Immunotherapy for Pulmonary Arterial Hypertension: From the Pathogenesis to Clinical Management.

Pulmonary hypertension (PH) is a progressive cardiovascular disease, which may lead to severe cardiopulmonary dysfunction. As one of the main PH disease groups, pulmonary artery hypertension (PAH) is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Increased pulmonary artery resistance consequently causes right heart failure, which is the major reason for morbidity and mortality in this disease. Although various treatment strategies have been available, the poor clinical prognosis of patients with PAH reminds us that further studies of the pathological mechanism of PAH are still needed. Inflammation has been elucidated as relevant to the initiation and progression of PAH, and plays a crucial and functional role in vascular remodeling. Many immune cells and cytokines have been demonstrated to be involved in the pulmonary vascular lesions in PAH patients, with the activation of downstream signaling pathways related to inflammation. Consistently, this influence has been found to correlate with the progression and clinical outcome of PAH, indicating that immunity and inflammation may have significant potential in PAH therapy. Therefore, we reviewed the pathogenesis of inflammation and immunity in PAH development, focusing on the potential targets and clinical application of anti-inflammatory and immunosuppressive therapy.

The c-Fos/AP-1 inhibitor inhibits sulfur mustard-induced chondrogenesis impairment in zebrafish larvae.

Sulfur mustard (SM, dichlorodiethyl sulfide) is a potent erosive chemical poison that can cause pulmonary lung, skin and eye disease complications in humans. Currently, there is no designated remedy for SM, and its operation's toxicological process remains unidentified. This work employed zebrafish as a model organism to investigate the toxic manifestations and mechanisms of exposure to SM, aiming to offer novel insights for preventing and treating this condition. The results showed that SM caused a decrease in the survival rate of the zebrafish larvae (LC50 = 2.47 mg/L), a reduction in the hatching rate, an increase in the pericardial area, and small head syndrome. However, T-5224 (a selective inhibitor of c-Fos/activator protein) attenuated the reduction in mortality (LC50 = 2.79 mg/L), the reduction in hatching rate, and the worsening of morphological changes. We discovered that SM causes cartilage developmental disorders in zebrafish larvae. The reverse transcription-quantitative polymerase chain reaction found that SM increased the expression of inflammation-related genes (IL-1ß, IL-6, and TNF-α) and significantly increased cartilage development-related gene expression (fosab, mmp9, and atf3). However, the expression of sox9a, sox9b, and Col2a1a was reduced. The protein level detection also found an increase in c-fos protein expression and a significant decrease in COL2A1 expression. However, T-5224,also and mitigated the changes in gene expression, and protein levels caused by SM exposure. The results of this study indicate that SM-induced cartilage development disorders are closely related to the c-Fos/AP-1 pathway in zebrafish.

Case report: Efficacy of icotinib treatment in lung adenocarcinoma with esophageal squamous cell carcinoma: a rare case of double primary malignant tumors.

Background: Lung adenocarcinoma with esophageal squamous cell carcinoma is rare and the prognosis is poor, therefore there is an urgent need to improve this situation. The objective of this study was to explore the effect of first-generation tyrosine kinase inhibitors (TKIs) in the patient of the double primary malignant tumors. Case report: We report a case of lung adenocarcinoma with esophageal squamous cell carcinoma treated by icotininb after five-year follow-up. A 71-year-old Chinese woman complaining of swallowing obstruction, heartburn, regurgitation of gastric acid for more than 2 months. An esophageal lesion was found by chest CT scans in T7 vertebral level. The diagnosis by gastroscopic biopsy was squamous cell carcinoma (SCC) with EGFR over-expression. Simultaneously, chest CT showed a 2 cm x 1 cm solitary lesion in the right superior pulmonary. The histological diagnosis by percutaneous lung Biopsy was "adenocarcinoma." Epidermal growth factor receptor (EGFR) gene mutation status was evaluated by Sanger sequencing, and an exon 21 point mutation (L858R) was identified. When the double primary malignant tumors were diagnosed, the patient refused operation and received a tyrosine kinase inhibitor (TKI), icotinib, at the dose of 125 mg, three times per day. All serum tumor biomarkers such as CEA and cancer antigen 125 (CA125) were in the normal range during the treatment period. After five-year follow-up, the patient has no evidence of recurrence or metastasis. The lung cancer was stable, meanwhile the esophageal lesion was almost cured. Conclusion: Icotininb is an effective treatment in the patients of the double primary malignant tumors of lung adenocarcinoma with EGFR gene mutation and esophageal squamous cell carcinoma with EGFR over-expression.

C-type lectin-like receptor 2: roles and drug target.

C-type lectin-like receptor-2 (CLEC-2) is a member of the C-type lectin superfamily of cell surface receptors. The first confirmed endogenous and exogenous ligands of CLEC-2 are podoplanin and rhodocytin, respectively. CLEC-2 is expressed on the surface of platelets, which participates in platelet activation and aggregation by binding with its ligands. CLEC-2 and its ligands are involved in pathophysiological processes, such as atherosclerosis, cancer, inflammatory thrombus status, maintenance of vascular wall integrity, and cancer-related thrombosis. In the last 5 years, different anti- podoplanin antibody types have been developed for the treatment of cancers, such as glioblastoma and lung cancer. New tests and new diagnostics targeting CLEC-2 are also discussed. CLEC-2 mediates thrombosis in various pathological states, but CLEC-2-specific deletion does not affect normal hemostasis, which would provide a new therapeutic tool for many thromboembolic diseases. The CLEC-2-podoplanin interaction is a target for cancer treatment. CLEC-2 may be applied in clinical practice and play a therapeutic role.

Preoperative risk prediction models for acute kidney injury after noncardiac surgery: an independent external validation cohort study.

BACKGROUND: Numerous models have been developed to predict acute kidney injury (AKI) after noncardiac surgery, yet there is a lack of independent validation and comparison among them. METHODS: We conducted a systematic literature search to review published risk prediction models for AKI after noncardiac surgery. An independent external validation was performed using a retrospective surgical cohort at a large Chinese hospital from January 2019 to October 2022. The cohort included patients undergoing a wide range of noncardiac surgeries with perioperative creatinine measurements. Postoperative AKI was defined according to the Kidney Disease Improving Global Outcomes creatinine criteria. Model performance was assessed in terms of discrimination (area under the receiver operating characteristic curve, AUROC), calibration (calibration plot), and clinical utility (net benefit), before and after model recalibration through intercept and slope updates. A sensitivity analysis was conducted by including patients without postoperative creatinine measurements in the validation cohort and categorising them as non-AKI cases. RESULTS: Nine prediction models were evaluated, each with varying clinical and methodological characteristics, including the types of surgical cohorts used for model development, AKI definitions, and predictors. In the validation cohort involving 13,186 patients, 650 (4.9%) developed AKI. Three models demonstrated fair discrimination (AUROC between 0.71 and 0.75); other models had poor or failed discrimination. All models exhibited some miscalibration; five of the nine models were well-calibrated after intercept and slope updates. Decision curve analysis indicated that the three models with fair discrimination consistently provided a positive net benefit after recalibration. The results were confirmed in the sensitivity analysis. CONCLUSIONS: We identified three models with fair discrimination and potential clinical utility after recalibration for assessing the risk of acute kidney injury after noncardiac surgery.

Photoelectrochemical-driven nitrogen reduction to ammonia by a Vo-SnO2/TiO2 composite electrode.

N2 molecules with the NN triple bond structure are difficult to cleave under mild conditions to achieve the nitrogen fixation reaction. Photoelectrochemical (PEC) catalysis technology combining the advantages of photocatalysis and electrocatalysis provides the possibility of the nitrogen reduction reaction under ambient conditions. Herein, an SnO2/TiO2 photoelectrode was first fabricated through depositing SnO2 quantum dots on TiO2 nanorod arrays via a simple hydrothermal method. The oxygen vacancy (Vo) content was then induced in SnO2 through annealing SnO2/TiO2 at high temperature under an inert atmosphere. The heterogeneous structure of Vo-SnO2 quantum dots and TiO2 nanorods boosted the separation of photocarriers. The photoelectrons generated by photoexcitation were transferred from the conduction band of TiO2 to the conduction band of Vo-SnO2 and trapped by Vo. Vo activates N2 molecules adsorbed on the catalyst surface, and reacts with H+ in the electrolyte to generate NH3. The nitrogen fixation yield of PEC catalysis and its faradaic efficiency can reach 19.41 µg cm-2 h-1, and 59.6% at -0.2 V bias potential, respectively. The heterogeneous structure of Vo-SnO2/TiO2, introduction of Vo and synergistic effect between light and electricity greatly promotes the PEC nitrogen reduction to NH3.

Construction of nanoparticle-on-mirror nanocavities and their applications in plasmon-enhanced spectroscopy.

Plasmonic nanocavities exhibit exceptional capabilities in visualizing the internal structure of a single molecule at sub-nanometer resolution. Among these, an easily manufacturable nanoparticle-on-mirror (NPoM) nanocavity is a successful and powerful platform for demonstrating various optical phenomena. Exciting advances in surface-enhanced spectroscopy using NPoM nanocavities have been developed and explored, including enhanced Raman, fluorescence, phosphorescence, upconversion, etc. This perspective emphasizes the construction of NPoM nanocavities and their applications in achieving higher enhancement capabilities or spatial resolution in dark-field scattering spectroscopy and plasmon-enhanced spectroscopy. We describe a systematic framework that elucidates how to meet the requirements for studying light-matter interactions through the creation of well-designed NPoM nanocavities. Additionally, it provides an outlook on the challenges, future development directions, and practical applications in the field of plasmon-enhanced spectroscopy.

Transcutaneous auricular vagus nerve stimulation ameliorates adolescent depressive- and anxiety-like behaviors via hippocampus glycolysis and inflammation response.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) is a crucial neuromodulation therapy for depression, yet its molecular mechanism remains unclear. Here, we aim to unveil the underlying mechanisms of antidepression by systematically evaluating the change of gene expression in different brain regions (i.e., hippocampus, anterior cingulate cortex, and medial prefrontal cortex). METHODS: The adolescent depression rat model was established by chronic unpredictable mild stress (CUMS), followed by the taVNS treatment for 3 weeks. The open field test (OFT), forced swimming test (FST), elevated plus maze test (EPM), and new object recognition (NOR) test were used to evaluate depressive- and anxiety-like behaviors. Gene expression analysis of three brain regions was conducted by RNA sequencing (RNA-seq) and further bioinformatics methods. RESULTS: The depressive- and anxiety-like behaviors in CUMS-exposed rats were manifested by decreased spontaneous locomotor activity of OFT, increased immobility time of FST, increased entries and time in the closed arms of EPM, and decreased new object index of NOR. Furthermore, CUMS exposure also led to alterations in gene expression within the hippocampus (HIP), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC), suggesting a potential link between adolescent stress and pathological changes within these brain regions. TaVNS could significantly ameliorate depressive- and anxiety-like behaviors. Its effects on these three brain regions were found related to regulation of the metabolism, and there were some brain region-specific findings. Compared with ACC and mPFC, taVNS has a more concrete effect on HIP by regulating the inflammation response and glycolysis. CONCLUSION: taVNS is capable of ameliorating adolescent depressive- and anxiety-like behaviors by regulating plenty of genes in the three brain regions. Suppressed level of inflammatory response and enhanced glycolysis manifests the dominant role of taVNS in HIP, which provides a theoretical foundation and data support for the molecular mechanism of antidepression by taVNS.

Site-selective sulfur anchoring produces sintering-resistant intermetallic ORR electrocatalysts for membrane electrode assemblies.

Intermetallic compounds are emerging as promising oxygen reduction reaction (ORR) catalysts for fuel cells due to their typically higher activity and durability compared to disordered alloys. However, the preparation of intermetallic catalysts often requires high-temperature annealing, which unfortunately leads to adverse sintering of the metal nanoparticles. Herein, we develop a scalable site-selective sulfur anchoring strategy that effectively suppresses alloy sintering, ensuring the formation of efficient intermetallic electrocatalysts with small sizes and high ordering degrees. The alloy-support interactions are precisely modulated by selectively modifying the alloy-support interfaces with oxidized sulfur species, thus simultaneously blocking both the nanoparticle migration and Oswald ripening pathways for sintering. Using this strategy, sub-5 nm PtCo intermetallic electrocatalysts enclosed by two atomic layers of Pt shells have been successfully prepared even at a metal loading higher than 30 wt%. The intermetallic catalysts exhibit excellent ORR performances in both rotating disk electrode and membrane electrode assembly conditions with a mass activity of 1.28 A mgPt-1 at 0.9 V (vs. RHE) and a power density of 1.0 W cm-2 at a current density of 1.5 A cm-2. The improved performances result from the enhanced Pt-Co electronic interactions and compressive surface strain generated by the highly ordering structure, while the atomic Pt shells prevent the dissolution of Co under highly acidic conditions. This work provides new insights to inhibit the sintering of nanoalloys and would promote the scalable synthesis and applications of platinum-based intermetallic catalysts.

The Advances, Challenges, and Perspectives on Electrocatalytic Reduction of Nitrogenous Substances to Ammonia: A Review.

Ammonia (NH3) is considered to be a critical chemical feedstock in agriculture, industry, and other fields. However, conventional Haber-Bosch (HB) ammonia (NH3) production suffers from high energy consumption, harsh reaction conditions, and large carbon dioxide emissions. Despite the emergence of electrocatalytic reduction of nitrogenous substances to NH3 under ambient conditions as a new frontier, there are several bottleneck problems that impede the commercialization process. These include low catalytic efficiency, competition with the hydrogen evolution reaction, and difficulties in breaking the N≡N triple bond. In this review, we explore the recent advances in electrocatalytic NH3 synthesis, using nitrogen and nitrate as reactants. We focus on the contribution of the catalyst design, specifically based on molecular-catalyst interaction mechanisms, as well as chemical bond breaking and directional coupling mechanisms, to address the aforementioned problems during electrocatalytic NH3 synthesis. Finally, we discuss the relevant opportunities and challenges in this field.