Role of macrophages in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary vascular disease characterized by progressive pulmonary artery pressure elevation, increased pulmonary vascular resistance and ultimately right heart failure. Studies have demonstrated the involvement of multiple immune cells in the development of PAH in patients with PAH and in experimental PAH. Among them, macrophages, as the predominant inflammatory cells infiltrating around PAH lesions, play a crucial role in exacerbating pulmonary vascular remodeling in PAH. Macrophages are generally polarized into (classic) M1 and (alternative) M2 phenotypes, they accelerate the process of PAH by secreting various chemokines and growth factors (CX3CR1, PDGF). In this review we summarize the mechanisms of immune cell action in PAH, as well as the key factors that regulate the polarization of macrophages in different directions and their functional changes after polarization. We also summarize the effects of different microenvironments on macrophages in PAH. The insight into the interactions between macrophages and other cells, chemokines and growth factors may provide important clues for the development of new, safe and effective immune-targeted therapies for PAH.

Epidemiology-based analysis of the risks and elimination strategies of the monkeypox outbreak in 2022.

Human monkeypox, caused by monkeypox virus, has spread unprecedentedly to more than 100 countries since May 2022. Here we summarized the epidemiology of monkeypox through a literature review and elucidated the risks and elimination strategies of this outbreak mainly based on the summarized epidemiology. We demonstrated that monkeypox virus became more contagious and less virulent in 2022, which could result from the fact that the virus entered a special transmission network favoring close contacts (i.e., sexual behaviors of men who have sex with men outside Africa) and the possibility that the virus accumulated a few adaptive mutations. We gave the reasons to investigate whether cattle, goats, sheep, and pigs are susceptible to monkeypox virus and whether infection with monkeypox virus could be latent in some primates. We listed six potential scenarios for the future of the outbreak (e.g., the outbreak could lead to endemicity outside Africa with increased transmissibility or virulence). We also listed multiple factors aiding or impeding the elimination of the outbreak. We showed that the control measures strengthened worldwide after the World Health Organization declared the outbreak a public health emergency of international concern (PHEIC) could eliminate the outbreak in 2022. We clarified eight strategies, i.e., publicity and education, case isolation, vaccine stockpiling, risk-based vaccination or ring vaccination, importation quarantine, international collaboration, and laboratory management, for the elimination of the outbreak.

A highly powerful nonspecific strategy to reduce COVID-19 deaths.

The coronavirus disease 2019 (COVID-19) pandemic caused by the coronavirus severe acute respiratory syndrome coronavirus 2 remains risky worldwide. We elucidate here that good IDM (isolation, disinfection, and maintenance of health) is powerful to reduce COVID-19 deaths based on the striking differences in COVID-19 case fatality rates among various scenarios. IDM means keeping COVID-19 cases away from each other and from other people, disinfecting their living environments, and maintaining their health through good nutrition, rest, and treatment of symptoms and pre-existing diseases (not through specific antiviral therapy). Good IDM could reduce COVID-19 deaths by more than 85% in 2020 and more than 99% in 2022. This is consistent with the fact that good IDM can minimize co-infections and maintain body functions and the fact that COVID-19 has become less pathogenic (this fact was supported with three novel data in this report). Although IDM has been frequently implemented worldwide to some degree, IDM has not been highlighted sufficiently. Good IDM is relative, nonspecific, flexible, and feasible in many countries, and can reduce deaths of some other relatively mild infectious diseases. IDM, vaccines, and antivirals aid each other to reduce COVID-19 deaths. The IDM concept and strategy can aid people to improve their health behavior and fight against COVID-19 and future pandemics worldwide.

Plasma metabolomics in the perioperative period of defect repair in patients with pulmonary arterial hypertension associated with congenital heart disease.

The quality of life and survival rates of patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) have been greatly improved by defect-repair surgery and personalized treatments. However, those who survive surgery may remain at risk of persistent PAH, the prognosis may be considerably worse than those unoperated. Dynamic monitoring of clinical measures during the perioperative period of shunt correction is therefore indispensable and of great value. In this study, we explored the plasma-metabolite profiling in 13 patients with CHD-PAH during the perioperative period of defect repair. Plasma was harvested at four time points: prior to cardiopulmonary bypass (CPB) after anesthesia (Pre), immediately after CPB (T0), 24 h (T24), and 48 h (T48) after defect repair. Untargeted metabolomics strategy based on UPLC Q-TOF MS was used to detect the metabolites. A total of 193 distinguishing metabolites were determined at different time points, enriched in pathways such as oxidation of branched-chain fatty acids. We found that 17 metabolite alterations were significantly correlated with the reduction in mean pulmonary arterial pressure (MPAP) at T48 versus Pre. Gradients in diastolic pulmonary arterial pressure (DPAP), bicarbonate in radial artery (aHCO3), bicarbonate in superior vena cava (svcHCO3), and the partial pressure of dissolved CO2 gas in radial artery (aPCO2) were positively correlated with MPAP gradient. Notably, these clinical-measure gradients were correlated with alterations in shunt-correction-associated metabolites. In total, 12 out of 17 identified metabolites in response to defect repair were increased at both T24 and T48 (all P < 0.05, except propionylcarnitine with P < 0.05 at T24). In contrast, galactinol dihydrate, guanosine monophosphate, and hydroxyphenylacetylglycine tended to decline at T24 and T48 (only galactinol dihydrate with P < 0.05 at T48). In conclusion, 17 metabolites that respond to shunt correction could be used as suitable noninvasive markers, and clinical measures, including DPAP, aHCO3, svcHCO3, and aPCO2, would be of great value in disease monitoring and evaluating future therapeutic interventions.

Patient pathway analysis of tuberculosis diagnostic delay: a multicentre retrospective cohort study in China.

OBJECTIVES: Delay in diagnosis of tuberculosis (TB) is an important but under-appreciated problem. Our study aimed to analyse the patient pathway and possible risk factors of long diagnostic delay (LDD). METHODS: We enrolled 400 new bacteriologically diagnosed patients with pulmonary TB from 20 hospitals across China. LDD was defined as an interval between the initial care visit and the confirmation of diagnosis exceeding 14 days. Its potential risk factors were investigated by multivariate logistic regression and multilevel logistic regression. Hospitals in China were classified by increasing size, from level 0 to level 3. TB laboratory equipment in hospitals was also evaluated. RESULTS: The median diagnostic delay was 20 days (IQR: 7-72 days), and 229 of 400 patients (57.3%, 95%CI 52.4-62.1) had LDD; 15% of participants were diagnosed at the initial care visit. Compared to level 0 facilities, choosing level 2 (OR 0.27, 95%CI 0.12-0.62, p 0.002) and level 3 facilities (OR 0.34, 95%CI 0.14-0.84, p 0.019) for the initial care visit was independently associated with shorter LDD. Equipping with smear, culture, and Xpert at initial care visit simultaneously also helped to avoid LDD (OR 0.28, 95%CI 0.09-0.82, p 0.020). The multilevel logistic regression yielded similar results. Availability of smear, culture, and Xpert was lower in level 0-1 facilities than in level 2-3 facilities (p < 0.001, respectively). CONCLUSIONS: Most patients failed to be diagnosed at the initial care visit. Patients who went to low-level facilities initially had a higher risk of LDD. Improvement of TB laboratory equipment, especially at low-level facilities, is urgently needed.

DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension.

DNA methylation plays critical roles in vascular pathology of pulmonary hypertension (PH). The underlying mechanism, however, remains undetermined. Here, we demonstrate that global DNA methylation was elevated in the lungs of PH rat models after monocrotaline administration or hypobaric hypoxia exposure. We showed that DNA methyltransferase 3B (DNMT3B) was up-regulated in both PH patients and rodent models. Furthermore, Dnmt3b -/- rats exhibited more severe pulmonary vascular remodeling. Consistently, inhibition of DNMT3B promoted proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in response to platelet-derived growth factor-BB (PDGF-BB). In contrast, overexpressing DNMT3B in PASMCs attenuated PDGF-BB-induced proliferation/migration and ameliorated hypoxia-mediated PH and right ventricular hypertrophy in mice. We also showed that DNMT3B transcriptionally regulated inflammatory pathways. Our results reveal that DNMT3B is a previously undefined mediator in the pathogenesis of PH, which couples epigenetic regulations with vascular remodeling and represents a therapeutic target to tackle PH.

Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension.

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

Potential for elimination of SAR-CoV-2 through vaccination as inspired by elimination of multiple influenza viruses through natural pandemics or mass vaccination.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed many lives worldwide. To combat the pandemic, multiple types of vaccines are under development with unprecedented rapidity. Theoretically, future vaccination against COVID-19 may fall into long-term costly guerrilla warfare between SARS-CoV-2 and humans. Elimination of SARS-CoV-2 through vaccination to avoid the potential long-term costly guerrilla warfare, if possible, is highly desired and worth intensive consideration. Human influenza pandemics emerging in 1957, 1968, and 2009 established strong global herd immunity and led to the elimination of three human influenza viruses, which circulated worldwide for years before the pandemics. Moreover, both clade 7.2 of subtype H5 highly pathogenic avian influenza virus and subtype H7N9 avian influenza virus circulated in poultry in China for years, and they have been virtually eliminated through mass vaccination in recent years. These facts suggest that the rapid establishment of global herd immunity through mass vaccination using an appropriate vaccine could eliminate SARS-CoV-2. The coming 2 years are a golden time for elimination through vaccination, which requires tremendous national and international collaboration. This review also prioritizes the efficacy of vaccines for COVID-19 and elucidates the importance of the development of more live vaccines for COVID-19.

Potential of live pathogen vaccines for defeating the COVID-19 pandemic: History and mechanism.

The whole world has entered a terrible crisis with a huge and increasing number of human deaths and economic losses in fighting the pandemic of COVID-19 caused by the novel coronavirus termed SARS-CoV-2. The live pathogen vaccine (LPV) strategy, which originated in ancient China for fighting smallpox, has been applied successfully by US military recruits for decades to control acute respiratory diseases caused by types 4 and 7 adenoviruses. This strategy has also been widely employed in veterinary medicine. These facts suggest a fast way out of the current pandemic crisis, namely that SARS-CoV-2 could be directly used as a live vaccine. Beyond the two traditional mechanisms to guarantee the LPV's safety (the LPV seed strain is properly selected; the LPV is inoculated bypassing the respiratory sites of pathology), three novel mechanisms to further ensure the LPV's safety are available (the virus replication is inhibited with early use of an antiviral drug; symptomatic LPV recipients are cured with convalescent plasma; the LPV is inoculated in the hot season). This LPV strategy has multiple potential advantages over other options and could reduce morbidity and mortality greatly as well as the economic loss caused by the pandemic. The safety and efficacy of this strategy should be investigated strictly using animal experiments and clinical trials, and even if the experiments and trials all support the strategy, it should be implemented with enough caution.

Quantification of the severity of an outbreak in human infection control.

BACKGROUND: The severity of an outbreak is a priority in decision-making for human infection control. However, there have been no reports on how to quantify the severity of an outbreak. METHODS: We propose a simple method to measure the severity of an infectious disease outbreak. It involves scoring the severity of clinical signs, the transmission of the infection, the number of cases, and the infection source. RESULTS: The method was evaluated using the data available at the early stage of some recent outbreaks of infectious diseases, including the influenza A (H1N1) pandemic in 2009, and the evaluation supports the design idea. CONCLUSION: The method is practical for rating the severity of an infectious disease outbreak, though it should be optimized. It could also be used to judge whether an event constitutes a public health emergency of international concern (PHEIC) or not.

Panorama phylogenetic diversity and distribution of type A influenza viruses based on their six internal gene sequences.

BACKGROUND: Type A influenza viruses are important pathogens of humans, birds, pigs, horses and some marine mammals. The viruses have evolved into multiple complicated subtypes, lineages and sublineages. Recently, the phylogenetic diversity of type A influenza viruses from a whole view has been described based on the viral external HA and NA gene sequences, but remains unclear in terms of their six internal genes (PB2, PB1, PA, NP, MP and NS). METHODS: In this report, 2798 representative sequences of the six viral internal genes were selected from GenBank using the web servers in NCBI Influenza Virus Resource. Then, the phylogenetic relationships among the representative sequences were calculated using the software tools MEGA 4.1 and RAxML 7.0.4. Lineages and sublineages were classified mainly according to topology of the phylogenetic trees and distribution of the viruses in hosts, regions and time. RESULTS: The panorama phylogenetic trees of the six internal genes of type A influenza viruses were constructed. Lineages and sublineages within the type based on the six internal genes were classified and designated by a tentative universal numerical nomenclature system. The diversity of influenza viruses circulating in different regions, periods, and hosts based on the panorama trees was analyzed. CONCLUSION: This study presents the first whole views to the phylogenetic diversity and distribution of type A influenza viruses based on their six internal genes. It also proposes a tentative universal nomenclature system for the viral lineages and sublineages. These can be a candidate framework to generalize the history and explore the future of the viruses, and will facilitate future scientific communications on the phylogenetic diversity and evolution of the viruses. In addition, it provides a novel phylogenetic view (i.e. the whole view) to recognize the viruses including the origin of the pandemic A(H1N1) influenza viruses.

[The design, synthesis and anticancer activity of 4-heteroarylamino-3-cyanoquinolines as dual inhibitors of c-Src and iNOS].

Because c-Src and iNOS are key regulatory enzymes in tumorigenesis, a new series of 4-heterocycle amine-3-quinolinecarbonitriles as potent dual inhibitors of both enzymes were designed, synthesized and evaluated as multiple targets agents in cancer therapy. All compounds were evaluated by two related enzyme inhibition assays and an anti-proliferation assay in vitro. The results showed that most compounds inhibited c-Src and iNOS well. The best compound 33 inhibited both enzymes with the IC50 values of 0.0484 micromol x L(-1) and 34.5 micromol x (-1), respectively. Some of the compounds also showed moderate anti-proliferation activities at 10 micromol x L(-1) against colon cancer HT-29 and liver cancer HepG2 cell lines.

A survey of human cases of H5N1 avian influenza reported by the WHO before June 2006 for infection control.

H5N1 avian influenza has been widely spreading in fowl in the Eastern Hemisphere and has caused hundreds of severe human cases. Here, information regarding the 224 human cases of H5N1 avian influenza reported by the World Health Organization (WHO) before June 2006 were surveyed and analyzed. The results suggested that human infections escalated in the past 3 years and that control of animal H5N1 influenza, avoidance of high-risk behaviors, and proper disposal of diseased or dead fowl are vital for the prevention of human infections. Age distribution of the human cases demonstrated that older people are more immune to the infection, possibly because of the cross protectivity induced by their previous infection with human influenza A viruses. This survey also suggested that live vaccines against human influenza may be of utility in the prevention of avian influenza virus infection in humans and that new preventive measures should be considered for the control of animal H5N1 influenza epidemics, which are likely more numerous than indicated by official reports.

A survey of human cases of H5N1 avian influenza reported by the WHO before June 2006 for infection control.

H5N1 avian influenza has been widely spreading in fowls in the Eastern Hemisphere and caused hundreds of severe human cases. Here, the information of the 224 human cases of H5N1 avian influenza reported by the World Health Organization before June 2006 were surveyed and analyzed. The results suggested that human infections escalated in the past 3 years, and control of animal H5N1 influenza, avoidance of high-risk behaviors, and proper disposal of diseased or dead fowls are vital for the prevention of the human infections. Age distribution of the human cases demonstrated that older people are more immune to the infection, possibly because of the cross protectivity induced by their previous infections with human influenza A viruses. This survey also suggested that live vaccines against human influenza may be of utility in the prevention of the avian influenza virus infections in humans, and new preventive measures should be considered for the control of animal H5N1 influenza epidemics, which are likely more serious than indicated by official reports.

The panorama of the diversity of H5 subtype influenza viruses.

To elucidate the global diversity of H5 influenza viruses from a dynamic view, haemagglutinin (HA) sequences of 170 isolates were selected and analyzed in this study. Our results showed that H5 influenza isolates could be divided into two distinct lineages that circulated in the Eastern Hemisphere and the Western Hemisphere, respectively. This may be due to the separate migration routes and habitats of birds in the two hemispheres. The two distinct lineages, having existed at least for decades, possibly began divergence in 1850s. Each of the two distinct HA lineages could be further divided into some sublineages, but there was little correlation between the minor lineages and their isolation places, isolation time, neuraminidase subtypes, host species or virulence. The panorama of the diversity of H5 influenza viruses presented here integrated all known H5 epidemics including the current severe H5N1 avian epidemics in the Eastern Hemisphere and suggested that H5 virulent viruses could originate from multiple sublineages and associate with multiple NA subtypes. Our study provided a framework for the studies on the evolution and epidemiology of H5 influenza viruses.

A preliminary panorama of the diversity of N1 subtype influenza viruses.

N1 subtype influenza viruses have caused many epidemics and even a few pandemics in humans, pigs and fowls including 1918 human H1N1 pandemic, which killed 20-50 million people and the current avian H5N1 pandemic in the Eastern Hemisphere, which has caused great economic losses and posed a severe threat to human public health. To elucidate the whole diversity of N1 influenza viruses from a dynamic view, 202 neuraminidase (NA) sequences of N1 subtype influenza isolates were selected and analyzed in this study. Our results showed that N1 influenza isolates could be divided into three distinct lineages (Human, Classic Swine and Avian), which largely circulated in the humans, pigs and fowls respectively, though viruses in the Avian lineage could infect mammals and even there was a sublineage in the Avian lineage wholly isolated from pigs. The Avian lineage and the Human lineage, which have existed at least for decades, possibly began divergence around in 1890 through regression analysis. Both of the Human and Avian lineages could be further divided into some sublineages, and the correlation between these lineages (or sublineages) and their isolation places, isolation time, hemagglutinin (HA) subtypes, host species, virulence, or epidemics were discussed. The panorama of the diversity of N1 influenza viruses presented in this study provided a framework for the studies on the evolution and epidemiology of N1 influenza viruses.

A stable and differentiable RNA positive control for reverse transcription-polymerase chain reaction.

Most RNA positive controls currently used for monitoring the quality of RT-PCR assays have some disadvantages, such as instability, inability to monitor the quality of the relevant primers and/or causing indifferentiable false positives. To avoid these disadvantages, a simple method to prepare stable and differentiable RNA positive controls is now demonstrated with a real-time RT-PCR assay for the detection of Nipah virus (NiV). A DNA sequence which was shorter than its counterpart in the NiV genome and contained the binding sites of the primers of the RT-PCR assay was designed, synthesized and inserted into a vector, and then amplified by PCR with two vector-specific primers both of which contained a T7 promoter at the 5' terminal. The RNA positive control was the dsRNA in vitro transcribed from the PCR amplicons flanked by two T7 promoters. The RNA positive control was stable and able to monitor the quality of the whole concerned RT-PCR assay. False positives caused by contaminations of the RNA positive control or its amplicons could be easily identified because the amplicons of the RNA positive control were obviously shorter than those of real positive samples. Thus, the RNA positive control reported in this study avoided some common disadvantages of current RNA positive controls.

Characterization of pegylated copolymeric micelles and in vivo pharmacokinetics and biodistribution studies.

The aim of this study was to evaluate the influence of pegylated copolymeric micelle carrier on the biodistribution of drug in rats. The copolymers were synthesized via a modified ring-opening copolymerization of lactone monomers (epsilon-caprolactone, delta-valerolactone, L-lactide) and poly(ethylene glycol) (PEG(10,000) and PEG(4000)). The molecular weights and the polydispersities of synthesized copolymers were in the range of 15,000-31,000 g/mol and 1.7-2.7, respectively. All of the pegylated amphiphilic copolymers were micelles formed with low CMC values in the range of 10(-7)-10(-8)M. The drug-loaded micelles were prepared via a dialysis method. The average particle size of micelles was around 150-200 nm. The cytotoxicity in terms of cell viability after treated with PCL-PEG, PVL-PEG, and PLA-PEG micelles was insignificant. PCL-PEG and PVL-PEG micelles without branch side chain in structures had higher drug loading than PLA-PEG micelles. In vitro release profiles indicated the release of indomethacin from these micelles exhibited a sustained release behavior. The similar phenomenon was also observed in vivo in rats. The pegylated copolymeric micelles not only decreased drug uptake by the liver and kidney, but also prolonged drug retention in the blood.