The role of sulfur cycle in new particle formation: Cycloaddition reaction of SO3 to H2S.

The chemistry of sulfur cycle contributes significantly to the atmospheric nucleation process, which is the first step of new particle formation (NPF). In the present study, cycloaddition reaction mechanism of sulfur trioxide (SO3) to hydrogen sulfide (H2S) which is a typical air pollutant and toxic gas detrimental to the environment were comprehensively investigate through theoretical calculations and Atmospheric Cluster Dynamic Code simulations. Gas-phase stability and nucleation potential of the product thiosulfuric acid (H2S2O3, TSA) were further analyzed to evaluate its atmospheric impact. Without any catalysts, the H2S + SO3 reaction is infeasible with a barrier of 24.2 kcal/mol. Atmospheric nucleation precursors formic acid (FA), sulfuric acid (SA), and water (H2O) could effectively lower the reaction barriers as catalysts, even to a barrierless reaction with the efficiency of cis-SA > trans-FA > trans-SA > H2O. Subsequently, the gas-phase stability of TSA was investigated. A hydrolysis reaction barrier of up to 61.4 kcal/mol alone with an endothermic isomerization reaction barrier of 5.1 kcal/mol under the catalytic effect of SA demonstrates the sufficient stability of TSA. Furthermore, topological and kinetic analysis were conducted to determine the nucleation potential of TSA. Atmospheric clusters formed by TSA and atmospheric nucleation precursors (SA, ammonia NH3, and dimethylamine DMA) were thermodynamically stable. Moreover, the gradually decreasing evaporation coefficients for TSA-base clusters, particularly for TSA-DMA, suggests that TSA may participate in NPF where the concentration of base molecules are relatively higher. The present new reaction mechanism may contributes to a better understanding of atmospheric sulfur cycle and NPF.

A Comprehensive Overview of the Stellate Ganglion Block Throughout the Past Three Decades: A Bibliometric Analysis.

BACKGROUND: Over the past 3 decades, clinicians and scholars have used and studied the stellate ganglion block (SGB) extensively, making this field a highly anticipated research hot spot. To the best of our knowledge, there has been no bibliometric analysis of the SGB until now. OBJECTIVE: Our study aimed to complete multiple tasks regarding SGB research: identify the collaboration and impact of countries, institutions, journals, and authors, evaluate the knowledge base, trace the trends in hot spots, and explore the emerging topics relevant to the field. STUDY DESIGN: A bibliometric analysis. METHODS: Publications that were associated with the SGB and published between the years of 1993 and 2022 were retrieved from the Web of Science Core Collection on September 21st, 2023. CiteSpace 6.1.R6 and VOSviewer 1.6.18 were used to perform bibliometric and knowledge-map analyses. RESULTS: This study found a total of 837 publications originating from 51 countries and 1006 institutions. These articles were published in 393 journals. The United States was the country that produced the most articles focused on SGB, and the University of California, Los Angeles was the institution associated with the greatest number of publications. The anesthesiology and cardiology journals surveyed for this study published the most articles and received the most citations. Among the authors whose works were examined, Kitajima T had the greatest number of published articles, and Lipov E was the most frequently cited co-author. Five main domains of SGB research included electrical storm and refractory ventricular arrhythmia, breast cancer and climacteric medicine, post-traumatic stress disorder, pain management, and cerebrovascular diseases. The latest hot topics involving this field focused on SGB's anti-arrhythmic and anti-cerebral vasospasm effects and its treatment of long COVID syndrome. LIMITATIONS: Data were retrieved only from the WoSCC; therefore, publications in other databases might have been missed. CONCLUSION: This comprehensive bibliometric analysis conducted a complete overview of SGB research, which was helpful in furthering our understanding of research trends and locating research hot spots and gaps in this domain. This field is developing rapidly and will garner significant and continuous attention from future scholars.

Transcranial ultrasound with electrical stimulation of the cerebello-parietal nucleus on cerebral blood flow and limb function in patients with stroke.

OBJECTIVE: To investigate the efficacy of transcranial ultrasound stimulation (TUS) combined with Fastigial nucleus stimulation (FNS) on cerebral blood flow and limb function in patients in the acute phase of ischemic stroke. METHODS: A total of 90 patients in the acute phase of ischemic stroke were randomly divided into an FNS, TUS, and TUS + FNS group (30 patients each), and all patients also received conventional treatment. The FNS group was treated with FNS alone. The TUS group was treated with TUS alone. The TUS + FNS group was treated with both TUS and FNS. The three groups were treated once a day for 6 days a week. RESULTS: The simplified Fugl-Meyer Assessment (FMA) and Barthel index scores (BI), and the peak systolic blood flow velocity (Vs) and the mean blood flow velocity (Vm) of the anterior cerebral artery, middle cerebral artery, and posterior cerebral artery, were significantly higher in all three groups compared with before treatment (P < 0.05). The scores for the TUS group were higher than for the FNS group (P < 0.05), and the scores of the TUS + FNS group were higher than the TUS and FNS groups, respectively (P < 0.05). The total effective rate was 63.3%, 70.0%, and 90.0% in the FNS, TUS, and TUS + FNS groups, respectively, and the difference between the three groups was statistically significant (P < 0.05). CONCLUSION: The FNS and TUS treatments improved the function of and accelerated cerebral blood flow in patients with acute ischemic stroke to different degrees, and the combined use of both treatment types was overall more effective.

Veno-venous or veno-arterial extracorporeal membrane oxygenation support for massive pulmonary embolism: a case report.

Background: With regard to the treatment of massive pulmonary embolism (MPE) with circulatory and respiratory collapse and thrombolytic contraindications, current guidelines and researches usually give the priority to veno-arterial extracorporeal membrane oxygenation (V-A ECMO). However, the objective of this clinical case report is to highlight the effective use of veno-venous extracorporeal membrane oxygenation (V-V ECMO) in a 35-year-old pregnant woman with MPE complicated by hemorrhage, persistent hypoxia and multiple cardiac arrests. Case Description: A 35-year-old pregnant woman with gestational mellitus suddenly presented with complaints of nausea, vomiting and dyspnea after going to the toilet, combined with increasing heart rate (HR) of 150 bpm, decreasing pulse oxygen saturation (SpO2) of 94%, larger right heart and the growing D-dimer at 11.2 µg/mL, who was considered as the pulmonary embolism. Unpredictable cardiac arrest occurred repeatedly before and after the cesarean section. Although cardiopulmonary resuscitation (CPR) was started timely and successfully, the maintenance of blood pressure still depended on high-dose pressor drugs, even terribly, the oxygenation was unstable under the assistance of mechanical ventilation with pure oxygen. Thus, V-V ECMO supporting was commenced following by gradual recovering in haemodynamics and respiratory function. And the diagnosis of MPE was ascertained again through computed tomographic pulmonary angiography (CTPA) and pulmonary angiography. Directing at the pathogeny, thrombolysis infusion catheters and anticoagulant therapy were initiated after bilateral uterine artery embolism for postpartum haemorrhage, later the patient discharged from hospital after recovery and had a good prognosis. Conclusions: V-V ECMO could be effective for some patients with MPE who suffer from successful CPR after cardiac arrest while still combined with severe hypotension and refractory hypoxemia.

Altitude and prognosis after PCI: A propensity score-matched analysis.

Background: The impact of altitude on the prognosis of patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) deserves further discussion and research. Methods: We conducted a post hoc analysis of a prospective observational study involving 5453 patients post-PCI, divided into medium-altitude and low-altitude groups. To control for confounding factors, propensity score matching was employed to pair patients with similar baseline characteristics between the two groups. The impact of altitude factors on patients' prognosis post-PCI was examined through endpoint events over a 2-year follow-up period. Results: During the 2-year follow-up, patients at medium altitude exhibited a lower risk of MACE (including cardiovascular mortality, myocardial infarction, revascularization, and stroke) compared to those at low altitude (1196 versus 1196 patients [medium-altitude versus low-altitude, respectively]; hazard ratio [HR], 0.781 [95 % CI, 0.629-0.969]; P = 0.025) during 2-year follow-up. Even after excluding stroke, a significant difference in heart-related adverse events (HRAE) persisted between the two groups (HR, 0.794; 95 % CI, 0.636-0.991; P = 0.042). The incidences of individual MACE components were not significantly different between the two groups. Conclusions: Patients post-PCI residing at medium altitude exhibited a lower risk of 2-year MACE compared to those at low altitude. Further research is necessary to provide more robust evidence.

Sesquiterpenoids from Carpesium abrotanoides and their anti-inflammatory activity both in vitro and in vivo.

Twenty-nine sesquiterpenoids, including pseudoguaiane-type (1-11), eudesmane-type (12-23), and carabrane-type (24-29), have been identified from the plant Carpesium abrotanoides. Of them, compounds 1-4, 12-15, and 24-27, namely carpabrotins A-L, are twelve previously undescribed ones. Compound 3 possessed a pseudoguaiane backbone with a rearrangement modification at C-11, C-12 and C-13, while compound 4 suffered a carbon bond break between the C-4 and C-5 to form a rare 4,5-seco-pseudoguaiane lactone. Compounds 1-3, 5, 13-16 and 25-27 exhibited anti-inflammatory activity by inhibiting NO production in LPS-induced RAW264.7 macrophages with IC50 values less than 40 µM, while compounds 1, 2, 5, 13, 14, 16, and 25-27 showed significant inhibitory activity comparable to that of dexamethasone. The anti-atopic dermatitis (AD) effects of compounds 5 and 16 were tested according to 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in KM mice, and the results revealed that the major products 5 and 16 improved the histological features of AD-like skin lesions and mast cell infiltration in mice. This study suggested that sesquiterpenoids in C. abrotanoides should play a key role in its anti-inflammatory use.

Association between single and multiple cardiometabolic diseases and all-cause mortality among Chinese older adults: A prospective, nationwide cohort study.

BACKGROUND AND AIM: Cardiometabolic diseases (CMDs) are leading causes of death and disability, but little is known about the additive mortality effects of multiple CMDs. This study aimed to examine the association between single and multiple CMDs and all-cause mortality among older Chinese population. METHODS AND RESULTS: Using the Chinese Longitudinal Healthy Longevity Survey (CLHLS) database, we analyzed data from 2008 to 2018 to assess the relationship between CMDs and mortality. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for single and multiple CMDs. At baseline, 11,351 participants (56.9% female) aged 60 years or older were included. 11.91% of participants had a single CMD, 1.51% had two CMDs, and 0.22% had three CMDs. Over a decade follow-up, 8992 deaths (79.2%) were recorded. A dose-response relationship was observed, with the mortality risk increasing by 17% for each additional disease. The fully-adjusted HRs for all-cause mortality were 1.16, 1.36, and 2.03 for one, two, and three CMDs, respectively. Larger effects of single and multiple CMDs were observed in the male group (P = 0.015) and the younger senior group (P < 0.001). CONCLUSIONS: This large-scale study found that CMDs multiply mortality risks, especially in younger seniors and males. The risk is highest when heart disease and stroke coexist, and diabetes further increases it. Public health efforts should prioritize evidence-based management and prevention of CMDs.

Ultrasound-responsive theranostic platform for the timely monitoring and efficient thrombolysis in thrombi of tPA resistance.

There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs' long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi.

Variation in phytotoxicity of rice seedlings caused by differential accumulation of azoxystrobin and pyraclostrobin in leaves.

The effectiveness of pyraclostrobin (Pyr) and azoxystrobin (Azo) with highly targeting the rice blast is noteworthy, but they have varied toxic levels towards non-target aquatic organisms. Nevertheless, the toxic selectivity and mechanism of non-target plants, specifically rice, remain uncertain. In this study, we investigated the potential phytotoxic effects of Pyr and Azo on rice seedlings, including plant morphology, plant growth, physiological and biochemical changes. The findings revealed that both Pyr and Azo caused toxic effects on rice, resulting in symptoms of chlorosis and inhibited growth. The toxicity of Azo was found to be more severe when applied at the recommended field dose. Disruption of oxidative stress could significantly impact the demonstrated levels of REC, leading to a decrease in photosynthetic pigments and potentially culminating in cell death. Furthermore, the toxic effect of Azo had a greater impact on rice leaves compared to Pyr at treatments of 400, 800, 1600, and 4000 mg/L. However, the in vitro cytotoxicity of Azo on rice leaves was lower than that of Pyr. Therefore, it can be inferred that the mechanism of phytotoxicity of Azo is directly linked to the increased accumulation of the compound on the leaf tips and edges. Additionally, the positive effects observed on plant morphology and growth parameters suggest that the mixed application of plant growth regulators (sodium nitrophenolate aqueous solution of 14 mg/L and diethyl aminoethyl hexanoat of 50 mg/L) can be a promising approach to mitigate the rice phytotoxicity of Azo at 400 and 800 mg/L.

Exploration and Practice of Introducing the Pharmaceutical Care Network Europe Classification System to Psychiatric Drugs.

This research aims to summarize and discuss issues related to psychiatric drugs by using the classification system of the Pharmaceutical Care Network Europe (PCNE) and to provide a reference for the development and direction of clinical pharmacists' work in the future. Psychiatric patients who were hospitalized in our hospital from Janurary 2023 to December 2023 were enrolled. Drug-related problems (DRPs) were evaluated using the PCNE classification system (version 9.0). The types, causes, intervention plans, acceptance of intervention plans, and statuses of DRPs were analyzed. A total of 362 patients were included, covering 405 DRP cases, with an average DRP of 1.12 for each patient. All 405 DRP cases underwent interventions, with a success rate of 83.46%. The main categories of related drugs were psychotropic drugs (70.37%), anti-infective drugs (8.89%), and cardiovascular system drugs (5.19%). The main DRPs were possible adverse drug events (21.24%), poor treatment effects (69.14%), and unnecessary medication treatment (9.63%). The main causes of DRPs were inappropriate drug selection (18.52%), inappropriate combinations of drugs (16.05%), and excessive drug dosage (13.58%). The PCNE classification system helps clinical pharmacists improve their ability to identify and solve DRPs faced by psychiatric departments, improve pharmaceutical care efficiency, and ensure rational drug use.

Relationship between exposure to fine particulate matter and cardiovascular risk factors and the modifying effect of socioeconomic status: a cross-sectional study in Beijing, China.

Accumulating research suggested that long-term exposure to fine particulate matter (PM2.5) is related to cardiovascular disease (CVD). However, evidence regarding the relationship between PM2.5 and CVD risk factors remains inconsistent. We hypothesized that this association may be partially modified by socioeconomic status (SES). To investigate the relationships and to test the modifying effect of SES, we included baseline data for 21,018 adults from September 2017 to May 2018. PM2.5 concentrations were determined by employing an amalgamation of linear measurements obtained from monitoring stations located near the participants' residential and workplace addresses. We assessed SES across several domains, including income, education, and occupation levels, as well as through a composite SES index. The results indicated that for every 10 µg/m3 increase in PM2.5 exposure, the risk of hypercholesterolemia, hyperbetalipoproteinemia, diabetes, and hyperhomocysteinemia (HHcy) increased by 7.7% [Odds ratio (OR) = 1.077, 95% Confidence Interval (CI) = 1.011, 1.146], 19.6% (OR = 1.196, 95% CI = 1.091, 1.312), 4.2% (OR = 1.042, 95% CI = 1.002, 1.084), and 17.1% (OR = 1.171, 95% CI = 1.133, 1.209), respectively. Compared to the high SES group, those with low SES are more prone to hypercholesterolemia, hyperbetalipoproteinemia, diabetes, and HHcy. Notably, the disparities in SES appear significant in the relationship between PM2.5 exposure and hypercholesterolemia as well as hyperbetalipoproteinemia. But for diabetes and HHcy, the modification effect of SES on PM2.5 shows an inconsistent pattern. In conclusion, the results confirm the association between PM2.5 and cardiovascular risk factors and low SES significantly amplified the adverse PM2.5 effect on dyslipidemia. It is crucial to emphasize a need to improve the socioeconomic inequality among adults in Beijing and contribute to the understanding of the urgency in protecting the health of vulnerable groups.

Validation of the JAMR upper-arm pressure monitor B23 according to the AAMI/ESH/ISO Universal Standard (ISO 81060- 2:2018/AMD 1:2020).

The aim of this study was to evaluate the accuracy of the JAMR upper-arm blood pressure monitor B23 in the general population according to the AAMI/ESH/ISO Universal Standard (ISO 81060-2 : 2018/AMD 1 : 2020). The study recruited participants who met the criteria of the AAMI/ESH/ISO Universal Standard in terms of their number, sex, age, limb size, and blood pressure (BP) distribution. The study involved measuring BP, including both SBP and DBP, using both the test device and a standard mercury sphygmomanometer in sequential measurements. Of 90 participants, 85 qualified participants were analyzed. A total of 255 sets of comparison data (three sets for each subject) were obtained and analyzed. For the validation criterion 1, the mean ±â€…SD of the differences between the JAMR B23 and mercury sphygmomanometer BP readings was -0.24 ±â€…6.52/-2.67 ±â€…5.6 mmHg (SBP/DBP). For criterion 2, the SD of the averaged BP (SBP/DBP) differences between the JAMR B23 and reference BP (SBP/DBP) per participant was 5.61/5.13 mmHg (the requirement was ≤6.95/6.43 mmHg by calculation). The JAMR B23 passed all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2 : 2018/AMD 1 : 2020) and can be recommended for clinical and self/home use in the general population.

Targeted pathophysiological treatment of ischemic stroke using nanoparticle-based drug delivery system.

Ischemic stroke poses significant challenges in terms of mortality and disability rates globally. A key obstacle to the successful treatment of ischemic stroke lies in the limited efficacy of administering therapeutic agents. Leveraging the unique properties of nanoparticles for brain targeting and crossing the blood-brain barrier, researchers have engineered diverse nanoparticle-based drug delivery systems to improve the therapeutic outcomes of ischemic stroke. This review provides a concise overview of the pathophysiological mechanisms implicated in ischemic stroke, encompassing oxidative stress, glutamate excitotoxicity, neuroinflammation, and cell death, to elucidate potential targets for nanoparticle-based drug delivery systems. Furthermore, the review outlines the classification of nanoparticle-based drug delivery systems according to these distinct physiological processes. This categorization aids in identifying the attributes and commonalities of nanoparticles that target specific pathophysiological pathways in ischemic stroke, thereby facilitating the advancement of nanomedicine development. The review discusses the potential benefits and existing challenges associated with employing nanoparticles in the treatment of ischemic stroke, offering new perspectives on designing efficacious nanoparticles to enhance ischemic stroke treatment outcomes.

Impact of UGT1A4 and UGT2B7 polymorphisms on lamotrigine plasma concentration in patients with bipolar disorder.

PURPOSE: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder. METHODS: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21 days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping. RESULTS: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [UGT1A4 -142T>G and UGT2B7 -161C>T (P < 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6 ±â€…1.1 and 1.7 ±â€…0.5 µg/ml per mg/kg) than those with the TT genotype (1.4 ±â€…1.1 µg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6 ±â€…1.1 µg/ml per mg/kg) than those with the CC genotype (1.3 ±â€…1.3 µg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics (P < 0.001). CONCLUSION: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder.

Invasion of human dental pulp fibroblasts by Porphyromonas gingivalis leads to autophagy via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling pathway.

OBJECTIVES: Porphyromonas gingivalis is a pathogenic bacterium that causes periodontitis and dental pulp infection. Autophagy is a potential mechanism involved in inflammatory disease. This study established an in vitro model of P. gingivalis intracellular infection in human dental pulp fibroblasts (HDPFs) to investigate the effects of live P. gingivalis on HDPFs. METHODS: Morphological and quantification techniques such as fluorescence microscopy, transmission electron microscopy (TEM), indirect immunofluorescence analysis, enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR), and western blotting were used in this study. RESULTS: After cell invasion, P. gingivalis is mainly localized in the cytoplasm and lysosomes. Additionally, P. gingivalis activates autophagy in HDPFs by upregulating the expression of autophagy-related gene Beclin-1, activate autophagy-related gene12 (ATG12), and microtubule-associated protein light chain 3 (LC3). Furthermore, the invasion of P. gingivalis leads to increased phosphorylation of PI3K, Akt, and mTOR with the addition of rapamycin, whereas the addition of wortmannin decreased phosphorylation. This invasion of P. gingivalis, also causes an inflammatory response, leading to the upregulation of IL-1ß, IL-6, and TNF-α. Rapamycin helps decrease levels of pro-inflammatory cytokines, but the addition of wortmannin increases them. These results show that the invasion of P. gingivalis can cause excessive inflammation and promote the autophagy of HDPFs, which is regulated by PI3K/Akt/mTOR. CONCLUSIONS: P. gingivalis escapes the immune system by inducing autophagy in the host cells, causing excessive inflammation. P. gingivalis regulates autophagy in HDPFs through the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway.

Single-cell exploration of active phosphate-solubilizing bacteria across diverse soil matrices for sustainable phosphorus management.

Phosphate-solubilizing bacteria (PSB) are crucial for enhancing phosphorus bioavailability and regulating phosphorus transformation processes. However, the in situ phosphorus-solubilizing activity and the link between phenotypes and genotypes for PSB remain unidentified. Here we employed single-cell Raman spectroscopy combined with heavy water to discern and quantify soil active PSB. Our results reveal that PSB abundance and in situ activity differed significantly between soil types and fertilization treatments. Inorganic fertilizer input was the key driver for active PSB distribution. Targeted single-cell sorting and metagenomic sequencing of active PSB uncovered several low-abundance genera that are easily overlooked within bulk soil microbiota. We elucidate the underlying functional genes and metabolic pathway, and the interplay between phosphorus and carbon cycling involved in high phosphorus solubilization activity. Our study provides a single-cell approach to exploring PSB from native environments, enabling the development of a microbial solution for the efficient agronomic use of phosphorus and mitigating the phosphorus crisis.

Otilonium bromide ameliorates pulmonary fibrosis in mice through activating phosphatase PPM1A.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC50 value of 4.23 µM. Treatment with OB (2.5, 5 mg·kg-1·d-1, i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-ß/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.

Hydrogen sulfide inhibits skeletal muscle ageing by up-regulating autophagy through promoting deubiquitination of adenosine 5'-monophosphate (AMP)-activated protein kinase α1 via ubiquitin specific peptidase 5.

BACKGROUND: Hydrogen sulfide (H2S), the third gasotransmitter discovered, regulates a variety of physiological functions. Whether H2S alleviates skeletal muscle ageing by regulating autophagy has not been reported. METHODS: Mice were administered 150 mg/kg/day of D-galactose ( D-gal), and C2C12 myotubes were cultured in 20 g/L D-gal to induce ageing. Sodium hydrosulfide (NaHS) was employed as an exogenous donor in the treatment group. The intracellular concentration of H2S was quantified by the 7-azido-4-methylcoumarin fluorescence probe. The proteins involved in the ubiquitin-mediated degradation of AMPKα1 were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (Co-IP). S-sulfhydration of USP5 was tested by a biotin-switch assay. Associated proteins were analysed by western blot. RESULTS: NaHS was found to effectively restore the H2S content in both ageing gastrocnemius (+91.89%, P < 0.001) and C2C12 myotubes (+27.55%, P < 0.001). In comparison to the D-gal group, NaHS was observed to increase the mean cross-sectional area of muscle fibres (+44.91%, P < 0.001), to decrease the collagen volume fraction of gastrocnemius (-81.32%, P = 0.001) and to reduce the ß-galactosidase-positive area of C2C12 myotubes (-28.74%, P < 0.001). NaHS was also found to reverse the expression of muscle atrophy F box protein (MAFbx), muscle-specific RING finger protein 1 (MuRF1), Cyclin D1 and p21 in the ageing gastrocnemius tissue (MAFbx: -31.73%, P = 0.008; MuRF1: -32.37%, P = 0.003; Cyclin D1: +45.34%, P = 0.010; p21: -25.53%, P = 0.022) and C2C12 myotubes (MAFbx: -16.38%, P < 0.001; MuRF1: -16.45%, P = 0.003; Cyclin D1: +40.23%, P < 0.001; p21: -35.85%, P = 0.026). The AMPKα1-ULK1 pathway was activated and autophagy was up-regulated in NaHS-treated gastrocnemius tissue (p-AMPKα1: +61.61%, P = 0.018; AMPKα1: +30.64%, P = 0.010; p-ULK1/ULK1: +85.87%, P = 0.005; p62: -29.07%, P < 0.001; Beclin1: +24.75%, P = 0.007; light chain 3 II/I [LC3 II/I]: +55.78%, P = 0.004) and C2C12 myotubes (p-AMPKα1: +77.49%, P = 0.018; AMPKα1: +26.18%, P = 0.022; p-ULK1/ULK1: +38.34%, P = 0.012; p62: -9.02%, P = 0.014; Beclin1: +13.36%, P < 0.001; LC3 II/I: +79.38%, P = 0.017; autophagy flux: +24.88%, P = 0.034) compared with the D-gal group. The effects of NaHS on autophagy were comparable to those of acadesine and LYN-1604, and chloroquine could reverse its effects on ageing. LC-MS/MS and Co-IP experiments demonstrated that USP5 is a deubiquitinating enzyme of AMPKα1. Following the knockdown of USP5, the activation of AMPKα1 was decreased (p-AMPKα1: -42.10%, P < 0.001; AMPKα1: -43.93%, P < 0.001), autophagy was inhibited (p-ULK1/ULK1: -27.51, P = 0.001; p62: +36.00, P < 0.001; Beclin1: -22.15%, P < 0.001) and NaHS lost its ability to up-regulate autophagy. NaHS was observed to restore the expression (gastrocnemius: +62.17%, P < 0.001; C2C12 myotubes: +37.51%, P = 0.003) and S-sulfhydration (+53.07%, P = 0.009) of USP5 and reduce the ubiquitination of AMPKα1. CONCLUSIONS: H2S promotes the deubiquitination of AMPKα1 by increasing the expression and S-sulfhydration of USP5, thereby up-regulating autophagy and alleviating skeletal muscle ageing.

Potential utility of ADNP in circulating tumor cells as biomarker for prognostics in non-muscle-invasive bladder cancer.

This study aims to evaluate the prognostic utility of Activity-dependent neuroprotective protein (ADNP) expression in Circulating Tumor Cells (CTCs) inpatients with Non-muscle-invasive Bladder Cancer (NMIBC) undergoing Transurethral Resection of Bladder Tumor (TURBT). A prospective cohort of 74 bladder cancer patients and 22 non-cancer controls were enrolled. The expression of ADNP mRNA was detected by immunomagnetic beads-droplet digital PCR. The ADNP mRNA expression was evaluated in patients with high-risk NMIBC and those with indeterminate invasion depth post 2nd TURBT. Primary cultured bladder cancer cells and PBMCs from healthy donors were immunofluorescence stained. Our findings suggest that baseline ADNP mRNA level in CTCs shows potential as a prognostic marker for NMIBC with a sensitivity of 83.33% and a specificity of 73.58%. In comparison to baseline, ADNP mRNA expression increased post 2nd TURBT in 5 patients, where 2 experienced recurrence. Meanwhile, among the 12 patients with decreased levels, only one patient relapsed. A considerable limitation of this study entails the small sample size. The Immuno-magnetic beads-ddPCR technique provided a viable method for ADNP mRNA detection in CTCs from bladder cancer patients. The preoperative ADNP mRNA level in CTCs was identified as a prognostic indicator for NMIBC. Longitudinal monitoring of ADNP mRNA in CTCs of bladder cancer patients shows promise in evaluating treatment responses and predicting prognosis.

SLC25A12 inhibits Japanese encephalitis virus replication by interacting with the NS1 and enhancing the type I interferon response.

Japanese encephalitis virus (JEV) is a mosquito-borne, zoonotic orthoflavivirus causing human encephalitis and reproductive disorders in pigs. Cell-intrinsic antiviral restriction factors are the first line of defense that prevent a virus from establishing a productive infection, while the molecular mechanism of the virus-host interaction is still not fully understood. Our in vitro experiments demonstrated that the Solute Carrier Family 25 Member 12 (SLC25A12) interacted with the JEV nonstructural protein 1 (NS1) and inhibited JEV replication. Furthermore, we showed that knockdown or knockout of SLC25A12 promoted JEV replication, while overexpression of SLC25A12 repressed viral replication. Finally, we demonstrated that SLC25A12 increased IRF7 mRNA levels, which promoted IFN-ß expression and subsequently induced antiviral effects. Collectively, our study revealed that SLC25A12 interacted with NS1, inhibiting viral RNA synthesis and transcription and enhancing type I interferon induction for antiviral effects.