Type 2 diabetic mellitus related osteoporosis: focusing on ferroptosis.

With the aging global population, type 2 diabetes mellitus (T2DM) and osteoporosis(OP) are becoming increasingly prevalent. Diabetic osteoporosis (DOP) is a metabolic bone disorder characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Studies have revealed a close association among diabetes, increased fracture risk, and disturbances in iron metabolism. This review explores the concept of ferroptosis, a non-apoptotic cell death process dependent on intracellular iron, focusing on its role in DOP. Iron-dependent lipid peroxidation, particularly impacting pancreatic ß-cells, osteoblasts (OBs) and osteoclasts (OCs), contributes to DOP. The intricate interplay between iron dysregulation, which comprises deficiency and overload, and DOP has been discussed, emphasizing how excessive iron accumulation triggers ferroptosis in DOP. This concise overview highlights the need to understand the complex relationship between T2DM and OP, particularly ferroptosis. This review aimed to elucidate the pathogenesis of ferroptosis in DOP and provide a prospective for future research targeting interventions in the field of ferroptosis.

Continuous operation of nano-catalytic ozonation using membrane separation coupling system: influence factors and mechanism.

The application of nano-catalysts in improving the ozonation removal efficiency for refractory organic compounds has been extensively investigated. However, cost-effective nano-catalysts separation remains a challenge. In this study, membrane separation processes were employed to separate nano-MgO catalysts from an ozonation system. A continuous nano-catalytic ozonation membrane separation (nCOMS) coupling system was successfully constructed for treating quinoline. The results showed that long hydraulic retention time (HRT) and high nano-MgO dosage could improve the quinolone removal efficiency but shorten operation cycles. At the optimal operation conditions of HRT=4 h and nano-MgO dosage=0.2 g/L, the nCOMS system achieved a stable quinoline removal efficiency of 85.2% for 240 min running with a transmembrane pressure lower than 10 kPa. The quinoline removal efficiency contribution for ozonation, catalysis and membrane separation was 57.1%, 24.9% and 18.0%, respectively. Compared to ozonation membrane separation system, the fouling rate index of the nCOMS system increased by 60% under optimal conditions, but the irreversible fouling was reduced to 28%. In addition, the nCOMS system exhibited reduced adverse effects of coexisting natural organic matter (NOM) on quinoline removal and membrane fouling. In conclusion, the nCOMS system demonstrated higher quinoline removal efficiency, lower irreversible fouling, and reduced adverse effect of coexisting NOM, thereby signifying its potential for practical applications in advanced treatment of industrial wastewater.

Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. Results: 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.

Prevalence and molecular characteristics of ceftazidime-avibactam resistance among carbapenem-resistant Pseudomonas aeruginosa clinical isolates.

OBJECTIVES: Resistance against ceftazidime-avibactam (CZA) in carbapenem-resistant Pseudomonas aeruginosa (CRPA) is emerging. This study was aimed at detecting the prevalence and molecular characteristics of CZA-resistant CRPA clinical isolates in Guangdong Province, China. METHODS: The antimicrobial susceptibility profile of these strains was determined. A subset of 16 CZA-resistant CRPA isolates was analysed by whole-genome sequencing (WGS). Genetic surroundings of carbapenem resistance genes and pan-genome-wide association analysis were further studied. RESULTS: Of the 250 CRPA isolates, CZA resistance rate was 6.4% (16/250). The minimum inhibitory concentration (MIC) of CZA range was from 0.25 to >256 mg/L. MIC50 and MIC90 were 2/4 and 8/4 mg/L, respectively. Among the 16 CZA-resistant CRPA strains, 31.3% (5/16) of them carried class B carbapenem resistance genes, including blaIMP-4, blaIMP-45, and blaVIM-2, located on IncP-2 megaplasmids or chromosomes, respectively. Pan-genome-wide association analysis of accessory genes for CZA-susceptible or -resistant CRPA isolates showed that PA1874, a hypothetical protein containing BapA prefix-like domain, was enriched in CZA-resistant group significantly. CONCLUSIONS: Class B carbapenem resistance genes play important roles in CZA resistance. Meanwhile, the PA1874 gene may be a novel mechanism involving in CZA resistance. It is necessary to continually monitor CZA-resistant CRPA isolates.

Natural product-derived ferroptosis mediators.

It has been 11 years since ferroptosis, a new mode of programmed cell death, was first proposed. Natural products are an important source of drug discovery. In the past five years, natural product-derived ferroptosis regulators have been discovered in an endless stream. Herein, 178 natural products discovered so far to trigger or resist ferroptosis are classified into 6 structural classes based on skeleton type, and the mechanisms of action that have been reported are elaborated upon. If pharmacodynamic data are sufficient, the structure and bioactivity relationship is also presented. This review will provide medicinal chemists with some effective ferroptosis regulators, which will promote the research of natural product-based treatment of ferroptosis-related diseases in the future.

Aberrant accumulation of ceramides in mitochondria triggers cell death by inducing autophagy in Arabidopsis.

Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides are central components of sphingolipid metabolism that are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found that ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramide accumulation and the acd5 cell death phenotype. Using immuno-electron microscopy, we observed hyperaccumulation of ceramides in acer acd5 double mutants, which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase in mitochondrial reactive oxygen species production. Interestingly, when compared with the wild type, autophagy-deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Furthermore, exogenous ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, an increase in the level of the autophagy-specific ubiquitin-like protein, ATG8e, associated with mitochondria, where it directly bound to ceramides. Taken together, we propose that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.

Microenvironment responsive charge-switchable nanoparticles act on biofilm eradication and virulence inhibition for chronic lung infection treatment.

Chronic pulmonary infection caused by Pseudomonas aeruginosa (P. aeruginosa) is a common lung disease with high mortality, posing severe threats to public health. Highly resistant biofilm and intrinsic resistance make P. aeruginosa hard to eradicate, while powerful virulence system of P. aeruginosa may give rise to the recurrence of infection and eventual failure of antibiotic therapy. To address these issues, infection-microenvironment responsive nanoparticles functioning on biofilm eradication and virulence inhibition were simply prepared by electrostatic complexation between dimethylmaleic anhydride (DA) modified negatively charged coating and epsilon-poly(l-lysine) derived cationic nanoparticles loaded with azithromycin (AZI) (DA-AZI NPs). Charge reversal responsive to acidic condition enabled DA-AZI NPs to successively penetrate through both mucus and biofilms, followed by targeting to P. aeruginosa and permeabilizing its outer/inner membrane. Then in situ released AZI, which was induced by the lipase-triggered NPs dissociation, could easily enter into bacteria to take effects. DA-AZI NPs exhibited enhanced eradication activity against P. aeruginosa biofilms with a decrease of >99.999% of bacterial colonies, as well as remarkable inhibitory effects on the production of virulence factors and bacteria re-adhesion & biofilm re-formation. In a chronic pulmonary infection model, nebulization of DA-AZI NPs into infected mice resulted in prolonged retention and increased accumulation of the NPs in the infected sites of the lungs. Moreover, they significantly reduced the burden of P. aeruginosa, effectively alleviating lung tissue damages and inflammation. Overall, the proposed DA-AZI NPs highlight an innovative strategy for treating chronic pulmonary infection.

Development of novel parameters for pathogen identification in clinical metagenomic next-generation sequencing.

Introduction: Metagenomic next-generation sequencing (mNGS) has emerged as a powerful tool for rapid pathogen identification in clinical practice. However, the parameters used to interpret mNGS data, such as read count, genus rank, and coverage, lack explicit performance evaluation. In this study, the developed indicators as well as novel parameters were assessed for their performance in bacterium detection. Methods: We developed several relevant parameters, including 10M normalized reads, double-discard reads, Genus Rank Ratio, King Genus Rank Ratio, Genus Rank Ratio*Genus Rank, and King Genus Rank Ratio*Genus Rank. These parameters, together with frequently used read indicators including raw reads, reads per million mapped reads (RPM), transcript per kilobase per million mapped reads (TPM), Genus Rank, and coverage were analyzed for their diagnostic efficiency in bronchoalveolar lavage fluid (BALF), a common source for detecting eight bacterium pathogens: Acinetobacter baumannii, Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Hemophilus influenzae, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Aspergillus fumigatus. Results: The results demonstrated that these indicators exhibited good diagnostic efficacy for the eight pathogens. The AUC values of all indicators were almost greater than 0.9, and the corresponding sensitivity and specificity values were almost greater than 0.8, excepted coverage. The negative predictive value of all indicators was greater than 0.9. The results showed that the use of double-discarded reads, Genus Rank Ratio*Genus Rank, and King Genus Rank Ratio*Genus Rank exhibited better diagnostic efficiency than that of raw reads, RPM, TPM, and in Genus Rank. These parameters can serve as a reference for interpreting mNGS data of BALF. Moreover, precision filters integrating our novel parameters were built to detect the eight bacterium pathogens in BALF samples through machine learning. Summary: In this study, we developed a set of novel parameters for pathogen identification in clinical mNGS based on reads and ranking. These parameters were found to be more effective in diagnosing pathogens than traditional approaches. The findings provide valuable insights for improving the interpretation of mNGS reports in clinical settings, specifically in BALF analysis.

Higher Cumulative Blood Pressure in Midlife Predicts an Increased Risk of Atrial Fibrillation: Evidence From the Atherosclerosis Risk in Communities Study.

BACKGROUND: Elevated blood pressure (BP) is reportedly associated with an increased risk of atrial fibrillation (AF). However, the association between cumulative BP exposure in midlife and incident AF in mid-to-late life remains unclear. METHODS AND RESULTS: Participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study with 4 consecutive BP measurements and no prevalent AF at baseline were included. Cumulative BP was calculated as the area under the curve from visit 1 to visit 4. Incident AF was identified by study visit ECGs, hospital discharge codes, or death certificates. A total of 9892 participants were included (44.6% men and mean age 62.9±5.7 years at visit 4) with 1550 (15.7%) individuals who developed new-onset AF during an average follow-up of 15.4 years. The incidence rates of AF per 1000 person-years across the 4 quartiles of cumulative systolic BP were 7.9, 9.2, 12.5, and 16.9, respectively. After multivariable adjustment, the hazard ratios for incident AF among participants in the highest quartile of cumulative systolic BP, pulse pressure, and mean arterial pressure were 1.48 (95% CI, 1.27-1.72), 1.81 (95% CI, 1.53-2.13), and 1.22 (95% CI, 1.05-1.41), respectively, compared with those in the lowest quartile. The addition of cumulative systolic BP or pulse pressure slightly improved the ability to predict new-onset AF. CONCLUSIONS: Higher exposure to cumulative systolic BP, pulse pressure, and mean arterial pressure was significantly associated with increased risk of incident AF.

Patient-derived organoids as personalized avatars and a potential immunotherapy model in cervical cancer.

Cervical cancer remains a significant health issue in developing countries. However, finding a preclinical model that accurately reproduces tumor characteristics is challenging. Therefore, we established a patient-derived organoids (PDOs) biobank containing 67 cases of heterogeneous cervical cancer that mimic the histopathological and genomic characteristics of parental tumors. The in vitro response of the organoids indicated their ability to capture the radiological heterogeneity of the patients. To model individual responses to adoptive T cell therapy (ACT), we expanded tumor-infiltrating lymphocytes (TILs) ex vivo and co-cultured them with paired organoids. The PDOs-TILs co-culture system demonstrates clear responses that correspond to established immunotherapy efficiency markers like the proportion of CTLs. This study supports the potential of the PDOs platform to guide treatment in prospective interventional trials in cervical cancer.

Diversity and Surgical Management of Intracranial Fungal Infections.

Intracranial fungal infection is a rare entity. This disease is mainly concentrated in dry and hot climates, such as India, Africa, California, and usually occurs in patients with immune deficiency. Now, we retrospectively analyzed the clinical manifestations, pathologic manifestations, imaging features, surgical methods, and prognosis of 4 patients with fungal infection who were confirmed by postoperative pathology. Intermittent pricking on the right face was presented in 2 patients, headache in 2 patients, orbital apex syndrome in 2 patients, and 1 patient presented with fever. Imaging showed the lesions of all patients were located in the right temporal, including 2 patients involving the right orbital, 1 patient involving the right trigeminal semilunar ganglion, 1 patient involving the right brainstem and tentorium cerebellum, 1 patient involving the right internal carotid artery. Craniotomy was performed in 2 patients, endoscopic biopsy in 1 patient, and stereotactic surgery in 1 patien. Aspergilloma was the most common pathogenic bacteria. One patient relapsed repeatedly and died. Secondary aneurysm complicated with subarachnoid hemorrhage occurred in 1 patient. Therefore, the author confirmed that intracranial fungal infection has diverse clinical, imaging, and pathologic manifestations. Neurosurgeons should be aware of the possibility of intracranial fungal infection when they find abnormal intracranial lesions, neurologic deficits, and inflammation of paranasal sinuses. Combining multiple clinical data may help doctors to improve the accuracy of diagnosis. Individualized and diversified surgical protocols should be selected for diverse lesions. Notably, secondary intracranial fungal vasculitis is common, with high mortality and disability rates.

Dynamic evolution of ceftazidime-avibactam resistance due to interchanges between blaKPC-2 and blaKPC-145 during treatment of Klebsiella pneumoniae infection.

Background: The emergence of ceftazidime-avibactam (CZA) resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP) is of major concern due to limited therapeutic options. Methods: In this study, 10 CRKP strains were isolated from different samples of a patient with CRKP infection receiving CZA treatment. Whole-genome sequencing (WGS) and conjugation experiments were performed to determine the transferability of the carbapenem resistance gene. Results: This infection began with a KPC-2-producing K. pneumoniae (CZA MIC = 2 µg/mL, imipenem MIC ≥ 16 µg/mL). After 20 days of CZA treatment, the strains switched to the amino acid substitution of T263A caused by a novel KPC-producing gene, blaKPC-145, which restored carbapenem susceptibility but showed CZA resistance (CZA MIC ≥ 256 µg/mL, imipenem MIC = 1 µg/mL). The blaKPC-145 gene was located on a 148,185-bp untransformable IncFII-type plasmid. The subsequent use of carbapenem against KPC-145-producing K. pneumoniae infection led to a reversion of KPC-2 production (CZA MIC = 2 µg/mL, imipenem MIC ≥ 16 µg/mL). WGS analysis showed that all isolates belonged to ST11-KL47, and the number of SNPs was 14. This implied that these blaKPC-positive K. pneumoniae isolates might originate from a single clone and have been colonized for a long time during the 120-day treatment period. Conclusion: This is the first report of CZA resistance caused by blaKPC-145, which emerged during the treatment with CZA against blaKPC-2-positive K. pneumoniae-associated infection in China. These findings indicated that routine testing for antibiotic susceptibility and carbapenemase genotype is essential during CZA treatment.

Orosomucoid proteins limit endoplasmic reticulum stress in plants.

Sphingolipids are cell membrane components and signaling molecules that induce endoplasmic reticulum (ER) stress responses, but the underlying mechanism is unknown. Orosomucoid proteins (ORMs) negatively regulate serine palmitoyltransferase activity, thus helping maintain proper sphingolipid levels in humans, yeast, and plants. In this report, we explored the roles of ORMs in regulating ER stress in Arabidopsis thaliana. Loss of ORM1 and ORM2 function caused constitutive activation of the unfolded protein response (UPR), as did treatment with the ceramide synthase inhibitor Fumonisin B1 (FB1) or ceramides. FB1 treatment induced the transcription factor bZIP28 to relocate from the ER membrane to the nucleus. The transcription factor WRKY75 positively regulates the UPR and physically interacted with bZIP28. We also found that the orm mutants showed impaired ER-associated degradation (ERAD), blocking the degradation of misfolded MILDEW RESISTANCE LOCUS-O 12 (MLO-12). ORM1 and ORM2 bind to EMS-MUTAGENIZED BRI1 SUPPRESSOR 7 (EBS7), a plant-specific component of the Arabidopsis ERAD complex, and regulate its stability. These data strongly suggest that ORMs in the ER membrane play vital roles in the UPR and ERAD pathways to prevent ER stress in Arabidopsis. Our results reveal that ORMs coordinate sphingolipid homeostasis with ER quality control and play a role in stress responses.

PlantMetSuite: A User-Friendly Web-Based Tool for Metabolomics Analysis and Visualisation.

The advancement of mass spectrometry technologies has revolutionised plant metabolomics research by enabling the acquisition of raw metabolomics data. However, the identification, analysis, and visualisation of these data require specialised tools. Existing solutions lack a dedicated plant-specific metabolite database and pose usability challenges. To address these limitations, we developed PlantMetSuite, a web-based tool for comprehensive metabolomics analysis and visualisation. PlantMetSuite encompasses interactive bioinformatics tools and databases specifically tailored to plant metabolomics data, facilitating upstream-to-downstream analysis in metabolomics and supporting integrative multi-omics investigations. PlantMetSuite can be accessed directly through a user's browser without the need for installation or programming skills. The tool is freely available and will undergo regular updates and expansions to incorporate additional libraries and newly published metabolomics analysis methods. The tool's significance lies in empowering researchers with an accessible and customisable platform for unlocking plant metabolomics insights.

Glossopharyngeal Neuralgia Characterized by Otalgia: A Retrospective Study.

Glossopharyngeal neuralgia (GPN) is an uncommon facial pain syndrome and is characterized by paroxysms of excruciating pain in the distributions of the auricular and pharyngeal branches of cranial nerves IX and X. Glossopharyngeal neuralgia characterized by otalgia alone is rare. Herein, the authors analyzed 2 patients with GPN with otalgia as the main clinical manifestation. The clinical features and prognosis of this rare group of patients with GPN were discussed. They both presented with paroxysmal pain in the external auditory meatus and preoperative magnetic resonance imaging suggested the vertebral artery were closely related to the glossopharyngeal nerves. In both patients, compression of the glossopharyngeal nerve was confirmed during microvascular decompression, and the symptoms were relieved immediately after surgery. At 11 to 15 months follow-up, there was no recurrence of pain. A variety of reasons can cause otalgia. The possibility of GPN is a clinical concern in patients with otalgia as the main complaint. The authors think the involvement of the glossopharyngeal nerve fibers in the tympanic plexus via Jacobson nerve may provide an important anatomic basis for GPN with predominant otalgia. Surface anesthesia test of the pharynx and preoperative magnetic resonance imaging is helpful for diagnosis. Microvascular decompression is effective in the treatment of GPN with predominant otalgia.

Effects of salinity on the performance, microbial community, and functional genes among 4-chlorophenol wastewater treatment.

Chlorophenols frequently occur alongside salinity in industrial wastewater; thus, the effects of low concentrations of salinity (NaCl, 100 mg/L) on sludge performance, microbial community, and functional genes were deeply analyzed among 4-chlorophenol (4-CP, 2.4-4.0 mg/L) wastewater treatment. The influent 4-CP was effectively degraded, but the efficiencies for PO43--P, NH4+-N, and organics reduction were slightly inhibited by NaCl stress. Long-term NaCl and 4-CP stress significantly stimulated the secretion of extracellular polymeric substances (EPS). The abundances of predominant microbes at different taxonomic levels were affected by NaCl, and the increased relative abundances of functional genes encoding proteins contributed to resist NaCl and 4-CP stress. The functional genes associated with phosphorus metabolism and nitrogen metabolism in nitrification were unaffected, but the functional genes in denitrification increased in diversity under NaCl stress in 4-CP wastewater treatment. This finding acquires useful insight into the wastewater treatment with low chlorophenols and low salinity.

Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities.

Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide  additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.

A simple ATTR-CM score to identify transthyretin amyloid cardiomyopathy burden in HFpEF patients.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is often found in patients with heart failure with preserved ejection fraction (HFpEF). However, the evidence regarding ATTR-CM and prognosis in HFpEF remains scarce. This study sought to determine whether the ATTR-CM burden was associated with clinical outcomes in HFpEF patients. METHODS: We evaluated the associations of baseline ATTR-CM score with adverse outcomes in HFpEF patients from the TOPCAT trial using the Cox proportional hazards model or the competing risk regression model. The discriminatory ability of the ATTR-CM score was assessed using the area under the time-dependent receiver operating characteristic curve (AUC). RESULTS: We included 870 HFpEF patients, 18.9% of which had an ATTR-CM score ≥6. Per 1 increment in the ATTR-CM score was significantly associated with an increased risk of the primary outcome (adjusted hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.12-1.27) with an AUC of 0.652 (0.594-0.711), whereas patients with ATTR-CM score ≥6 presented higher risks of the primary outcome (adjusted HR 2.20, 95% CI 1.65-2.95). Similar results were observed toward the secondary outcomes. CONCLUSIONS: The simple ATTR-CM score identified an 18.9% ATTR-CM burden in HFpEF patients, and a higher ATTR-CM burden might predict adverse outcomes with moderate discriminatory abilities in HFpEF.

MicroRNA-146a Improved Acute Lung Injury Induced by hepatic Ischemia-reperfusion Injury by Inhibiting PRDX1.

Hepatic ischemia-reperfusion injury (HIRI)-induced acute lung injury (ALI) is characterized by high incidence and poor prognosis. The regulatory role of microRNA-146a (miR-146a) in HIRI has been reported, but if miR-146a could affect the progression of HIRI-induced ALI has not been reported. The mice HIRI model was established by ligating left hepatic portal vein and hepatic artery for 60 minutes and then treating with reperfusion for 4 hours. Hypoxia-reoxygenation (HR) was performed to establish cell model. The binding site between miR-146a and Peroxidase 1 (PRDX1) was predicted and validated. The levels of inflammation factors and redox markers were detected with commercial kits. Significant lower expression of miR-146a and higher expression of PRDX1 in HIRI animal model were observed. miR-146a inhibited the liver injury after HIRI induction through targeting PRDX1. miR-146a inhibited the lung injury caused by HIRI via regulating PRDX1. The inhibition of cell apoptosis and inflammation factors by miR-146a were reversed by pcDNA-PRDX1. This research demonstrated that miR-146a improved ALI caused by HIRI by inhibiting apoptosis, inflammation, oxidative condition through targeting PRDX1. This study might provide a novel thought for the prevention and treatment of ALI caused by HIRI by regulating miR-146a/PRDX1 axis.