Poorly Controlled Diabetes Mellitus Increases the Risk of Deaths and Castration-Resistance in Locally Advanced Prostate Cancer Patients.

The association between DM and prostate cancer progression remains controversial. Previous studies mainly focused on early stage prostate cancer patients. We aimed to study the association between DM and prostate cancer progression in locally advanced prostate cancer patients. 598 locally advanced prostate cancer patients in a top tertiary hospital in China between 2012 and 2021 were divided into three groups based on the postoperative average HbA1c level. The follow-up time is 46.96 ± 27.07 months. Three hundred and forty-eight (58.2%) were normal glucose, 175 (29.3%) were moderate glucose, and 75 (12.5%) were high glucose. Higher postoperative-average HbA1c was associated with poorer OS, PCSM, and PSA-RFS. We concluded that poorly controlled DM was correlated with poorer OS, PCSM, and PSA-RFS in locally advanced prostate cancer patients.

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.

CSDR Coupling with Exo III for Ultrasensitive Electrochemistry Determination of miR-145.

Recently, miRNAs have become a promising biomarker for disease diagnostics. miRNA-145 is closely related to strokes. The accuracy determination of miRNA-145 (miR-145) in stroke patients still remains challenging due to its heterogeneity and low abundance, as well as the complexity of the blood matrix. In this work, we developed a novel electrochemical miRNA-145 biosensor via subtly coupling the cascade strand displacement reaction (CSDR), exonuclease III (Exo III), and magnetic nanoparticles (MNPs). The developed electrochemical biosensor can quantitatively detect miRNA-145 ranging from 1 × 102 to 1 × 106 aM with a detection limit as low down as 100 aM. This biosensor also exhibits excellent specificity to distinguish similar miRNA sequences even with single-base differences. It has been successfully applied to distinguish healthy people from stroke patients. The results of this biosensor are consistent with the results of the reverse transcription quantitative polymerase chain reaction (RT-qPCR). The proposed electrochemical biosensor has great potential applications for biomedical research on and clinical diagnosis of strokes.

Fruchterman-Reingold Hexagon Empowered Node Deployment in Wireless Sensor Network Application.

Internet of Things (IoT) and Big Data technologies are becoming increasingly significant parts of national defense and the military, as well as in the civilian usage. The proper deployment of large-scale wireless sensor network (WSN) provides the foundation for these advanced technologies. Based on the Fruchterman-Reingold graph layout, we propose the Fruchterman-Reingold Hexagon (FR-HEX) algorithm for the deployment of WSNs. By allocating edges of hexagonal topology to sensor nodes, the network forms hexagonal network topology. A comprehensive evaluation of 50 simulations is conducted, which utilizes three evaluation metrics: average moving distance, pair correlation diversion (PCD), and system coverage rate. The FR-HEX algorithm performs consistently, the WSN topologies are properly regulated, the PCD values are below 0.05, and the WSN system coverage rate reaches 94%. Simulations involving obstacles and failed nodes are carried out to explore the practical applicability of the FR-HEX algorithm. In general, the FR-HEX algorithm can take full advantage of sensors' hardware capabilities in the deployment. It may be a viable option for some IoT and Big Data applications in the near future.

A Novel 3D Node Deployment Inspired by Dusty Plasma Crystallization in UAV-Assisted Wireless Sensor Network Applications.

With the rapid progress of hardware and software, a wireless sensor network has been widely used in many applications in various fields. However, most discussions for the WSN node deployment mainly concentrated on the two-dimensional plane. In such a case, some large scale applications, such as information detection in deep space or deep sea, will require a good three dimensional (3D) sensor deployment scenario and also attract most scientists' interests. Excellent deployment algorithms enable sensors to be quickly deployed in designated areas with the help of unmanned aerial vehicles (UAVs). In this paper, for the first time, we present a three dimensional network deployment algorithm inspired by physical dusty plasma crystallization theory in large-scale WSN applications. Four kinds of performance evaluation methods in 3D space, such as the moving distance, the spatial distribution diversion, system coverage rate, and the system utilization are introduced and have been carefully tested.Furthermore, in order to improve the performance of the final deployment, we integrated the system coverage rate and the system utilization to analyze the parameter effects of the Debye length and the node sensing radius. This criterion attempts to find the optimal sensing radius with a fixed Debye length to maximize the sensing range of the sensor network while reducing the system redundancy. The results suggest that our 3D algorithm can quickly complete an overall 3D network deployment and then dynamically adjust parameters to achieve a better distribution. In practical applications, engineers may choose appropriate parameters based on the sensor's hardware capabilities to achieve a better 3D sensor network deployment. It may be significantly used in some large-scale 3D WSN applications in the near future.

Structural and functional definition of the pulmonary vein system in a chronic hypoxia-induced pulmonary hypertension rat model.

Unlike the pulmonary artery (PA), the pathophysiological changes of the pulmonary vein (PV) in the development of pulmonary hypertension (PH) remain largely unknown. In this study, we comprehensively investigated the structural and functional changes in the PV isolated from the chronic hypoxia (CH; 10% O2, 21 days)-induced PH rat model (CHPH). Results showed that CH caused an increase in right ventricular pressure but did not affect the mean pulmonary venous pressure and the left atrial pressure. Similar to the PA, vascular lumen stenosis and medial thickening were also observed in the intrapulmonary veins isolated from the CHPH rats. Notably, CH induced more severe loss in the endothelium of intrapulmonary veins than the arteries. Then, the contractile response to 5-HT and U46619 was significantly greater in the intrapulmonary small veins (ISPV) and arteries (ISPA) isolated from CHPH rats than those from normoxic rats but not in the extrapulmonary and intrapulmonary large veins. Treatment with nifedipine (Nif), SKF96365 (SKF), or ryanodine and caffeine either partially attenuated (Nif) or dramatically abolished (SKF or ryanodine and caffeine) 5-HT-induced maximal contraction in ISPV from both normoxic and CHPH rats. Because of the severe loss of endothelium in the PV of CHPH rats, the decrease in acetylcholine (ACh)-induced endothelium-dependent relaxation was significantly larger in ISPV than ISPA, whereas the sodium nitroprusside-induced endothelium-independent relaxation was not altered in both ISPA and ISPV. In conclusion, our results provide fundamental data to comprehensively define the PV system in CHPH rat model.

[Verification of accuracy of warfarin stable dose prediction models in Shandong population].

OBJECTIVE: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population. METHODS: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE). RESULTS: The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively. CONCLUSION: The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.

A Hybrid Optimization from Two Virtual Physical Force Algorithms for Dynamic Node Deployment in WSN Applications.

With the rapid development of unmanned aerial vehicle in space exploration and national defense, large-scale wireless sensor network (WSN) became an important and effective technology. It may require highly accurate locating for the nodes in some real applications. The dynamic node topology control of a large-scale WSN in an unmanned region becomes a hot research topic recently, which helps improve the system connectivity and coverage. In this paper, a hybrid optimization based on two different virtual force algorithms inspired by the interactions among physical sensor nodes is proposed to address the self-consistent node deployment in a large-scale WSN. At the early stage, the deployment algorithm was to deploy the sensor nodes by leveraging the particle motions in dusty plasma to achieve the hexagonal topology of the so-called "Yukawa crystal". After that, another virtual exchange force model was combined to present a hybrid optimization, which could yield perfect hexagonal topology, better network uniformity, higher coverage rate, and faster convergence speed. The influence of node position, velocity, and acceleration during the node deployment stage on the final network topology are carefully discussed for this scheme. It can aid engineers to control the network topology for a large number of wireless sensors with affordable system cost by choosing suitable parameters based on physical environments or application scenarios in the near future.

Investigation of Parameter Effects on Virtual-Spring-Force Algorithm for Wireless-Sensor-Network Applications.

Virtual-force algorithms (VFAs) have been widely studied for accurate node deployment in wireless-sensor-network (WSN) applications. Their main purpose is to achieve the maximum coverage area with the minimum number of sensor nodes in the target area. Recently, we reported a new VFA based on virtual spring force (VFA-SF) and discussed in detail the corresponding efficiency via statistical analysis. The optimized strategy by adding an external central force (VFA-SF-OPT) was presented, which effectively eliminates the coverage hole or twisted structure in the final network distribution. In this paper, the parameter effects on VFA-SF and the VFA-SF-OPT were further investigated: (1) Node velocity dramatically affects the convergence rate of the node-deployment process. (2) A suitable external central force improves equilibrium distance and reduces energy consumption. (3) The effects of VFA-SF and VFA-SF-OPT for different types of obstacles are discussed. Generally, by choosing suitable parameters, both VFA-SF and VFA-SF-OPT can effectively improve node deployment and energy consumption for the whole sensor network. The results give important insight in parameter selection and information fusion in the application of a large-scale WSN.

An Optimized Node Deployment Solution Based on a Virtual Spring Force Algorithm for Wireless Sensor Network Applications.

How to effectively deploy all wireless sensors and save a system's energy consumption is a key issue in current wireless sensor network (WSN) applications. Theoretical analysis has proven that a hexagonal structure is the best topology in the two-dimensional network, which can provide the maximum coverage area with the minimum number of sensor nodes and minimum energy consumption. Recently, many scientists presented their self-deployment strategies based on different virtual forces and discussed the corresponding efficiency via several case studies. However, according to our statistical analysis, some virtual force algorithms, e.g., virtual spring force, can still cause holes or twisted structure in a small region of the final network distribution, which cannot achieve the ideal network topology and will waste the system energy in real applications. In this paper, we first statistically analyzed the convergence and deployment effect of the virtual spring force algorithm to derive our question. Then we presented an optimized strategy that sensor deployment begins from the center of the target region by adding an external central force. At the early stage, the external force will be added to the most peripheral nodes to promote the formation of hexagonal topology and avoid covering holes or unusual structure. Finally, a series of independent simulation experiments and corresponding statistical results proved that our optimized deployment solution is very stable and effective, which can improve the energy consumption of the whole sensor network and be used in the application of a large scale WSN.

Revolving Vernier Mechanism Controls Size of Linear Homomultimer.

A new kind of the Vernier mechanism that is able to control the size of linear assembly of DNA origami nanostructures is proposed. The mechanism is realized by mechanical design of DNA origami, which consists of a hollow cylinder and a rotatable shaft in it connected through the same scaffold. This nanostructure stacks with each other by the shape complementarity at its top and bottom surfaces of the cylinder, while the number of stacking is limited by twisting angle of the shaft. Experiments have shown that the size distribution of multimeric assembly of the origami depends on the twisting angle of the shaft; the average lengths of the multimer are decamer, hexamer, and tetramer for 0°, 10°, and 20° twist, respectively. In summary, it is possible to affect the number of polymerization by adjusting the precise shape and movability of a molecular structure.

[Study on Microbial Diversity of Peri-implantitis Subgingival by High-throughput Sequencing].

OBJECTIVE: To study microbial diversity of peri-implantitis subgingival with high-throughput sequencing, and investigate microbiological etiology of peri-implantitis. METHODS: Subgingival plaques were sampled from the patients with peri-implantitis (D group) and non-peri-implantitis subjects (N group). The microbiological diversity of the subgingival plaques was detected by sequencing V4 region of 16S rRNA with Illumina Miseq platform. The diversity of the community structure was analyzed using Mothur software. RESULTS: A total of 156 507 gene sequences were detected in nine samples and 4 402 operational taxonomic units (OTUs) were found. Selenomonas, Pseudomonas, and Fusobacterium were dominant bacteria in D group, while Fusobacterium, Veillonella and Streptococcus were dominant bacteria in N group. Differences between peri-implantitis and non-peri-implantitis bacterial communities were observed at all phylogenetic levels by LEfSe, which was also found in PcoA test. CONCLUSION: The occurrence of peri-implantitis is not only related to periodontitis pathogenic microbe, but also related with the changes of oral microbial community structure. Treponema, Herbaspirillum, Butyricimonas and Phaeobacte may be closely related to the occurrence and development of peri-implantitis.

Oral delivery of biomacromolecules by overcoming biological barriers in the gastrointestinal tract: an update.

INTRODUCTION: Biomacromolecules have proven to be an attractive choice for treating diseases due to their properties of strong specificity, high efficiency, and low toxicity. Besides greatly improving the patient's complaint, oral delivery of macromolecules also complies with hormone physiological secretion, which has become one of the most innovative fields of research in recent years. AREAS COVERED: Oral delivery biological barriers for biomacromolecule, transport mechanisms, and various administration strategies were discussed in this review, including absorption enhancers, targeting nanoparticles, mucoadhesion nanoparticles, mucus penetration nanoparticles, and intelligent bionic drug delivery systems. EXPERT OPINION: The oral delivery of biomacromolecules has important clinical implications; however, these are still facing the challenges of low bioavailability due to certain barriers. Various promising technologies have been developed to overcome the barriers and improve the therapeutic effect of oral biomacromolecules. By considering safety and efficacy comprehensively, the development of intelligent nanoparticles based on the GIT environment has demonstrated some promise in overcoming these barriers; however, a more comprehensive understanding of the oral fate of oral biomacromolecules is still required.

Making contract users safer: Towards building a Safe Browsing platform on Ethereum.

There are many papers and tools regarding the detection of unsafe contracts, but few ways for detection results to practically benefit contract users and owners. This paper presents a Blockchain Safe Browsing (BSB) platform to safely disseminate those detection results. An encrypted blacklist will be generated to provide privacy preserving user warning before they make transactions with unsafe contracts. Contract owners will be notified that there are vulnerabilities in their contracts, and they can purchase related reports which record how to exploit the vulnerabilities. The profits inspire the researchers to contribute their update-to-date lists of unsafe contracts. An effective encryption scheme is developed to guarantee that only contract owners can decrypt the encrypted reports. Extensive evaluations demonstrate that our prototype can function as intended without sacrificing user experience.

[Pollution Characteristics of Carbonaceous Components in PM10 and PM2.5 of Road Dust Fall and Soil Dust in Xi'an].

To investigate the pollution characteristics of carbonaceous components in PM10 and PM2.5 of road dust fall and soil dust in Xi'an and enrich their source profiles, samples from five sites of road dust fall and 16 sites of soil dust were collected in Xi'an from April to May 2015. The ZDA-CY01 particulate matter resuspension sampler was used to obtain PM10 and PM2.5 samples, and the Model5L-NDIR OC and EC analyzer were used to determine the concentrations of organic carbon (OC) and elemental carbon (EC) in PM10 and PM2.5. The pollution and sources of carbonaceous aerosol in PM10 and PM2.5 were investigated by analyzing OC and EC characteristics, ratio, and the principal component analysis statistical model. The results showed that the proportions of OC in PM10 and PM2.5 at the various dust fall sites differed, ranging from 6.0% to 19.4% and 7.6% to 29.8%, respectively. The ratios of EC in PM10 and PM2.5at the different dust fall sites were relatively small, accounting for 0.6%-2.2% and 0.2%-3.6% in urban sites, respectively; however, EC was almost undetectable in most peripheral soil dust. The proportions of carbonaceous components in PM10 and PM2.5 followed the order of urban road dust fall>external control dust>river beach soil dust>soil dust and urban road dust fall>soil dust>external control dust>river beach soil dust, respectively. OC dominated the carbonaceous aerosols at the different sites, which was relatively low in urban road dust fall. The OC to total carbon (TC) ratios in PM10 and PM2.5 at urban road dust fall were 85.2%-95.3% and 87.9%-98.9%, respectively. The OC to TC ratios in PM10 and PM2.5 of soil dust were relatively high, exceeding 99%. Carbonaceous components were primarily concentrated in fine particles. The pollution distribution of carbonaceous components in the urban road dust fall sites was consistent, whereas that in the different soil dust sites were quite different. The carbonaceous components in urban road dust fall and soil dust were primarily affected by pollutant source emissions such as biomass burning, coal burning, gasoline, and diesel vehicle exhaust. There were differences in the source contribution rates of carbonaceous aerosols in PM10 and PM2.5.

Airway delivery of Streptococcus salivarius is sufficient to induce experimental pulmonary hypertension in rats.

BACKGROUND AND PURPOSE: The causal relationship between altered host microbiome composition, especially the respiratory tract microbiome, and the occurrence of pulmonary hypertension (PH) has not yet been studied. An increased abundance of airway streptococci is seen in patients with PH compared with healthy individuals. This study aimed to determine the causal link between elevated airway exposure to Streptococcus and PH. EXPERIMENTAL APPROACH: The dose-, time- and bacterium-specific effects of Streptococcus salivarius (S. salivarius), a selective streptococci, on PH pathogenesis were investigated in a rat model established by intratracheal instillation. KEY RESULTS: Exposure to S. salivarius successfully induced typical PH characteristics, such as elevated right ventricular systolic pressure (RVSP), right ventricular hypertrophy (Fulton's index) and pulmonary vascular remodelling, in a dose- and time-dependent manner. Moreover, the S. salivarius-induced characteristics were absent in either the inactivated S. salivarius (inactivated bacteria control) treatment group or the Bacillus subtilis (active bacteria control) treatment group. Notably, S. salivarius-induced PH is characterized by elevated inflammatory infiltration in the lungs, in a pattern different from the classic hypoxia-induced PH model. Moreover, in comparison with the SU5416/hypoxia-induced PH model (SuHx-PH), S. salivarius-induced PH causes similar histological changes (pulmonary vascular remodelling) but less severe haemodynamic changes (RVSP, Fulton's index). S. salivarius-induced PH is also associated with altered gut microbiome composition, suggesting potential communication of the lung-gut axis. CONCLUSION AND IMPLICATIONS: This study provides the first evidence that the delivery of S. salivarius in the respiratory tract could cause experimental PH in rats.

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.

[Emission Characteristics of Organic Carbon and Elemental Carbon in PM10 and PM2.5 from Vehicle Exhaust and Civil Combustion Fuels].

To study the emission characteristics of carbonaceous aerosol in particulate matter emitted from vehicle exhaust and main civil combustion fuels, organic carbon (OC) and elemental carbon (EC) in PM10 and PM2.5 samples from vehicle sources (gasoline vehicles, light duty diesel vehicles, and heavy duty diesel vehicles), civil coal (chunk coal and briquette coal), and biomass fuels (wheat straw, wood plank, and grape branches) were collected and analyzed by using a multifunctional portable dilution channel sampler and the Model 5L-NDIR OC/EC analyzer. The results showed that there were significant differences in the proportion of carbonaceous aerosols in PM10 and PM2.5from different emission sources. The proportions of total carbon (TC) in PM10 and PM2.5 of different emission sources were 40.8%-68.5% and 30.5%-70.9%, respectively, and the OC/EC were 1.49-31.56 and 1.90-87.57, respectively. The carbon components produced by different emission sources were dominated by OC, and the OC/TC values in PM10 and PM2.5 were 56.3%-97.0% and 65.0%-98.7%, respectively. The proportions of OC in carbonaceous aerosols in PM10and PM2.5 were in the descending order of:briquette coal>chunk coal>gasoline vehicle>wood plank>wheat straw>light duty diesel vehicle>heavy duty diesel vehicle and briquette coal>gasoline car>grape branches>chunk coal>light duty diesel vehicle>heavy duty diesel vehicle, respectively. The main components of carbonaceous aerosols in PM10 and PM2.5 emitted from the various emission sources were different, and source apportionment of carbonaceous aerosols could be accurately distinguished by their ingredient composition profiles.

The Novel Lysosomal Autophagy Inhibitor (ROC-325) Ameliorates Experimental Pulmonary Hypertension.

BACKGROUND: Autophagy plays an important role in the pathogenesis of pulmonary hypertension (PH). ROC-325 is a novel small molecule lysosomal autophagy inhibitor that has more potent anticancer activity than the antimalarial drug hydroxychloroquine, the latter has been prevalently used to inhibit autophagy. Here, we sought to determine the therapeutic benefit and mechanism of action of ROC-325 in experimental PH models. METHODS AND RESULTS: Hemodynamics, echocardiography, and histology measurement showed that ROC-325 treatment prevented the development of PH, right ventricular hypertrophy, fibrosis, dysfunction, and vascular remodeling after monocrotaline and Sugen5416/hypoxia administration. ROC-325 attenuated high K+ or alveolar hypoxia-induced pulmonary vasoconstriction and enhanced endothelial-dependent relaxation in isolated pulmonary artery rings. ROC-325 treatment inhibited autophagy and enhanced endothelial nitric oxide synthase activity in lung tissues of monocrotaline-PH rats. In cultured human and rat pulmonary arterial smooth muscle cell and pulmonary arterial endothelial cell under hypoxia exposure, ROC-325 increased LC3B (light chain 3 beta) and p62 accumulation, endothelial cell nitric oxide production via phosphorylation of endothelial nitric oxide synthase (Ser1177) and dephosphorylation of endothelial nitric oxide synthase (Thr495) as well as decreased HIF (hypoxia-inducible factor)-1α and HIF-2α stabilization. CONCLUSIONS: These data indicate that ROC-325 is a promising novel agent for the treatment of PH that inhibits autophagy, downregulates HIF levels, and increases nitric oxide production.

SARS-CoV-2 spike protein induces IL-18-mediated cardiopulmonary inflammation via reduced mitophagy.

Cardiopulmonary complications are major drivers of mortality caused by the SARS-CoV-2 virus. Interleukin-18, an inflammasome-induced cytokine, has emerged as a novel mediator of cardiopulmonary pathologies but its regulation via SARS-CoV-2 signaling remains unknown. Based on a screening panel, IL-18 was identified amongst 19 cytokines to stratify mortality and hospitalization burden in patients hospitalized with COVID-19. Supporting clinical data, administration of SARS-CoV-2 Spike 1 (S1) glycoprotein or receptor-binding domain (RBD) proteins into human angiotensin-converting enzyme 2 (hACE2) transgenic mice induced cardiac fibrosis and dysfunction associated with higher NF-κB phosphorylation (pNF-κB) and cardiopulmonary-derived IL-18 and NLRP3 expression. IL-18 inhibition via IL-18BP resulted in decreased cardiac pNF-κB and improved cardiac fibrosis and dysfunction in S1- or RBD-exposed hACE2 mice. Through in vivo and in vitro work, both S1 and RBD proteins induced NLRP3 inflammasome and IL-18 expression by inhibiting mitophagy and increasing mitochondrial reactive oxygenation species. Enhancing mitophagy prevented Spike protein-mediated IL-18 expression. Moreover, IL-18 inhibition reduced Spike protein-mediated pNF-κB and EC permeability. Overall, the link between reduced mitophagy and inflammasome activation represents a novel mechanism during COVID-19 pathogenesis and suggests IL-18 and mitophagy as potential therapeutic targets.