The Relationship Between Negotiable Fate and Life Satisfaction: The Serial Mediation by Self-Esteem and Positive Psychological Capital.

Purpose: Negotiable fate as a belief in coping with the difficulties and uncertainties of life has an impact on people's mental health. This study aims to understand the influence of negotiate fate on college students' life satisfaction and its underlying mechanism. Methods: A cross-sectional study was conducted with the participation of 1523 students from six universities across China. The study aimed to measure the variables of negotiable fate, self-esteem, positive psychological capital, and life satisfaction of all participants. To investigate the effect of negotiable fate on college students' life satisfaction and the mediating roles of self-esteem and positive psychological capital in this relationship, a serial mediation effects model using Hayes' PROCESS was employed. Results: The results suggest that negotiable fate has a positive predictive effect on college students' life satisfaction. The impact of negotiable fate on college students' life satisfaction was mediated by self-esteem and positive psychological capital, and the chained mediation of self-esteem and positive psychological capital. Conclusion: To summarize, the belief of negotiable fate has practical significance for the enhancement of college student's mental health and quality of life, and the cultivation of college students' belief of negotiable fate can be actively promoted in the future to help them better cope with the uncertainties and challenges in their lives to improve their life satisfaction.

Carbon-based Nanomaterials in Photothermal Therapy Guided by Photoacoustic Imaging: State of Knowledge and Recent Advances.

Carbon-based nanomaterials (CBNM)have been widely used in various fields due to their excellent physicochemical properties. In particular, in the area of tumor diagnosis and treatment, researchers have frequently reported them for their potential fluorescence, photoacoustic (PA), and ultrasound imaging performance, as well as their photothermal, photodynamic, sonodynamic, and other therapeutic properties. As the functions of CBNM are increasingly developed, their excellent imaging properties and superior tumor treatment effects make them extremely promising theranostic agents. This review aims to integrate the considered and researched information in a specific field of this research topic and systematically present, summarize, and comment on the efforts made by authoritative scholars. In this review, we summarized the work exploring carbon-based materials in the field of tumor imaging and therapy, focusing on PA imaging-guided photothermal therapy (PTT) and discussing their imaging and therapeutic mechanisms and developments. Finally, the current challenges and potential opportunities of carbon-based materials for PA imaging-guided PTT are presented, and issues that researchers should be aware of when studying CBNM are provided.

Perspective insights into versatile hydrogels for stroke: From molecular mechanisms to functional applications.

As the leading killer of life and health, stroke leads to limb paralysis, speech disorder, dysphagia, cognitive impairment, mental depression and other symptoms, which entail a significant financial burden to society and families. At present, physiology, clinical medicine, engineering, and materials science, advanced biomaterials standing on the foothold of these interdisciplinary disciplines provide new opportunities and possibilities for the cure of stroke. Among them, hydrogels have been endowed with more possibilities. It is well-known that hydrogels can be employed as potential biosensors, medication delivery vectors, and cell transporters or matrices in tissue engineering in tissue engineering, and outperform many traditional therapeutic drugs, surgery, and materials. Therefore, hydrogels become a popular scaffolding treatment option for stroke. Diverse synthetic hydrogels were designed according to different pathophysiological mechanisms from the recently reported literature will be thoroughly explored. The biological uses of several types of hydrogels will be highlighted, including pro-angiogenesis, pro-neurogenesis, anti-oxidation, anti-inflammation and anti-apoptosis. Finally, considerations and challenges of using hydrogels in the treatment of stroke are summarized.

Hypoxia preconditioning of human amniotic mesenchymal stem cells enhances proliferation and migration and promotes their homing via the HGF/C-MET signaling axis to augment the repair of acute liver failure.

BACKGROUND: Transplantation of mesenchymal stem cells (MSCs) is a newly developed strategy for treating acute liver failure (ALF). Nonetheless, the low survival rate of MSCs after transplantation and their poor homing to damaged tissues limit the clinical application of MSCs. The research assessed whether hypoxic preconditioning (HPC) can improve the biological activity of human amniotic mesenchymal stem cells (hA-MSCs), promote their homing ability to the liver of mice with ALF, and influence liver tissue repair. METHODS: Flow cytometry, CCK8, Transwell, and Western blotting assays were conducted to assess the effects of hypoxic preconditioning on the phenotype, proliferation, and migration of hA-MSCs and the changes in the c-Met and CXCR4 gene expression levels were studied. To evaluate the effects of the transplantation of hypoxic preconditioning of hA-MSCs on the homing and repair of D-galactosamine (D-GalN)/LPS-induced ALF, the mechanism was elucidated by adding c-Met, CXCR4-specific blockers (SU11274 and AMD3100). RESULTS: After hypoxia pretreatment (1% oxygen volume fraction), hA-MSCs maintained the morphological characteristics of adherence and vortex colony growth and showed high CD44, CD90, and CD105 and low CD31, CD34, and CD45 expression levels. Hypoxic preconditioning of hA-MSCs significantly increased their proliferation and migration and highly expressed the c-Met and CXCR4 genes. In vivo and in vitro, this migration-promoting effect was suppressed by the c-Met specific blocker SU11274. In the acute liver failure mouse model, the HGF expression level was considerably elevated in the liver than that in the serum, lungs and kidneys. The transplantation of hypoxic preconditioned hA-MSCs introduced a remarkable improvement in the liver function and survival rate of mice with ALF and enhanced the anti-apoptosis ability of liver cells. The anti-apoptotic enhancing effect of hypoxic preconditioning was suppressed by the c-Met specific blocker SU11274. Hypoxic hA-MSCs administration was observed to have considerably increased the fluorescent cells in the liver than that recorded after administering normal oxygen-hA-MSCs. The number of hepatic fluorescent cells decreased remarkably after adding the c-Met inhibitor SU11274, compared to that recorded after hypoxic pretreatment, whereas the effect of c-Met inhibitor SU11274 on normal oxygen-hA-MSCs was not significant. CONCLUSIONS: Hypoxic preconditioning depicted no impact on the morphology and phenotype features of the human amniotic mesenchymal stem cells, but it can promote their proliferation, migration, anti-apoptotic effect, and homing rate and improve the repair of acute liver failure, which might be mediated by the HGF/c-Met signaling axis.

Effects of purple potato anthocyanins on the in vitro digestive properties of starches of different crystalline types.

This study explored the potential of purple potato anthocyanins (PPAs) in regulating the digestive properties of starches of various crystalline types. In vitro digestion experiments indicated that PPAs inhibit the hydrolysis of rice starch (A-type) better than that of garden pea starch (C-type) and potato starch (B-type). Further structural assessment of different PPA-starch systems showed that PPAs and starch likely interact through non-covalent bonds, resulting in structural changes. Microstructural changes observed in the starches were consistent with the in vitro digestion results, and the chain length and proportions of short/long chains in amylopectin molecules affected the binding strengths and interaction modes between PPAs and starch. Hence, the three starches differed in their PPA loading efficiency and digestibility. These discoveries contribute to a deeper understanding of the mechanisms underlying the inhibition of starch digestibility by PPAs. They can aid the formulation of value-added products and low-glycemic-index foods.

Maximal dietary responsiveness after tetrahydrobiopterin (BH4) in 19 phenylalanine hydroxylase deficiency patients: What super-responders can expect.

Background: Inherited phenylalanine hydroxylase deficiency, also known as phenylketonuria (PKU), causes poor growth and neurologic deficits in the untreated state. After ascertainment through newborn screen and dietary phenylalanine (Phe) restriction to achieve plasma Phe in the range of 120-360 µmol/L, these disease manifestations can be prevented. Poor compliance with protein restricted diets supported by medical food is typical in later years, beginning in the late toddler and teenage years. Pharmacologic doses of oral tetrahydrobiopterin (BH4; sapropterin dihydrochloride) is effective in reducing plasma Phe in about 40-50% of PKU patients but effectiveness is highly variable. Objective: To assess the maximal responsiveness to 20 mg/kg/day oral BH4 as it affects plasma Phe and dietary Phe allowance in PKU patients. Materials and methods: This was a single-center, retrospective observational study, combining case reports of individual patients. We reported an outcome of 85 patients with PKU who were trialed on BH4. Phe levels and dietary records of 19 BH4 "super-responders" were analyzed. Results: Overall, 63.5% of the patients (54/85) were considered BH4 responders. However, we quantitated the dietary liberalization of 19 of our responsive patients (35%), those with at least a 2-fold increase in dietary Phe and maintenance of plasma Phe in treatment range. In these "super-responders", the mean plasma Phe at baseline was 371 ± 237 µmol/L and decreased to 284 ± 273 µmol/L after 1 year on BH4. Mean dietary Phe tolerance increased significantly from 595 ± 256 to 2260 ± 1414 mg/day (p ≤0.0001), while maintaining mean plasma Phe levels within treatment range. Four patients no longer required dietary Phe restriction and could discontinue medical food. The majority of patients had at least one BH4-responsive genotype. Conclusion: This cohort demonstrates the maximally achievable dietary liberalization which some PKU patients may expect with BH4 therapy. Health benefits are considered to accrue in patients with increased intact protein.

Development and validation of a deep interpretable network for continuous acute kidney injury prediction in critically ill patients.

Early detection of acute kidney injury (AKI) may provide a crucial window of opportunity to prevent further injury, which helps improve clinical outcomes. This study aimed to develop a deep interpretable network for continuously predicting the 24-hour AKI risk in real-time and evaluate its performance internally and externally in critically ill patients. A total of 21,163 patients' electronic health records sourced from Beth Israel Deaconess Medical Center (BIDMC) were first included in building the model. Two external validation populations included 3025 patients from the Philips eICU Research Institute and 2625 patients from Zhongda Hospital Southeast University. A total of 152 intelligently engineered predictors were extracted on an hourly basis. The prediction model referred to as DeepAKI was designed with the basic framework of squeeze-and-excitation networks with dilated causal convolution embedded. The integrated gradients method was utilized to explain the prediction model. When performed on the internal validation set (3175 [15 %] patients from BIDMC) and the two external validation sets, DeepAKI obtained the area under the curve of 0.799 (95 % CI 0.791-0.806), 0.763 (95 % CI 0.755-0.771) and 0.676 (95 % CI 0.668-0.684) for continuousAKI prediction, respectively. For model interpretability, clinically relevant important variables contributing to the model prediction were informed, and individual explanations along the timeline were explored to show how AKI risk arose. The potential threats to generalisability in deep learning-based models when deployed across health systems in real-world settings were analyzed.

Constructing FeNiPt@C Trifunctional Catalyst by High Spin-Induced Water Oxidation Activity for Zn-Air Battery and Anion Exchange Membrane Water Electrolyzer.

Developing cost-efficient trifunctional catalysts capable of facilitating hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR) activity is essential for the progression of energy devices. Engineering these catalysts to optimize their active sites and integrate them into a cohesive system presents a significant challenge. This study introduces a nanoflower (NFs)-like carbon-encapsulated FeNiPt nanoalloy catalyst (FeNiPt@C NFs), synthesized by substituting Co2+ ions with high-spin Fe2+ ions in Hofmann-type metal-organic framework, followed by carbonization and pickling processes. The FeNiPt@C NFs catalyst, characterized by its nitrogen-doped carbon-encapsulated metal alloy structure and phase-segregated FeNiPt alloy with slight surface oxidization, exhibits excellent trifunctional catalytic performance. This is evidenced by its activities in HER (-25 mV at 10 mA cm-2 ), ORR (half-wave potential of 0.93 V), and OER (294 mV at 10 mA cm-2 ), with the enhanced water oxidation activity attributed to the high-spin state of the Fe element. Consequently, the Zn-air battery and anion exchange membrane water electrolyzer assembled by FeNiPt@C NFs catalyst demonstrate remarkable power density (168 mW cm-2 ) and industrial-scale current density (698 mA cm-2 at 1.85 V), respectively. This innovative integration of multifunctional catalytic sites paves the way for the advancement of sustainable energy systems.

XPORT ENTRAP: A droplet microfluidic platform for enhanced DNA transfer between microbial species.

A significant hurdle for the widespread implementation and use of synthetic biology is the challenge of highly efficient introduction of DNA into microorganisms. This is especially a barrier for the utilization of non-model organisms and/or novel chassis species for a variety of applications, ranging from molecular biology to biotechnology and biomanufacturing applications. Common approaches to episomal and chromosomal gene editing, which employ techniques such as chemical competence and electroporation, are typically only amenable to a small subset of microbial species while leaving the vast majority of microorganisms in nature genetically inaccessible. To address this challenge, we have employed the previously described B. subtilis broad-host conjugation strain, XPORT, which was modularly designed for loading DNA cargo and conjugating such DNA into recalcitrant microbes. In this current work, we have leveraged and adapted the XPORT strain for use in a droplet microfluidic platform to enable increased efficiency of conjugation-based DNA transfer. The system named DNA ENTRAP (DNA ENhanced TRAnsfer Platform) utilizes cell-encapsulated water-in-oil emulsion droplets as pico-liter-volume bioreactors that allows controlled contacts between the donor and receiver cells within the emulsion bioreactor. This allowed enhanced XPORT-mediated genetic transfer over the current benchtop XPORT process, demonstrated using two different Bacillus subtilis strains (donor and receiver), as well as increased throughput (e.g., number of successfully conjugated cells) due to the automated assay steps inherent to microfluidic lab-on-a-chip systems. DNA ENTRAP paves the way for a streamlined automation of culturing and XPORT-mediated genetic transfer processes as well as future high-throughput cell engineering and screening applications.

No causal association between atopic dermatitis and COVID-19 outcomes: A Mendelian randomization study.

BACKGROUND: Frequent hand washing and disinfection during the corona virus disease (COVID-19) pandemic may lead to skin-related disability. The causal relationship between atopic dermatitis (AD), the most common chronic, noninfectious, inflammatory skin disease, and COVID-19 remains unclear. We used Mendelian randomization (MR) to explore the causal inference of atopic dermatitis with COVID-19 outcomes. METHODS: Genome-wide association study (GWAS) data for AD, consisting of 8383 cases and 236,162 controls of European ethnicity, were provided by the FinnGen database. The GWAS outcome data were derived from the COVID-19 Host Genetics Initiative and consisted of COVID-19 susceptibility (122,616 cases and 2,475,240 controls), hospitalization (32,519 cases and 2,062,805 controls), and very severe respiratory disease (13,769 cases and 1,072,442 controls). The inverse variance weighted with a fixed effects model (IVW (fe)) was used as the main statistical approach to assess the causality between AD and COVID-19 in this study. Several other analytical methods have also been used to complement or identify pleiotropy and heterogeneity. RESULTS: MR analysis showed no causality between AD and COVID-19 outcomes. The odds ratios (OR) were 1.00 (95% confidence interval (CI), 0.99-1.02) for susceptibility, 1.00 (95% CI, 0.96-1.04) for hospitalization, 0.97 (95% CI, 0.92-1.03) for very severe respiratory disease by the method of IVW (fe). CONCLUSION: In conclusion, we found no causal relationship between AD and COVID-19 outcomes. This study provides additional ideas for the exploration of the risk factors for COVID-19.

Student Loss: Towards the Probability Assumption in Inaccurate Supervision.

Noisy labels are often encountered in datasets, but learning with them is challenging. Although natural discrepancies between clean and mislabeled samples in a noisy category exist, most techniques in this field still gather them indiscriminately, which leads to their performances being partially robust. In this paper, we reveal both empirically and theoretically that the learning robustness can be improved by assuming deep features with the same labels follow a student distribution, resulting in a more intuitive method called student loss. By embedding the student distribution and exploiting the sharpness of its curve, our method is naturally data-selective and can offer extra strength to resist mislabeled samples. This ability makes clean samples aggregate tightly in the center, while mislabeled samples scatter, even if they share the same label. Additionally, we employ the metric learning strategy and develop a large-margin student (LT) loss for better capability. It should be noted that our approach is the first work that adopts the prior probability assumption in feature representation to decrease the contributions of mislabeled samples. This strategy can enhance various losses to join the student loss family, even if they have been robust losses. Experiments demonstrate that our approach is more effective in inaccurate supervision. Enhanced LT losses significantly outperform various state-of-the-art methods in most cases. Even huge improvements of over 50% can be obtained under some conditions.

Integrated ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry-based components analysis and network pharmacology strategy of Gancao Xiexin Decoction in treating gastric ulcer.

Gancao Xiexin Decoction (GCXXD) is a traditional Chinese decoction that is often used in treating gastric ulcers. However, the substance basis and mechanism of action remain unclear. In this study, in vivo and in vitro components of GCXXD were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry. The compound Discover platform was used to ultimately enable rapid identification of compounds. Acquire X intelligent data acquisition technology software was innovatively adopted. In the process of collecting drug-containing plasma, all components detected in blank plasma samples were excluded to eliminate the interference and influence of endogenous components in plasma, making the analysis results more accurate and reliable. At the same time, the possibility of selecting precursor parent ions with low concentration levels within the chromatographic peak can be increased, improving the coverage and integrality of the detection of components in vivo. Also, the targeted network pharmacology strategy combined with molecular docking was established to explore the mechanism of GCXXD in treating gastric ulcers. As a result, 113 components were identified, 41 of which could enter the bloodstream and exert therapeutic effects in vivo. The main effective components are glycyrrhizic acid, 6-gingerol, jatrorrhizine, wogonin, palmatine, and liquiritigenin, main targets in vivo were related to ALB, IL6, and VEGF, which play an important role in anti-inflammatory and promoting angiogenesis. In summary, this study adopted a comprehensive analysis strategy to reveal the pharmacodynamic material basis and mechanism of GCXXD against gastric ulcers, providing a scientific basis for its clinical application.

Severe pneumonia with co-infection of H5N1 and SARS-CoV-2: a case report.

BACKGROUND: The H5N1 influenza virus is a cause of severe pneumonia. Co-infection of influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to poor prognosis of patients during the COVID-19 epidemic. However, reports on patients co-infected with avian influenza virus and SARS-CoV-2 are scarce. CASE PRESENTATION: A 52-year-old woman presented with a fever, which has persisted for the past eight days, along with worsening shortness of breath and decreased blood pressure. Computed tomography (CT) revealed an air bronchogram, lung consolidation, and bilateral pleural effusion. The subsequent polymerase chain reaction (PCR) of the bronchoalveolar lavage fluid (BALF) revealed positivity for H5N1 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). CONCLUSION: The H5N1 influenza virus is a cause of severe pneumonia. The clinical presentation of the patient had a predomination of H5N1 influenza rather than COVID-19. A PCR analysis for the identification of the virus is necessary to reveal the pathogen causing the severe pneumonia. The patient exhibited an excellent prognosis upon the use of the appropriate antiviral medicine.

Amorphous Engineering of Scalable Metal-Organic Framework-Derived Electrocatalyst for Highly Efficient Oxygen Evolution Reaction.

The engineering of amorphous metal-organic frameworks (MOFs) offers potential opportunities for the construction of electrocatalysts for efficient oxygen evolution reaction (OER). Herein, highly efficient OER performance and durability in alkaline electrolyte are discovered for MOF-derived amorphous and porous electrocatalysts, which are synthesized in a brief procedure and can be facilely produced in scalable quantities. The structural inheritance of MOF amorphous catalysts is significant for the retention of catalytic sites and the diffusion of electrolytes, and the presence of Fe sites can change the electronic structure and effectively control the adsorption behavior of important intermediates, accelerating reaction kinetics. The obtained amorphous A-FeNi can be transformed from FeNi-MOF effortlessly and instantly, and it only needs low overpotentials of 152 and 232 mV at 10 and 100 mA cm-2 with a Tafel slope of 17 mV dec-1 in 1 m KOH for OER. Moreover, A-FeNi possesses high corrosion resistance and durability, therefore A-FeNi can work continually for at least 400 h at 100 mA cm-2 . This work may pave a new avenue for the design of MOFs-related amorphous electrocatalyst.

Constructing Nitrogen-Doped Carbon Hierarchy Structure Derived from Metal-Organic Framework as High-Performance ORR Cathode Material for Zn-Air Battery.

The development of efficient and low-cost catalysts for cathodic oxygen reduction reaction (ORR) in Zn-air battery (ZAB) is a key factor in reducing costs and achieving industrialization. Here, a novel segregated CoNiPt alloy embedded in N-doped porous carbon with a nanoflowers (NFs)-like hierarchy structure is synthesized through pyrolyzing Hofmann-type metal-organic frameworks (MOFs). The unique hierarchical NFs structure exposes more active sites and facilitates the transportation of reaction intermediates, thus accelerating the reaction kinetics. Impressively, the resulting 15% CoNiPt@C NFs catalyst exhibits outstanding alkaline ORR activity with a half-wave potential of 0.93 V, and its mass activity is 7.5 times higher than that of commercial Pt/C catalyst, surpassing state-of-the-art noble metal-based catalysts. Furthermore, the assembled CoNiPt@C+RuO2 ZAB demonstrates a maximum power density of 172 mW cm-2 , which is superior to that of commercial Pt/C+RuO2 ZAB. Experimental results reveal that the intrinsic ORR mass activity is attributed to the synergistic interaction between oxygen defects and pyrrolic/graphitic N species, which optimizes the adsorption energy of the intermediate species in the ORR process and greatly enhances catalytic activity. This work provides a practical and feasible strategy for synthesizing cost-effective alkaline ORR catalysts by optimizing the electronic structure of MOF-derived catalysts.

Gabapentinoids for the treatment of stroke.

ABSTRACT: Gabapentinoid drugs (pregabalin and gabapentin) have been successfully used in the treatment of neuropathic pain and in focal seizure prevention. Recent research has demonstrated their potent activities in modulating neurotransmitter release in neuronal tissue, oxidative stress, and inflammation, which matches the mechanism of action via voltage-gated calcium channels. In this review, we briefly elaborate on the medicinal history and ligand-binding sites of gabapentinoids. We systematically summarize the preclinical and clinical research on gabapentinoids in stroke, including ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, seizures after stroke, cortical spreading depolarization after stroke, pain after stroke, and nerve regeneration after stroke. This review also discusses the potential targets of gabapentinoids in stroke; however, the existing results are still uncertain regarding the effect of gabapentinoids on stroke and related diseases. Further preclinical and clinical trials are needed to test the therapeutic potential of gabapentinoids in stroke. Therefore, gabapentinoids have both opportunities and challenges in the treatment of stroke.

Cardiovascular Safety Evaluation of Febuxostat and Allopurinol: Findings from the FDA Adverse Event Reporting System.

BACKGROUND: Febuxostat and allopurinol are the most commonly used uric acid-lowering medications, and their safety is of great concern, especially the cardiovascular adverse reactions associated with febuxostat. We propose to study the cardiovascular toxicity of febuxostat and allopurinol using the FDA Adverse Event Reporting System (FAERS) database. METHODS: A total of 64 quarters of FAERS data were downloaded from 2004 to 2019. Febuxostat- and allopurinol-related cardiovascular adverse events were extracted after data cleaning. Signal detection was conducted by reporting odds ratio (ROR) and proportional reporting ratio (PRR). RESULTS: There were 2939 and 25,219 reports of febuxostat- and allopurinol-related cardiovascular adverse events (CVAEs), respectively. The most frequent CVAEs with febuxostat and allopurinol were edema peripheral (14.38%) and peripheral swelling (8.76%), respectively. In elderly gout patients, febuxostat is associated with an increased risk of heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Febuxostat in combination with acetic acid derivatives nonsteroidal anti-inflammatory drug (NSAIDS) also increases the risk of cardiovascular adverse events. CONCLUSIONS: Compared with allopurinol, febuxostat may increase cardiovascular toxicity in patients with gout.

An integrated approach based on ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, network pharmacology, and molecular docking to study the key effective compounds and mechanism of action of Platycodi Radix in the treatment of chronic obstructive pulmonary disease.

Platycodi Radix (PR) is a valuable herb that is widely used in the treatment of chronic obstructive pulmonary disease in clinics. However, the mechanism of action for the treatment of chronic obstructive pulmonary disease remains unclear due to the lack of in vivo studies. Our study established a novel integrated strategy based on ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry, network pharmacology, and molecular docking to systematically analyze the tissue distribution and active compounds of PR in vivo and the therapeutic mechanism of chronic obstructive pulmonary disease. First, tissue distribution studies have shown that the lung is the organ with the highest distribution of PR compounds. Subsequently, network pharmacology results showed that the tumor necrosis factor signaling pathway, interleukin-17 signaling pathway, and mitogen-activated protein kinase signaling pathway were the critical mechanisms of PR against chronic obstructive pulmonary disease. Ultimately, molecular docking results showed that the key targets were stably bound to the corresponding active compounds of PR. Our study is of great significance for the screening of the key effective compounds and the study of the mechanism of action in traditional Chinese medicine and provides data to support the further development and utilization of PR.

METTL14 reverses liver fibrosis by inhibiting NOVA2 through an m6A-YTHDF2-dependent mechanism.

BACKGROUND: N6-methyladenosine (m6A), the most prevalent internal RNA modification in eukaryotic cells, is dynamically regulated in response to a wide range of physiological and pathological states. Nonetheless, the involvement of METTL14-induced m6A in liver fibrosis (LF) has yet to be established. METHODS: In vitro, HSC cell lines with knock-down and overexpression of METTL14 were constructed, and the effects of METTL14 gene on the phenotypic function of activated HSCs were observed. The proliferation rate was measured by CCK8 and EDU, the cell proliferation cycle was measured by flow detector, the migration rate was measured by Transwell, and the contractility of F-actin was observed after phalloidin staining. The downstream target gene NOVA2 of METTL14 was screened by combined sequencing of MeRIP-seq and RNA-seq, combined with signal analysis. Adeno-associated virus (AAV) was injected into the tail vein in vivo to knock down the expression of METTL14, so as to further observe the role of METTL14 in the progress of LF. RESULTS: our research showed that the methylase METTL14 content was decreased in hepatic tissue from patients with LF, leading to a lowered degree of m6A modification. Functionally, we discovered that knocking down m6A methyltransferase METTL14 led to increased HSC activation and a substantial worsening of LF. Mechanically, as shown in a multiomics study of HSCs, depleting METTL14 levels decreased m6A deposition onNOVA2 mRNA transcripts, which prompted the activation of YTHDF2 to detect and degrade the decrease of NOVA2 mRNA. CONCLUSIONS: METTL14 functioned as a profibrotic gene by suppressing NOVA2 activity in a mechanism dependent on m6A-YTHDF2. Moreover, knocking down METTL14 exacerbated LF, while NOVA2 prevented its development and partly reversed the damage.