Application of association rules and simulated annealing algorithms in optimizing traditional Chinese medicine placement schemes.

BACKGROUND AND AIM: China has used traditional Chinese medicine (TCM) to treat diseases for more than 2000 years. Traditionally, TCMs in medicine cabinets are arranged alphabetically or on the basis of experience, but this arrangement greatly affects dispensing efficiency. However, owing to the unique properties and qualities of TCM, very few automatic approaches or systems have specifically addressed TCM dispensing problems. Therefore, it is necessary to establish a method of optimizing the traditional Chinese medicine placement scheme (TCMPS) via computer algorithms to improve the work efficiency of pharmacists. METHODS: A prescription dataset from a hospital in 2022 was obtained, and the association rule algorithm (ARA) was used to calculate the frequency of use for each type of TCM and the associations between different types of TCMs. On the basis of these association and frequency data, the optimal TCMPS was calculated using the simulated annealing algorithm (SAA) and then verified using the prescription dataset from 2023. RESULTS: A total of 10,601 prescriptions were collected in 2022, involving 360 different TCMs, and each prescription contained an average of 9.485 TCMs, with Danggui (3628) being the most frequently used. When the threshold of support was set to 0.05 and the confidence was set to 0.8, 78 couplet medicines used in orthopedics clinics were found through ARA. When the threshold value of support was set to 0, the confidence was set to 0, and the rule length was 2, a total of 129,240 rules were obtained, indicating support between all pairwise TCMs. The TCMPS, calculated using SAA, had a correlation sum of 14.183 and a distance sum of 3.292. The TCMPS was verified using a prescription dataset from 2023 and theoretically improved the dispensing efficiency of pharmacists by approximately 50%. CONCLUSIONS: In this study, the ARA and SAA were successfully applied to pharmacies for the first time, and the optimal TCMPS was calculated. This approach not only significantly improves the dispensing efficiency of pharmacists and reduces patient waiting time but also enhances the quality of medical services and patient satisfaction, and provides a valuable reference for the development of smart medicine.

Evaluation and mechanistic analysis of the effect of the addition of alkaline earth metal CaO on Cd solidification enhancement in lightweight aggregate preparation.

The volatilization of Cd during the preparation of lightweight aggregates (LWAs) can cause serious damage to the environment, so a method to harmlessly transform Cd during this process is required. In this regard, the alkaline earth metal CaO was added to Cd-containing aggregate raw materials for treatment, and the effect of CaO addition on the properties of LWAs in the presence of chlorine and sulfate was investigated. Kinetic models of the Cd volatilization were established by using the Arrhenius equation to predict the volatilization of Cd at different sintering stages. The results showed that 0.8% wt of CaO under the influence of chlorine can reduce the Cd volatilization rate from 84.9% to 12.64%, corresponding to an increase in the reaction activation energy (E a) from 22.62 to 49.55 kJ mol-1. Additionally, the Cd volatilization rate under the influence of sulfate was reduced from 30% to 8%, with an increase in the E a from 33.25 to 42.62 kJ mol-1. The activation energy increase suggests that the addition of CaO is beneficial because it increases the energy required for Cd volatilization. According to the Cd leaching experiments conducted on the LWAs, it was found that the solidification ratio of Cd was higher than 99.9% for all samples after the addition of CaO. The addition of CaO promotes the formation of CdFe2O4 and anorthite for effective solidification of Cd, thus optimizing the structures of the LWAs. This work may provide a new idea for Cd waste recycling.

Association between antipsychotics and pulmonary embolism: a pharmacovigilance analysis.

BACKGROUND: Previous studies have documented an increased risk of pulmonary embolism (PE) in patients with schizophrenia taking antipsychotics (APs). However, specific data from real-world studies remain limited. This study aims to investigate the potential relationship between APs and PE. RESEARCH DESIGN AND METHODS: In the Food and Drug Administration Adverse Event Reporting System (FAERS), from the first quarter of 2018 to the first quarter of 2023, all PE cases suspected of being induced by APs were collected for disproportionality analysis, and the reporting odds ratio (ROR) was used to evaluate associations. Mortality, life-threatening events, and hospitalizations were also analyzed for each APs. RESULTS: A total of 1,676 cases of PE related to APs were included. APs were significantly associated with PE (ROR 2.00, 1.91-2.10), including chlorpromazine (n = 41), haloperidol (n = 164), loxapine (n = 37), olanzapine (n = 461), paliperidone (n = 161), quetiapine (n = 526), risperidone (n = 274), aripiprazole (n = 254), and clozapine (n = 234). The median onset time of PE was 29 days. Among all cases, 347 (20.7%) resulted in death, with haloperidol (53.2%) having a higher mortality rate than other APs. CONCLUSIONS: APs may increase the risk of PE in patients with schizophrenia.

Oleanolic acid induces hepatic injury by disrupting hepatocyte tight junction and dysregulation of farnesoid X receptor-mediated bile acid efflux transporters.

Oleanolic acid (OA) is a naturally occurring pentacyclic triterpene compound that has been reported to cause cholestatic liver injury. However, the regulation and pathogenic role of bile acids in OA-induced development of cholestatic liver injury remains largely unclear. Farnesoid X receptor (FXR) is a metabolic nuclear receptor that plays an important role in bile acid homeostasis in the liver by regulating efflux transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2). The aim of this study was to investigate the effect of OA on hepatocyte tight junction function and determine the role of FXR, BSEP, and MRP2 in the mechanism of impairment of transport of bile acids induced by OA. Both in vivo and in vitro models were used to characterize the OA-induced liver injury. The liquid chromatography-tandem mass spectrometry (LC-MS) was employed to characterize the efflux function of the transporters, and the results showed that OA caused a blockage of bile acids efflux. OA treatment resulted in decreased expression levels of the tight junction proteins zonula occludens-1 and occludin. Immunofluorescence results showed that OA treatment significantly reduced the number of bile ducts and the immunofluorescence intensity. Pretreatment with agonists of FXR and MRP2, respectively, in animal experiments attenuated OA-induced liver injury, while pretreatment with inhibitors of BSEP and MRP2 further aggravated OA-induced liver injury. These results suggest that OA inhibits FXR-mediated BSEP and MRP2, leading to impaired bile acid efflux and disruption of tight junctions between liver cells, resulting in liver damage.

Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury.

Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.

Therapeutic potential of ADSC-EV-derived lncRNA DLEU2: A novel molecular pathway in alleviating sepsis-induced lung injury via the miR-106a-5p/LXN axis.

This study investigates the molecular mechanisms by which extracellular vesicles (EVs) derived from adipose-derived mesenchymal stem cells (ADSCs) promote M2 polarization of macrophages and thus reduce lung injury caused by sepsis. High-throughput sequencing was used to identify differentially expressed genes related to long non-coding RNA (lncRNA) in ADSC-derived EVs (ADSC-EVs) in sepsis lung tissue. Weighted gene co-expression network analysis (WGCNA) was employed to predict the downstream target genes of the lncRNA DLEU2. The RNAInter database predicted miRNAs that interact with DLEU2 and LXN. Functional and pathway enrichment analyses were performed using GO and KEGG analysis. A mouse model of sepsis was established, and treatment with a placebo or ADSC-EVs was administered, followed by RT-qPCR analysis. ADSC-EVs were isolated and identified. In vitro cell experiments were conducted using the mouse lung epithelial cell line MLE-12, mouse macrophage cell line RAW264.7, and mouse lung epithelial cell line (LEPC). ADSC-EVs were co-cultured with RAW264.7 and MLE-12/LEPC cells to study the regulatory mechanism of the lncRNA DLEU2. Cell viability, proliferation, and apoptosis of lung injury cells were assessed using CCK-8, EdU, and flow cytometry. ELISA was used to measure the levels of inflammatory cytokines in the sepsis mouse model, flow cytometry was performed to determine the number of M1 and M2 macrophages, lung tissue pathology was evaluated by H&E staining, and immunohistochemistry was conducted to examine the expression of proliferation- and apoptosis-related proteins. High-throughput sequencing and bioinformatics analysis revealed enrichment of the lncRNA DLEU2 in ADSC-EVs in sepsis lung tissue. Animal and in vitro cell experiments showed increased expression of the lncRNA DLEU2 in sepsis lung tissue after treatment with ADSC-EVs. Furthermore, ADSC-EVs were found to transfer the lncRNA DLEU2 to macrophages, promoting M2 polarization, reducing inflammation response in lung injury cells, and enhancing their viability, proliferation, and apoptosis inhibition. Further functional experiments indicated that lncRNA DLEU2 promotes M2 polarization of macrophages by regulating miR-106a-5p/LXN, thereby enhancing the viability and proliferation of lung injury cells and inhibiting apoptosis. Overexpression of miR-106a-5p could reverse the biological effects of ADSC-EVs-DLEU2 on MLE-12 and LEPC in vitro cell models. Lastly, in vivo animal experiments confirmed that ADSC-EVs-DLEU2 promotes high expression of LXN by inhibiting the expression of miR-106a-5p, further facilitating M2 macrophage polarization and reducing lung edema, thus alleviating sepsis-induced lung injury. lncRNA DLEU2 in ADSC-EVs may promote M2 polarization of macrophages and enhance the viability and proliferation of lung injury cells while inhibiting inflammation and apoptosis reactions, thus ameliorating sepsis-induced lung injury in a mechanism involving the regulation of the miR-106a-5p/LXN axis.

Extracellular Vesicles Derived from Human Adipose-Derived Mesenchymal Stem Cells Alleviate Sepsis-Induced Acute Lung Injury through a MicroRNA-150-5p-Dependent Mechanism.

Extracellular vesicles (EVs) derived from human adipose mesenchymal stem cells (hADSCs) may exert a therapeutic benefit in alleviating sepsis-induced organ dysfunction by delivering cargos that include RNAs and proteins to target cells. The current study aims to explore the protective effect of miR-150-5p delivered by hADSC-EVs on sepsis-induced acute lung injury (ALI). We noted low expression of miR-150-5p in plasma and bronchoalveolar lavage fluid samples from patients with sepsis-induced ALI. The hADSC-EVs were isolated and subsequently cocultured with macrophages. It was established that hADSC-EVs transferred miR-150-5p to macrophages, where miR-150-5p targeted HMGA2 to inhibit its expression and, consequently, inactivated the MAPK pathway. This effect contributed to the promotion of M2 polarization of macrophages and the inhibition of proinflammatory cytokines. Further, mice were made septic by cecal ligation and puncture in vivo and treated with hADSC-EVs to elucidate the effect of hADSC-EVs on sepsis-induced ALI. The in vivo experimental results confirmed a suppressive role of hADSC-EVs in sepsis-induced ALI. Our findings suggest that hADSC-EV-mediated transfer of miR-150-5p may be a novel mechanism underlying the paracrine effects of hADSC-EVs on the M2 polarization of macrophages in sepsis-induced ALI.

Characterizing environmental pollution with civil complaints and social media data: A case of the Greater Taipei Area.

Environmental pollution is a major cause of nuisance and ill health among urban residents. Complaints are traditionally self-reported through phone-based systems. Social media provide novel channels to detect pollution-related incidents; however, their reliability has not been sufficiently evaluated. This study aimed to compare pollution incidents expressed on Twitter with those extracted from phone-based systems and to identify the built environment and socioeconomic attributes that can predict the likelihood of pollution incidents. A total of 639,746 tweets were retrieved from the Greater Taipei Area in 2017 and 110,716 self-reported pollution incidents were extracted from the Public Nuisance Petition system during the same period. The results suggest that complaints collected from phone-based systems and Twitter were found to have correlated with each other spatially, albeit they differ in temporal profiles and by the proportion of pollution categories. Catering businesses and the entertainment activities they attract appear to be the main sources of pollution complaints and can be precisely captured by geotagged tweets. This can serve as a strong predictor for pollution incidents, more than traditional indicators such as population density or industrial activities, as suggested by earlier studies. Social media analytics, with their ability to monitor and analyze online discussions in a timely manner, can be a valuable supplement to existing phone-based pollution monitoring procedures. The methodologies developed in this study have the potential to support the proactive management of urban environmental pollution, in which resources can be prioritized in key areas to further enhance the quality of urban services.

circSSPO boosts growth of esophageal squamous cell carcinoma through upregulation of micrRNA-6820-5p-mediated KLK8 and PKD1 expression.

Investigation on a competitive endogenous RNA (ceRNA) network attracted lots of attention due its function in cancer regulation. Here, we probed into the possible molecular mechanism of circSSPO/microRNA-6820-5p (miR-6820-5p)/kallikrein-related peptidase 8 (KLK8)/PKD1 network in the esophageal squamous cell carcinoma (ESCC). Following whole-transcriptome sequencing and differential analysis in collected ESCC tissue samples, circRNA-miRNA-mRNA regulatory network affecting ESCC was investigated. After interaction measurement among circSSPO/miR-6820-5p/KLK8/PKD1, their regulatory roles in ESCC cell functions in vitro and xenograft tumor growth and lung metastasis in vivo were analyzed. The bioinformatics prediction and sequencing results screened that circSSPO, miR-6820-5p, KLK8, and PKD1 were associated with ESCC development. In ESCC, miR-6820-5p was expressed at very low levels, while circSSPO, KLK8, and PKD1 were highly expressed. In vitro cell experiments further proved that circSSPO competitively inhibited miR-6820-5p to induce ESCC cell malignant properties. Moreover, knockdown of KLK8 or PKD1 inhibited ESCC cell malignant properties. circSSPO also promoted the tumorigenic and metastasis of ESCC through the upregulation of KLK8 and PKD1 expression in vivo. We found that circSSPO was an oncogenic circRNA that was significantly abundant in ESCC tissues and circSSPO exhibited an oncogenic activity in ESCC by elevating expression of KLK8 and PKD1 through suppressing miR-6820-5p expression.

Immobilization enhancement of heavy metals in lightweight aggregate by component regulation of multi-source solid waste.

Integrated recycling of solid waste containing heavy metals is a critical environmental challenge. In this study, a green solution to reduce heavy metal leaching from solid waste is demonstrated by combining contaminated soil, industrial sludge and lithium slag in pairs to produce lightweight aggregates (LWAs). The physical properties and heavy metal leaching behavior of LWA samples were systematically investigated and characterized. The results showed that industrial sludge reduced the density and water absorption of LWA, while the high content of lithium slag was detrimental to the physical properties. LWA containing 80% contaminated soil and 20% lithium slag had the lowest particle density of 1.47 g/cm3 due to the hollow structure caused by the low viscosity and violent generation of SO2. LWAs with lithium slag leached excessive Cu and Cr relatively, while heavy metals were immobilized well in LWAs with contaminated soil and industrial sludge as the main components. Because the flux components of industrial sludge could enhance the encapsulation of heavy metals by glass phase. In addition, the co-immobilization of multiple heavy metals was observed in the spinel phase. This study provides an efficient and safe method for the synergistic recycling of solid waste.

Contributions of residential traffic noise to depression and mental wellbeing in Hong Kong: A prospective cohort study.

Prior studies on the association between traffic noise and mental health have been mostly conducted in settings with lower population densities. However, evidence is lacking in high population-density settings where traffic noise is more pervasive and varies by topography and the vertical elevation of the residential unit. This study aimed to assess the mental health impact of residential traffic noise in one of the world's most urbanised populations. Data were analysed from 13,401 participants aged ≥15 years in a prospective cohort in Hong Kong from 2009 to 2014. Residential traffic noise level was estimated using 3D-geocoding and validated models that accounted for sound propagation in a highly vertical landscape. The 24-h day-night exposure to traffic noise, denoted as Ldn, was estimated with a 10-dB(A) penalty for night hours. Probable depression and mental wellbeing were assessed using the Patient Health Questionnaire-9 and the Short Form Health Questionnaire SF-12v2, respectively. Mixed effect regressions with random intercepts were used to examine the association between traffic noise and mental health outcomes. Residential road traffic noise (for each increment of 10 A-weighted decibels [dB(A)] 24-h average exposure) was associated with probable depression (odds ratio (OR) = 1.17, 95% CI: 1.05, 1.31), and poorer mental wellbeing (mean difference = -0.19, 95% CI: 0.31, -0.06), adjusting for sociodemographics, smoking, body mass index, self-reported health, proximity to green space, and neighbourhood characteristics (average household income, population density, and Gini coefficient). The results were robust to further adjustment for air pollution. In stratified analyses, residential traffic noise was associated with probable depression and poorer mental wellbeing among students and individuals aged 15-34 years. Residential traffic noise was associated with probable depression and poorer mental wellbeing in a highly urbanised setting. As traffic noise is increasing in urban settings, the public health impact of noise pollution could be substantial.

miR-214 could promote myocardial fibrosis and cardiac mesenchymal transition in VMC mice through regulation of the p53 or PTEN-PI3K-Akt signali pathway, promoting CF proliferation and inhibiting its ng pathway.

INTRODUCTION: This study aimed to investigate the role of miR-214 in the bidirectional regulation of p53 and PTEN and its influence on myocardial fibrosis and cardiac mesenchymal transformation in mice with viral myocarditis (VMC). METHODS: The study established a VMC model in BALB/c mice by injecting them with the CVB3 virus intraperitoneally. Techniques such as ELISA, H&E staining, Masson staining, immunohistochemical staining, RT-qPCR, western blot, and dual-luciferase reporter gene assay were used to detect the expression levels of relevant factors in tissues and cells. Isolation and culture of cardiac fibroblasts (CFs) were also conducted. RESULTS: The study found that miR-214 bidirectional regulation of p53 and PTEN promotes myocardial fibrosis and cardiac mesenchymal transformation in mice with VMC. The expression levels of collagen-related peptides, inflammatory-related factors, miR-214, mesenchymal transformation-related factors, and fibrosis-related factors were significantly increased, while the expression levels of p53, PTEN, and epithelial/endothelial cell phenotype marker factors were significantly decreased. Downregulation of miR-214 or upregulation of p53 and PTEN expression inhibited inflammatory cell and fibroblast infiltration in VMC mouse myocardial tissue. It reduced the proliferation ability while increasing the apoptosis of cardiac fibroblasts. CONCLUSION: miR-214 plays a significant role in the bidirectional inhibition of p53 and PTEN, which leads to myocardial fibrosis and cardiac mesenchymal transformation in mice with VMC. Downregulation of miR-214 or upregulation of p53 and PTEN expression may provide potential therapeutic targets for treating VMC-induced cardiac fibrosis and mesenchymal transformation.

Study on Photochemical Properties of a Sr-SnS2/CaIn2S4 Heterostructure to Improve Cr(VI) Removal.

Compound semiconductor photocatalysis technology is considered to be a promising treatment for solving water problems efficiently. The point of designing high-efficiency catalysts is to optimize the band gap structure and facilitate the separation of charge carriers by establishing new electron migration pathways. Recently, 3D porous CaIn2S4 was found to have good photocatalytic ability. However, the quick recombination and agglomeration of carriers still limit its application. Herein, we prepared a heterostructure by introducing 2D Sr-doped SnS2 to 3D CaIn2S4 by a hydrothermal synthesis method. The optimal dosage of Sr-SnS2 is 3%, and the photocatalytic Cr(VI) removal efficiency of 3% Sr-SnS2/CaIn2S4 (SSCS-3) is 5.82 and 10.83 times those of pure CaIn2S4 and SnS2, respectively. According to the results of characterization tests and calculation verification, we inferred that the enhanced photocatalytic removal of Cr(VI) is due to the introduction of Sr-SnS2 that can promote the rapid transfer of photogenerated electrons to the surface of CaIn2S4, and the heterostructure formed between 2D Sr-SnS2 and 3D CaIn2S4 can also provide abundant reaction sites. The promotion of carrier separation is mainly due to the formation of a built-in electric field of the Sr-SnS2/CaIn2S4 heterostructure. This work provides new ideas and technologies for the treatment of Cr(VI) in wastewater.

Monocyte-derived exosomal XIST exacerbates acute lung injury by regulating the miR-448-5p/HMGB2 axis.

Monocyte-derived exosomes (Exos) have been implicated in inflammation-related autoimmune/inflammatory diseases via transferring bioactive cargoes to recipient cells. The purpose of this study was to investigate the possible effect of monocyte-derived Exos on the initiation and the development of acute lung injury (ALI) by delivering long non-coding RNA XIST. Key factors and regulatory mechanisms in ALI were predicted by bioinformatics methods. BALB/c mice were treated with lipopolysaccharide (LPS) to establish an ALI in vivo model and then injected with Exos isolated from monocytes transduced with sh-XIST to evaluate the effect of monocyte-derived exosomal XIST on ALI. HBE1 cells were co-cultured with Exos isolated from monocytes transduced with sh-XIST for further exploration of its effect. Luciferase reporter, RIP and RNA pull-down assays were performed to verify the interaction between miR-448-5p and XIST, miR-448-5p and HMGB2. miR-448-5p was significantly poorly expressed while XIST and HMGB2 were highly expressed in the LPS-induced mouse model of ALI. Monocyte-derived Exos transferred XIST into HBE1 cells where XIST competitively inhibited miR-448-5p and reduced the binding of miR-448-5p to HMGB2, thus upregulating the expression of HMGB2. Furthermore, in vivo data revealed that XIST delivered by monocyte-derived Exos downregulated miR-448-5p expression and up-regulated HMGB2 expression, ultimately contributing to ALI in mice. Overall, our results indicate that XIST delivered by monocyte-derived Exos aggravates ALI via regulating the miR-448-5p/HMGB2 signaling axis.

Direct Visualization of the Dynamic Process of Epsilon Toxin on Hemolysis.

Hemolysis is the process of rupturing erythrocytes (red blood cells) by forming nanopores on their membranes using hemolysins, which then impede membrane permeability. However, the self-assembly process before the state of transmembrane pores and underlying mechanisms of conformational change are not fully understood. In this work, theoretical and experimental evidence of the pre-pore morphology of Clostridium perfringens epsilon toxin (ETX), a typical hemolysin, is provided using in situ atomic force microscopy (AFM) complemented by molecular dynamics (MD) simulations to detect the conformational distribution of different states in Mica. The AFM suggests that the ETX pore is formed in two stages: ETX monomers first attach to the membrane and form a pre-pore in no special conditions required, which then undergo a conformational change to form a transmembrane pore at temperatures above the critical point in the presence of receptors. The authors' MD simulations reveal that initial nucleation occurs when specific amino acids adsorb to negatively charged mica cavities. This work fills the knowledge gap in understanding the early stage of hemolysis and the oligomerization of hemolysins. Moreover, the newly identified pre-pore of ETX holds promise as a candidate for nanopore applications.

Influence of Core Topologies on Poly-l-lysine Dendrimer Structures.

Poly-l-lysine (PLL) dendrimers have emerged as promising nanomaterials for gene/drug delivery, bioimaging, and biosensing due to their high efficacy and biocompatibility. In our previous works, we successfully synthesized two categories of PLL dendrimers with two different cores: the planar-shaped perylenediimide and the cubic-shaped polyhedral oligomeric silsesquioxanes. However, the effect of these two topologies on the PLL dendrimer structures is not clearly understood. In this work, we carried out in-depth investigations on the influence of core topologies on the PLL dendrimer structures using molecular dynamics simulations. We show that, even at high generations, the core topology affects the shape and branch distribution of the PLL dendrimer, which may further determine their performance. Moreover, our findings suggest that the core topology on the PLL dendrimer structures can be further designed and improved to fully exploit and utilize their potential in biomedical applications.

Suppression of SIRT1/FXR signaling pathway contributes to oleanolic acid-induced liver injury.

Oleanolic acid (OA) is a pentacyclic triterpenoid compound used clinically for acute and chronic hepatitis. However, high dose or long-term use of OA causes hepatotoxicity, which limits its clinical application. Hepatic Sirtuin (SIRT1) participates in the regulation of FXR signaling and maintains hepatic metabolic homeostasis. This study was designed to determine whether SIRT1/FXR signaling pathway contributes to the hepatotoxicity caused by OA. C57BL/6J mice were administered with OA for 4 consecutive days to induce hepatotoxicity. The results showed that OA suppressed the expression of FXR and its downstream targets CYP7A1, CYP8B1, BSEP and MRP2 at both mRNA and protein levels, breaking the homeostasis of bile acid leading to hepatotoxicity. However, treatment with FXR agonist GW4064 noticeably attenuated hepatotoxicity caused by OA. Furthermore, it was found that OA inhibited protein expression of SIRT1. Activation of SIRT1 by its agonist SRT1720 significantly improved OA-induced hepatotoxicity. Meanwhile, SRT1720 significantly reduced the inhibition of protein expression of FXR and FXR-downstream proteins. These results suggested that OA may cause hepatotoxicity through SIRT1 dependent suppression of FXR signaling pathway. In vitro experiments confirmed that OA suppressed protein expressions of FXR and its targets through inhibition of SIRT1. It was further revealed that silencing of HNF1α with siRNA significantly weakened regulatory effects of SIRT1 on the expression of FXR as well as its target genes. In conclusion, our study reveals that SIRT1/FXR pathway is crucial in OA-induced hepatotoxicity. Activation of SIRT1/HNF1α/FXR axis may represent a novel therapeutic target for ameliorating OA and other herb-induced hepatotoxicity.

Novel Inhibitory Role of Fenofibric Acid by Targeting Cryptic Site on the RBD of SARS-CoV-2.

The emergence of the recent pandemic causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an alarming situation worldwide. It also prompted extensive research on drug repurposing to find a potential treatment for SARS-CoV-2 infection. An active metabolite of the hyperlipidemic drug fenofibrate (also called fenofibric acid or FA) was found to destabilize the receptor-binding domain (RBD) of the viral spike protein and therefore inhibit its binding to human angiotensin-converting enzyme 2 (hACE2) receptor. Despite being considered as a potential drug candidate for SARS-CoV-2, FA's inhibitory mechanism remains to be elucidated. We used molecular dynamics (MD) simulations to investigate the binding of FA to the RBD of the SARS-CoV-2 spike protein and revealed a potential cryptic FA binding site. Free energy calculations were performed for different FA-bound RBD complexes. The results suggest that the interaction of FA with the cryptic binding site of RBD alters the conformation of the binding loop of RBD and effectively reduces its binding affinity towards ACE2. Our study provides new insights for the design of SARS-CoV-2 inhibitors targeting cryptic sites on the RBD of SARS-CoV-2.

AMP-activated protein kinase-farnesoid X receptor pathway contributes to oleanolic acid-induced liver injury.

Natural pentacyclic triterpenoid oleanolic acid (OA) is used as an over-the-counter drug for acute and chronic hepatitis. However, clinical use of OA-containing herbal medicines has been reported to cause cholestasis, and the specific mechanism is unknown. The purpose of this study was to explore how OA causes cholestatic liver injury via the AMP-activated protein kinase (AMPK)-farnesoid X receptor (FXR) pathway. In animal experiments, it was found that OA treatment activated AMPK and decreased FXR and bile acid efflux transport proteins expression. When intervened with the specific inhibitor Compound C (CC), it was observed that AMPK activation was inhibited, the reduction of FXR and bile acid efflux transport protein expression was effectively alleviated, serum biochemical indicators were significantly reduced, and liver pathological damage brought about by OA was effectively ameliorated. In addition, OA was found to downregulate the expression of FXR and bile acid efflux transport proteins by activating the ERK1/2-LKB1-AMPK pathway in cellular experiments. The ERK1/2 inhibitor U0126 was used to pretreat primary hepatocytes, and this drastically reduced the phosphorylation levels of LKB1 and AMPK. The inhibition effects of OA on FXR and bile acid efflux transport proteins were also effectively alleviated after pretreatment with CC. In addition, OA-induced downregulation of FXR gene and protein expression levels was significantly prevented after silencing AMPKα1 expression in AML12 cells. Our study demonstrated that OA inhibited FXR and bile acid efflux transporters through the activation of AMPK, thus leading to cholestatic liver injury.

Immune checkpoint inhibitors increase the risk of kidney transplant rejection: a real-world pharmacovigilance study.

BACKGROUND: Kidney transplant recipients with cancer are at higher risk of kidney transplant rejection (KTR), and the safety of immune checkpoint inhibitors (ICIs) is unclear. The present study investigates the relationship between ICIs and KTR using data from the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: Case reports of KTR inducted by ICIs in FAERS from 1 January 2011, to 30 June 2021, were collected, and a disproportionate analysis was performed to assess the correlation between ICIs and KTR. RESULTS: A total of 99 cases of ICI-related KTR were reported in the FAERS database. Most of them were male patients (n = 63, 84.0%), and more than half of patients suffered from malignant melanoma (n = 46, 52.9%). The median onset time after the medication was 22 days, the withdrawal rates of ICIs were 78.0%, and the overall death rate was 29.3%. In general, there was a significant relevance between ICIs and KTR (ROR = 3.92[3.21-4.79] IC025 = 1.56), of which PD-1 was the most prominent (n = 81 ROR = 5.26[4.22-6.57] IC025 = 1.86). CONCLUSIONS: ICIs may increase the risk of KTR in organ transplant recipients with cancer.