, propionate) and pathogenic metabolites (e.g., proinflammatory mediators) were seen in the gut metabolome of LPAL-PH versus SHAM rats. In addition, the altered gut microbiome strongly correlated with the altered metabolome patterns in both the gut and lung of LPAL-PH rats. In conclusion, this study revealed significant gut dysbiosis in LPAL-PH rats, characterized by altered gut microbiota composition, in association with specific changes in gut and lung metabolome profiles. These findings enriched our understanding of the unique signature of the gut microbiome and the close association of the "gut-lung axis" in LPAL-PH induced by long-term high flow, leading to novel therapeutic, diagnostic or management paradigms for this subtype of PH.

Visibility, wind speed, and dew point temperature are important factors in SARS-CoV-2 transmissibility.

The aim of this study is to provide evidence for the influencing factors of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus mutation by determining the impact of geographical and meteorological factors on SARS-CoV-2 transmission, and the different impacts of SARS-CoV-2 variant strains. From January 20 to March 10, 2020, we collected a number of daily confirmed new cases and meteorological factors in all cities and regions in China and Italy affected by the Alpha "variants of concern" (VOC). We also collected the daily confirmed cases of the Delta VOC infection in China and Italy from May 21 to November 30, 2021. The relationships between daily meteorological data and daily verified new cases of SARS-CoV-2 transmission were then investigated using a general additive model (GAM) with a log link function and Poisson family. The results revealed that latitude was substantially connected with daily confirmed new instances of the Alpha VOC, while there was no such correlation with Delta VOC transmission. When visibility is greater than 7 m, the propagation of the Alpha and Delta VOCs in Italy and China can be controlled. Furthermore, greater temperatures and increased wind speed reduce the transmission of the Alpha and Delta VOCs. In conclusion, geographical and meteorological factors play an important role in SARS-CoV-2 transmissibility and should be considered in virus mitigation strategies.

Bufei huoxue capsules in the management of convalescent COVID-19 infection: study protocol for a multicenter, double-blind, and randomized controlled trial.

Up to 30 May 2021, the cumulative number of patients diagnosed with corona virus disease-19 (COVID-19) globally has exceeded 170 million, with more than 152 million patients recovered from COVID-19. However, the long-term effect of the virus infection on the human body's function is unknown for convalescent patients. It was reported that about 63% of COVID-19 patients had observable lung damage on CT scans after being released from the hospital. Bufei Huoxue (BFHX) capsules, including three active ingredients of traditional Chinese herbal medicine, has been used clinically to prevent and treat pulmonary heart diseases with Qi deficiency and blood stasis syndrome. Some small-scale clinical trials have found that BFHX can improve lung ventilation function, reduce blood viscosity, and improve cardiopulmonary function. However, the efficacy and safety of BFHX in the treatment of the recovery phase of COVID-19 are unknown. This study is a multicenter, double-blinded, randomized, controlled trial. Subjects with convalescent COVID-19 were randomized (1:1) into either a BFHX or control group and observed for three months concomitant with receiving routine treatment. The primary efficacy indicators are the evaluation results and changes of the St. George's Respiratory Questionnaire score, Fatigue Assessment Inventory, and 6-min walk distance. Based on the intention-to-treat principle, all randomly assigned participants will be included in the statistical analysis. The last visit's outcomes will be used as the final outcomes for participants who prematurely withdraw from the trial. Per protocol set will pick up from the full analysis set for analysis. Efficacy analysis will be performed on the intention-to-treat datasets and per-protocol datasets. This study and its protocol were approved by the Ethics Committee of our University. Prior to participation, all subjects provided written informed consent. Results will be disseminated at medical conferences and in journal publications. We aimed to determine the efficacy and safety of BFHX for the treatment of the convalescent COVID-19 patients. Trial registration number: ChiCTR2000032573.

Upregulation of Piezo1 (Piezo Type Mechanosensitive Ion Channel Component 1) Enhances the Intracellular Free Calcium in Pulmonary Arterial Smooth Muscle Cells From Idiopathic Pulmonary Arterial Hypertension Patients.

[Figure: see text].

Altered Airway Microbiota Composition in Patients With Pulmonary Hypertension.

Alteration in microbiota composition of respiratory tract has been reported in the progression of many chronic lung diseases, yet, the correlation and causal link between respiratory tract microbiota and the disease development of pulmonary hypertension (PH) remain largely unknown. This study aims to define and compare the respiratory microbiota composition in pharyngeal swab samples between patients with PH and reference subjects. A total of 118 patients with PH and 79 reference subjects were recruited, and the pharyngeal swab samples were collected to sequence the 16S ribosomal RNA (16S rRNA) V3-V4 region of respiratory microbiome. The relative abundances in patients with PH were profoundly different from reference subjects. The Ace and Sobs indexes indicated that the microbiota richness of pharynx value is significantly higher; while the community diversity value is markedly lower in patients with PH, comparing to those of the reference subjects. The microbiota on pharynx showed a different profile between the 2 groups by principal component analysis. The linear discriminant analysis effect size also revealed a significantly higher proportion of Streptococcus, Lautropia, and Ralstonia in patients with PH than reference subjects. The linear discriminant analysis effect size output, which represents the microbial gene functions, suggest genes related to bacterial invasion of epithelial cells, bacterial toxins were enhanced, while genes related to energy metabolism, protein digestion and absorption, and cell division pathways were attenuated in patients with PH versus reference subjects. In summary, our study reports the first systematic definition and divergent profile of the upper respiratory tract microbiota between patients with PH and reference subjects.

Topographic location of unisolated pontine infarction.

BACKGROUND: The topographic location of acute pontine infarction is associated with clinical syndromes and prognosis. Previous studies focused on isolated pontine infarction, but the topographic location of unisolated pontine infarction has remained unclear. METHODS: This was a prospective, multicenter, longitudinal registry study. Patients with acute pontine infarction confirmed by magnetic resonance imaging (MRI) were enrolled. Based on the territory of the pontine artery, the topographic location was divided into anteromedial, anterolateral, tegmental, bilateral and unilateral multiple infarctions. RESULTS: From May 1, 2003, to Oct 31, 2017, 1003 patients were enrolled, and 330 had unisolated pontine infarction. For isolated pontine infarction, 44.9, 19.8, 16.0, 13.1 and 6.2% of patients had anteromedial, anterolateral, tegmental, bilateral and unilateral multiple pontine infarctions, respectively. For unisolated pontine infarction, 30.3, 19.7, 24.5, 15.2 and 10.3% of patients had anteromedial, anterolateral, tegmental, bilateral and unilateral multiple pontine infarctions, respectively. CONCLUSION: In this large series study, our data revealed fewer anteromedial infarctions and more tegmental and unilateral multiple infarctions in patients with unisolated pontine infarction than in patients with isolated pontine infarction.