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Background: Hemodialysis patients are at an increased risk of SARS-CoV-2 infection and are excluded from preauthorization COVID-19 vaccine trials; therefore, their immunogenicity is uncertain. Methods: To compare the antibody responses to homologous ChAdOx1 and mRNA-1273 SARS-CoV-2 vaccination in hemodialysis patients, 103 age- and sex-matched hemodialysis patients with two homologous prime-boost vaccinations were recruited to detect anti-receptor-binding domain (RBD) IgG levels and seroconversion rates (SCRs) 14 days after a prime dose (PD14), before and 28 days after a boost dose (pre-BD0 and BD28). Results: Both mRNA-1273 and ChAdOx1 vaccinations elicited immunogenicity in study subjects, and the former induced higher anti-RBD IgG levels than the latter. The SCRs of both groups increased over time and varied widely from 1.82% to 97.92%, and were significantly different at PD14 and pre-BD0 regardless of different thresholds. At BD28, the SCRs of the ChAdOx1 group and the mRNA-1273 group were comparable using a threshold ≥ 7.1 BAU/mL (93.96% vs. 97.92%) and a threshold ≥ 17 BAU/mL (92.73% vs. 97.92%), respectively, but they were significantly different using a threshold ≥ 20.2% of convalescent serum anti-RBD levels (52.73% vs. 95.83%). The seroconversion (≥20.2% of convalescent level) at BD28 was associated with mRNA-1273 vaccination after being adjusted for age, sex, body mass index, and the presence of solicited reactogenicity after a prime vaccination. Conclusion: Our prospective, observational cohort indicates that a full prime-boost mRNA-1273 vaccination is likely to provide higher immune protection in hemodialysis patients compared to ChAdOx1, and this population with a prime-boost ChAdOx1 vaccination should be prioritized for a third dose.

Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (p = 0.003), disease-free interval < 24 months (p = 0.041), and biologically effective dose (BED10) < 100 Gy (p = 0.006) were independently associated with inferior OS. BED10 ≥ 100 Gy (p = 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (p = 0.017) and EPD (p = 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED10 ≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.

Toll-like receptor (TLR) is essential for the immune response to Mycobacterium tuberculosis (MTB) infection. However, the mechanism whereby TLR mediates the MTB-induced pleural mesothelial hyperpermeability in tuberculous pleural effusion (TBPE) remains unclear. Pleural effusion size and pleural fluid levels of vascular endothelial growth factor (VEGF) and soluble TLR2 (sTLR2) in patients with TBPE (n = 36) or transudative pleural effusion (TPE, n = 16) were measured. The effects of MTB H37Ra (MTBRa) on pleural mesothelial permeability and the expression of VEGF and zonula occludens (ZO)-1 in human pleural mesothelial cells (PMCs) were assessed. Levels of VEGF and sTLR2 were significantly elevated in TBPE compared to TPE. Moreover, effusion VEGF levels correlated positively, while sTLR2 values correlated negatively, with pleural effusion size in TBPE. In human PMCs, MTBRa substantially activated JNK/AP-1 signaling and upregulated VEGF expression, whereas knockdown of TLR2 remarkably inhibited MTBRa-induced JNK phosphorylation and VEGF overexpression. Additionally, both MTBRa and VEGF markedly reduced ZO-1 expression and induced pleural mesothelial permeability, while TLR2 silencing or pretreatment with anti-VEGF antibody significantly attenuated the MTBRa-triggered effects. Collectively, TLR2 mediates VEGF overproduction and downregulates ZO-1 expression in human PMCs, leading to mesothelial hyperpermeability in TBPE. Targeting TLR2/VEGF pathway may confer a potential treatment strategy for TBPE.

Platelets are crucial for hemostasis and arterial thrombosis, which may lead to severe cardiovascular diseases (CVDs). Thus, therapeutic agents must be developed to prevent pathological platelet activation. Glabridin, a major bioalkaloid extracted from licorice root, improves metabolic abnormalities (i.e., obesity and diabetes) and protects against CVDs and neuronal disorders. To the best of our knowledge, no studies have focused on glabridin’s effects on platelet activation. Therefore, we investigated these effects in humans and mice. Glabridin exhibited the highest inhibitory effects on collagen-stimulated platelet aggregation and moderate effects on arachidonic-acid-stimulated activation; however, no effects were observed for any other agonists (e.g., thrombin or U46619). Glabridin evidently reduced P-selectin expression, ATP release, and intracellular Ca2+ ([Ca2+]i) mobilization and thromboxane A2 formation; it further reduced the activation of phospholipase C (PLC)γ2/protein kinase C (PKC), phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β), mitogen-activated protein kinase (MAPK), and NF-κB. In mice, glabridin reduced the mortality rate caused by acute pulmonary thromboembolism without altering bleeding time. Thus, glabridin effectively inhibits the PLCγ2/PKC cascade and prevents the activation of the PI3K/Akt/GSK3β and MAPK pathways; this leads to a reduction in [Ca2+]i mobilization, which eventually inhibits platelet aggregation. Therefore, glabridin may be a promising therapeutic agent for thromboembolic disorders.

Background: The ChAdOx1 nCoV-19 vaccine has been widely administered against SARS-CoV-2 infection; however, data regarding its immunogenicity, reactogenicity, and potential differences in responses among Asian populations remain scarce. Methods: 270 participants without prior COVID-19 were enrolled to receive ChAdOx1 nCoV-19 vaccination with a prime–boost interval of 8–9 weeks. Their specific SARS-CoV-2 antibodies, neutralizing antibody titers (NT50), platelet counts, and D-dimer levels were analyzed before and after vaccination. Results: The seroconversion rates of anti-RBD and anti-spike IgG at day 28 after a boost vaccination (BD28) were 100% and 95.19%, respectively. Anti-RBD and anti-spike IgG levels were highly correlated (r = 0.7891), which were 172.9 ± 170.4 and 179.3 ± 76.88 BAU/mL at BD28, respectively. The geometric mean concentrations (GMCs) of NT50 for all participants increased to 132.9 IU/mL (95% CI 120.0–147.1) at BD28 and were highly correlated with anti-RBD and anti-spike IgG levels (r = 0.8248 and 0.7474, respectively). Body weight index was statistically significantly associated with anti-RBD IgG levels (p = 0.035), while female recipients had higher anti-spike IgG levels (p = 0.038). The GMCs of NT50 declined with age (p = 0.0163) and were significantly different across age groups (159.7 IU/mL for 20–29 years, 99.4 IU/mL for ≥50 years, p = 0.0026). Injection-site pain, fever, and fatigue were the major reactogenicity, which were more pronounced after prime vaccination and in younger participants (

Platelets play a critical role in arterial thrombosis. Rutaecarpine (RUT) was purified from Tetradium ruticarpum, a well-known Chinese medicine. This study examined the relative activity of RUT with NF-κB inhibitors in human platelets. BAY11-7082 (an inhibitor of IκB kinase [IKK]), Ro106-9920 (an inhibitor of proteasomes), and RUT concentration-dependently (1–6 μM) inhibited platelet aggregation and P-selectin expression. RUT was found to have a similar effect to that of BAY11-7082; however, it exhibits more effectiveness than Ro106-9920. RUT suppresses the NF-κB pathway as it inhibits IKK, IκBα, and p65 phosphorylation and reverses IκBα degradation in activated platelets. This study also investigated the role of p38 and NF-κB in cell signaling events and found that SB203580 (an inhibitor of p38) markedly reduced p38, IKK, and p65 phosphorylation and reversed IκBα degradation as well as p65 activation in a confocal microscope, whereas BAY11-7082 had no effects in p38 phosphorylation. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay shows that RUT and BAY11-7082 did not exhibit free radical scavenging activity. In the in vivo study, compared with BAY11-7082, RUT more effectively reduced mortality in adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism without affecting the bleeding time. In conclusion, a distinctive pathway of p38-mediated NF-κB activation may involve RUT-mediated antiplatelet activation, and RUT could act as a strong prophylactic or therapeutic drug for cardiovascular diseases.

Lipoteichoic acid (LTA) stimulates pleural mesothelial cell (PMC) to overproduce plasminogen activator inhibitor-1 (PAI-1), and thus may promote pleural fibrosis in Gram-positive bacteria (GPB) parapneumonic effusion (PPE). Histone deacetylase inhibitor (HDACi) was found to possess anti-fibrotic properties. However, the effects of HDACi on pleural fibrosis remain unclear. The effusion PAI-1 was measured among 64 patients with GPB PPE. Pleural fibrosis was measured as radiographical residual pleural thickening (RPT) and opacity at a 12-month follow-up. The LTA−stimulated human PMCs and intrapleural doxycycline−injected rats were pretreated with or without the pan-HDACi, m-carboxycinnamic acid bis-hydroxamide (CBHA), then PAI-1 and collagen expression and activated signalings in PMCs, and morphologic pleural changes in rats were measured. Effusion PAI-1 levels were significantly higher in GPB PPE patients with RPT > 10 mm (n = 26) than those without (n = 38), and had positive correlation with pleural fibrosis shadowing. CBHA significantly reduced LTA−induced PAI-1 and collagen expression via inhibition of JNK, and decreased PAI-1 promoter activity and mRNA levels in PMCs. Furthermore, in doxycycline−treated rats, CBHA substantially repressed PAI-1 and collagen synthesis in pleural mesothelium and minimized pleural fibrosis. Conclusively, CBHA abrogates LTA−induced PAI-1 and collagen expression in PMCs and attenuates experimental pleural fibrosis. PAI-1 inhibition by HDACi may confer potential therapy for pleural fibrosis.

Pterostilbene (PTE), a natural stilbenoid occurring in grapes and berries, is recognized as a dimethylated analogue of resveratrol. This compound shows numerous notable pharmacological activities, including antiaging, anticancer, antidiabetes, antioxidant, and neuroprotection. This study investigates the anti-inflammatory properties of PTE in macrophage cells (RAW 264.7) against the lipoteichoic acid (LTA) stimulation. The expression of inflammatory tumor necrosis factor (TNF-α), interleukin-1β (IL-1 β), and inducible nitric oxide synthase (iNOS) and the content of nitric oxide (NO) were detected in LTA-induced cells. In addition, a Western blot assay was used to detect mitogen-activated protein kinases: extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and c-Jun N-terminal kinase (JNK). The phosphorylation of IκB and p65 and translocation of nuclear factor kappa B (NF-κB) were assessed by Western blot and immuno-fluorescence staining. The results showed that PTE significantly attenuated NO production and TNF-α, IL-1 β, and iNOS expression in LTA stimulated cells. Among the activation of ERK, JNK, and p38 in cells treated with LTA, PTE at higher concentration had only inhibited ERK activation. However, PTE blocked IκB phosphorylation, phosphorylation and nuclear translocation of p65NF-κB. Fascinatingly, PTE enhanced antioxidant defense molecules as verified by the enhanced heme oxygenase-1 (HO-1) expression, catalase (CAT) antioxidant enzyme, and non-enzymatic antioxidant, and reduced glutathione (GSH) in LTA-induced RAW 264.7 cells. These results suggest that PTE exerts an anti-inflammatory property via attenuating NF-κB/ERK signaling pathways as well as enriching antioxidant defense mechanisms.

Platelets are major players in the occurrence of cardiovascular diseases. Auraptene is the most abundant coumarin derivative from plants, and it has been demonstrated to possess a potent capacity to inhibit platelet activation. Although platelets are anucleated cells, they also express the transcription factor, nuclear factor-κB (NF-κB), that may exert non-genomic functions in platelet activation. In the current study, we further investigated the inhibitory roles of auraptene in NF-κB-mediated signal events in platelets. MG-132 (an inhibitor of proteasome) and BAY11-7082 (an inhibitor of IκB kinase; IKK), obviously inhibited platelet aggregation; however, BAY11-7082 exhibited more potent activity than MG-132 in this reaction. The existence of NF-κB (p65) in platelets was observed by confocal microscopy, and auraptene attenuated NF-κB activation such as IκBα and p65 phosphorylation and reversed IκBα degradation in collagen-activated platelets. To investigate cellular signaling events between PLCγ2-PKC and NF-κB, we found that BAY11-7082 abolished PLCγ2-PKC activation; nevertheless, neither U73122 nor Ro31-8220 had effect on NF-κB activation. Furthermore, both auraptene and BAY11-7082 significantly diminished HO• formation in activated platelets. For in vivo study, auraptene prolonged the occlusion time of platelet plug in mice. In conclusion, we propose a novel inhibitory pathway of NF-κB-mediated PLCγ2-PKC activation by auraptene in human platelets, and further supported that auraptene possesses potent activity for thromboembolic diseases.

The activation of capsaicin-sensitive lung vagal (CSLV) afferents can elicit airway reflexes. Hypersensitivity of these afferents is known to contribute to the airway hypersensitivity during airway inflammation. Hydrogen sulfide (H2S) has been suggested as a potential therapeutic agent for airway hypersensitivity diseases, such as asthma, because of its relaxing effect on airway smooth muscle and anti-inflammatory effect. However, it is still unknown whether H2S affects airway reflexes. Our previous study demonstrated that exogenous application of H2S sensitized CSLV afferents and enhanced Ca2+ transients in CSLV neurons. The present study aimed to determine whether the H2S-induced sensitization leads to functional changes in airway reflexes and elevates the electrical excitability of the CSLV neurons. Our results showed that, first and foremost, in anesthetized, spontaneously breathing rats, the inhalation of aerosolized sodium hydrosulfide (NaHS, a donor of H2S; 5 mg/mL, 3 min) caused an enhancement in apneic response evoked by several stimulants of the CSLV afferents. This enhancement effect was found 5 min after NaHS inhalation and returned to control 30 min later. However, NaHS no longer enhanced the apneic response after perineural capsaicin treatment on both cervical vagi that blocked the conduction of CSLV fibers. Furthermore, the enhancing effect of NaHS on apneic response was totally abolished by pretreatment with intravenous HC-030031 (a TRPA1 antagonist; 8 mg/kg), whereas the potentiating effect was not affected by the pretreatment with the vehicle of HC-030031. We also found that intracerebroventricular infusion pretreated with HC-030031 failed to alter the potentiating effect of NaHS on the apneic response. Besides, the cough reflex elicited by capsaicin aerosol was enhanced by inhalation of NaHS in conscious guinea pigs. Nevertheless, this effect was entirely eliminated by pretreatment with HC-030031, not by its vehicle. Last but not least, voltage-clamp electrophysiological analysis of isolated rat CSLV neurons showed a similar pattern of potentiating effects of NaHS on capsaicin-induced inward current, and the involvement of TRPA1 receptors was also distinctly shown. In conclusion, these results suggest that H2S non-specifically enhances the airway reflex responses, at least in part, through action on the TRPA1 receptors expressed on the CSLV afferents. Therefore, H2S should be used with caution when applying for therapeutic purposes in airway hypersensitivity diseases.

Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial−mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT > 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated α-smooth muscle actin (α-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, α-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa−stimulated PAI-1 expression and MMT. Consistently, prothrombin/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin/PAR-1 inhibition may confer potential therapy for pleural fibrosis.

Morin hydrate, a bioactive flavonoid, has been proven to prevent inflammation and apoptosis of cells. Flavonoids can reduce the risk of cardiovascular diseases, in which platelet activation plays a major role. This study investigated the effect of morin hydrate on platelet activation in vitro and in vivo. Morin hydrate markedly inhibited platelet aggregation stimulated by collagen in human platelets but not that stimulated by other agonists. In collagen-activated platelets, morin hydrate inhibited adenosine triphosphate (ATP) release; intracellular Ca2+ mobilization; P-selectin expression; and phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), and Akt. In mitogen-activated protein kinase (MAPK) activation, morin hydrate evidently diminished ERK2 or JNK1 activation, except for p38 MAPK. Additionally, morin hydrate markedly reduced the OH· signals in platelet suspensions but not in the cell-free system (Fenton reaction solution). Moreover, morin hydrate substantially increased the occlusion time of thrombotic platelet plug formation but had no effect on bleeding time in mice. In conclusion, morin hydrate crucially inhibits platelet activation through inhibition of the PLCγ2–PKC cascade and subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, this paper suggests that morin hydrate constitutes a novel and potential natural therapeutic product for preventing or treating thromboembolic disorders.

Traumatic brain injury (TBI) is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied by neuroinflammation, microglial activation, and additional cell death subsequently occur. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers, and some types of acute inflammation. In the present study, the neuroprotective effects of platonin against TBI were explored in a controlled cortical impact (CCI) injury model in mice. Treatment with platonin (200 µg/kg) significantly reduced the neurological severity score, general locomotor activity, and anxiety-related behavior, and improved the rotarod performance of CCI-injured mice. In addition, platonin reduced lesion volumes, the expression of cleaved caspase-3, and microglial activation in TBI-insulted brains. Platonin also suppressed messenger (m)RNA levels of caspase-3, caspase-1, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β. On the other hand, free radical production after TBI was obviously attenuated in platonin-treated mice. Treatment with platonin exhibited prominent neuroprotective properties against TBI in a CCI mouse model through its anti-inflammatory, anti-apoptotic, and anti-free radical capabilities. This evidence collectively indicates that platonin may be a potential therapeutic medicine for use with TBIs.