A real-world study of antifibrotic drugs-related adverse events based on the United States food and drug administration adverse event reporting system and VigiAccess databases.

Objectives: This study aims to investigate adverse events (AEs) and adverse drug reactions (ADRs) associated with pirfenidone and nintedanib, two antifibrotic drugs used to treat idiopathic pulmonary fibrosis (IPF). Methods: Reporting odds ratio (ROR) and proportional reporting ratio (PRR) analyses were conducted to assess the association between these drugs and signals at both the preferred term (PT) and system organ class (SOC) levels. Results: 55,949 reports for pirfenidone and 35,884 reports for nintedanib were obtained from the FAERS database. The VigiAccess database provided 37,187 reports for pirfenidone and 23,134 reports for nintedanib. Male patients and individuals over the age of 65 were more likely to report AEs. Gastrointestinal disorders emerged as the most significant signal at SOC level for both drugs. Furthermore, nausea, diarrhoea, and decreased appetite were observed at the PT level. We further identified notable signals, including hemiplegic migraine for pirfenidone and asthenia, constipation, and flatulence for nintedanib, which were previously unknown or underestimated ADRs. Conclusion: This study has identified AEs and ADRs associated with pirfenidone and nintedanib, confirming that the majority of the corresponding label information indicates relative safety. However, it is essential to take unexpected risk signals seriously, necessitating further research to manage the safety profiles of these drugs.

Investigating the causal effects of smoking, sleep, and BMI on major depressive disorder and bipolar disorder: a univariable and multivariable two-sample Mendelian randomization study.

Background: Mental disorders, characterized as products of biopsychosocial interactions, have emerged as a leading contributor to the worldwide rise in overall morbidity and disability rates. Life's essentials can affect nearly every aspect of our lives, from physical to mental health. In this study, we try to identify the associations between life's essentials and mental disorders. Method: Three assumptions of Mendelian randomization (MR) were applied to obtain the genetic instruments associated with smoking, sleep, and body mass index (BMI) in genome-wide association studies. Then, we conducted univariable MR (UVMR) and multivariable MR (MVMR) two-sample analyses to estimate the causal effects of these life's essentials on two mental disorders namely, major depressive disorder (MDD) and bipolar disorder (BD). Additionally, multiple sensitivity analyses were performed to evaluate the reliability and stability of the study results. Results: In the MR analysis of the association of smoking, sleep, and BMI with MDD, we obtained 78, 39, and 302 genetic instruments, respectively. Smoking [odds ratio (OR), 1.03; 95% confidence interval (CI), 1.01-1.06; p = 0.004], sleep (OR, 1.04; 95% CI, 1.02-1.06; p < 0.001), and BMI (OR, 1.01; 95% CI, 1.01-1.02; p < 0.001) were all considered as risk factors for MDD and were independent of each other (smoking: OR, 1.03, 95% CI, 1.01-1.06, p = 0.008; sleep: OR, 1.03, 95% CI, 1.01-1.05, p = 0.001; and BMI: OR, 1.01, 95% CI, 1.01-1.02, p < 0.001). Additionally, 78, 38, and 297 genetic instruments were obtained in the MR analysis of smoking, sleep, and BMI with BD, respectively. Causal associations were observed between smoking (OR, 2.46; 95% CI, 1.17-5.15; p = 0.017), sleep (OR, 2.73; 95% CI, 1.52-4.92; p < 0.001), and BD, and smoking (OR, 2.43; 95% CI, 1.69-3.16; p = 0.018) might be a mediator in the causal effects of sleep on BD. Finally, there was no inconsistency between sensitivity and causality analysis, proving that our results are convincing. Conclusion: The study results provide strong evidence that smoking, sleep, and BMI are causally related to MDD and BD, which need further research to clarify the underlying mechanism.

Role of Circular RNAs in Pulmonary Fibrosis.

Pulmonary fibrosis is a chronic progressive form of interstitial lung disease, characterized by the histopathological pattern of usual interstitial pneumonia. Apart from aberrant alterations of protein-coding genes, dysregulation of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs), is crucial to the initiation and progression of pulmonary fibrosis. CircRNAs are single-stranded RNAs that form covalently closed loops without 5' caps and 3' tails. Different from canonical splicing of mRNA, they are produced from the back-splicing of precursor mRNAs and have unique biological functions, as well as potential biomedical implications. They function as important gene regulators through multiple actions, including sponging microRNAs and proteins, regulating transcription, and splicing, as well as protein-coding and translation in a cap-independent manner. This review comprehensively summarizes the alteration and functional role of circRNAs in pulmonary fibrosis, with a focus on the involvement of the circRNA in the context of cell-specific pathophysiology. In addition, we discuss the diagnostic and therapeutic potential of targeting circRNA and their regulatory pathway mediators, which may facilitate the translation of recent advances from bench to bedside in the future.

Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC.

Ferroptosis is a new type of iron-dependent programmed cell death. In recent years, its role in the diagnosis and treatment of multiple tumors, including non-small cell lung cancer (NSCLC), has been continuously observed. The relationship between the ferroptosis-related genes and the prognosis of patients with NSCLC needs to be clarified. In this study, The Cancer Genome Atlas (TCGA) and the Gene Expression Synthesis database (Gene Expression Omnibus, GEO) were used to build a model of ferroptosis-related differentially expressed genes (DEGs). A total of 101 ferroptosis-related DEGs were screened using R language, and a 12-gene signature was finally established through univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression analysis. According to the risk scores, the patients were divided into a high-risk or a low-risk group, with patients in the low-risk group showing better prognosis. AURKA, one of the genes in the 12-gene signature, was found to be highly expressed in tumors. In addition, further study verified AURKA to be a negative regulator of ferroptosis in NSCLC cells. Ophiopogonin B (OP-B) had been reported to induce apoptosis, mitotic catastrophe, and autophagy in NSCLC cells. Herein, proteomic sequencing analysis and OP-B administration revealed the upregulation of AURKA and the downregulation of PHKG2 and SLC7A5 in the 12-gene signature, indicating that OP-B induced ferroptosis in NSCLC. Determination of the concentrations of malondialdehyde (MDA), glutathione (GSH), and intracellular iron and the mitochondrial membrane potential (MMP) confirmed the induction of ferroptosis by OP-B in vitro. Furthermore, transmission electron microscopy (TEM) examination of lung cancer xenotransplantation in nude mice confirmed that OP-B induced ferroptosis in vivo. Further study of the molecular mechanism showed that the ferroptosis effect caused by OP-B can be partially reversed by the overexpression of AURKA. Overall, our study established a new ferroptosis-related risk prediction model for the prognosis of patients with NSCLC, revealed the enrichment pathways of ferroptosis in NSCLC, and discovered the negative regulation of AURKA in ferroptosis. On this basis, we demonstrated that OP-B can induce ferroptosis in NSCLC and clarified the specific molecular mechanism of OP-B inducing ferroptosis by regulating the expression of AURKA.

Effects of Gentiopicroside on activation of NLRP3 inflammasome in acute gouty arthritis mice induced by MSU.

Acute gouty arthritis is a self-limiting inflammatory disease resulting from the deposition of monosodium urate (MSU) crystals. It has been shown that Gentiopicroside (GPS) possesses anti-inflammatory and analgesic functions. The aim of this study was to parse out whether GPS has an effect on acute gouty arthritis. We established an acute gouty arthritis model by the injection of MSU into the paw, and found that GPS relieves MSU-induced mechanical, thermal hyperalgesia, and paw swelling. Furthermore, GPS down-regulated the release of pro-inflammatory cytokines in paw tissues, including IL-1ß, IL-6, IL-18, and TNF-α. The results of H&E staining and MPO activity measurement showed that GPS inhibits neutrophil infiltration. And the over-expressions of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1 induced by MSU were inhibited by treatment with GPS. These results revealed that GPS can treat acute gouty arthritis based on anti-inflammatory and analgesic properties in vivo, which might be ascribed to the inhibition on NLRP3 inflammasome. Furthermore, we performed in vitro study to confirm the results of in vivo study. Consistently, the results proved that GPS could inhibit the activation of NLRP3 inflammasome in RAW264.7 macrophages stimulated by LPS-MSU. In conclusion, this study provides an experimental basis for the application of GPS and expands the potential value of GPS in the therapy of acute gouty arthritis.

Amelioration of Neuropathic Pain and Attenuation of Neuroinflammation Responses by Tetrahydropalmatine Through the p38MAPK/NF-κB/iNOS Signaling Pathways in Animal and Cellular Models.

Neuropathic pain (NP) treatment remains a challenge because the pathomechanism is not yet fully understood. Because of low treatment efficacy, there is an important unmet need in neuropathic pain patients, and the development of a more effective pharmacotherapy is urgently required. Neuroinflammation induced by oxidative stress-mediated activation of nuclear factor-kappa B (NF-κB) plays an important role in NP. In this study, we aimed to investigate the protective properties of tetrahydropalmatine (THP) on a spared nerve injury (SNI) model of neuropathic pain in mice in in vivo and also in in vitro experiments. THP decreased mechanical hyperalgesia and cold allodynia compared with the SNI group. A microarray was applied to analyze differentially expressed of mRNA among different groups, and THP noticeably changed the expression of MAPK-related proteins compared with the SNI groups. H&E staining showed that the THP changed the inflammation after the spared nerve injury, with decreased NO expression in the THP group as compared to the SNI group. In addition, SNI-induced pain was reversed by intraperitoneal administration of THP, and further results indicated that THP suppressed inducible nitric oxide synthase (iNOS, pro-nociceptive mediators), phosphorylated MAPKs, and p65 in the dorsal root ganglions and sciatic nerve, while the serum levels of the pro-inflammatory cytokines IL-1ß were significantly higher in the SNI group as compared to the THP group. To identify the molecular mechanism of the antineuropathic activity of THP, sodium nitroprusside (SNP)-induced neuro-2a (N2a) cells, LPS-induced BV2 cells, and LTA-induced astrocytes were further investigated in signaling pathways. In vitro experiments indicated that THP suppressed the expression of IL-1ß, iNOS, phosphorylated MAPKs, and p65, which were assayed using western blotting, and immunofluorescence.

Electroacupuncture attenuates spared nerve injury-induced neuropathic pain possibly by promoting the progression of AMPK/mTOR-mediated autophagy in spinal microglia.

Background: Neuropathic pain (NP) is a syndrome that arises from central or peripheral nerve injury, which manifests primarily as hyperalgesia, spontaneous pain, and allodynia. The recent trend has exhibited a shift towards the development of therapies for managing NP. Activation of autophagy is involved in the function of the glial cells, which may be implicated further to attenuate pain. Methods: In this study, the analgesic effects of electroacupuncture (EA) were evaluated among NP rats developed using spared nerve injury (SNI). Acupuncture treatment or EA was carried out after 7 days of SNI at two acupoints, i.e., the Zusanli (ST36) and Huantiao (GB30). Results: The application of EA was found to attenuate mechanical hyperalgesia. The marker protein for microglial cells (CD11b) alone, without either the astrocyte marker or neuronal marker, was co-expressed with the autophagy indicator p62, as illustrated with immunofluorescence staining. Western blotting demonstrated that the expression levels of p62, Beclin-1, and LC3-II/LC3-I were elevated in the spinal cords of rats in the SNI group compared to the control levels. EA treatment resulted in reduced expression of p62, while the expressions of Beclin-1 and LC3-II/LC3-I were increased. The electron microscopy results indicated that EA could induce autophagy progression in the microglia of the spinal dorsal horn in SNI rats. Furthermore, we explored the causal relationship between EA-induced inhibition of NP and increased autophagic levels in microglia using the AMPK inhibitor compound C, and found that the mechanism of EA-induced analgesia may contribute to the promotion of AMPK/mTOR-mediated autophagy in spinal microglia. Conclusions: Our work showed that the analgesic impact of EA is partly related to AMPK/mTOR pathway activation and autophagy induction in microglial cells, providing a potential therapeutic target for NP.

Electroacupuncture alleviates neuropathic pain caused by spared nerve injury by promoting AMPK/mTOR-mediated autophagy in dorsal root ganglion macrophage.

Background: Dorsal root ganglia (DRG) plays an important role in mediating the peripheral sensation transduction through the primary afferent neurons in pain research. Neuropathic pain (NP) is a syndrome of hyperalgesia, spontaneous pain and allodynia caused by central or peripheral nerve injury. Recent trends of study are turning towards the development of therapies for the management of NP. Activation of autophagy in glial cells in the spinal cord has been reported to be associated with attenuation of NP, but the autophagic process in DRG is rarely studied. Methods: The analgesic effect of electroacupuncture (EA) was evaluated in NP-induced rats developed using spared nerve injury (SNI). Acupuncture or EA was performed after 7 days of SNI at Zusanli (ST36) and Huantiao (GB30) acupoints. Then, the activation status of autophagy process in DRGs of rats treated with SNI and EA were investigated, and the possible mechanism of the analgesic effect of EA were explored. Results: Application of EA has been found to reduce mechanical hyperalgesia. Autophagy indicator p62 was colocalized with the marker proteins for macrophages (CD11b), but not with NeuN (marker protein for neurons) or GFAP (marker protein for satellite glial cells), as shown by immunofluorescence. Western blots results indicate that the expression levels of p62, Beclin-1 and LC3-II in the L4-L6 DRG of rats in the SNI group were increased, compared with that in the control group. EA treatment resulted in decreased expression of p62 and increased expression of Beclin-1 and LC3-II/LC3-I. Furthermore, we explored the causal relationship between EA-induced suppression of NP and increased levels of autophagy in DRG using electron microscopy and the AMPK (AMP-activated protein kinase) inhibitor compound C. Conclusions: SNI achieved a significant upregulation of autophagy levels in DRG macrophages. Furthermore, EA attenuated NP, which may contribute to the promotion of AMPK/mTOR (mammalian target of rapamycin)-mediated autophagy in DRG macrophages. Therefore, this strategy provides a new target for therapeutic intervention of NP.

Comparison of total intravenous anesthesia and inhalation anesthesia on postoperative quality of recovery after laparoscopic hysterectomy: A protocol for systematic review and meta-analysis.

BACKGROUND: Postoperative recovery is a complex process and affected mainly by factors from patients, surgery and anesthesia. Although we have all kinds of sedatives and hypnotics now, the selection of an ideal medication for general anesthesia is still challenging. In this study, we perform a protocol for systematic review and meta-analysis to compare the effect of propofol-based total intravenous anesthesia and sevoflurane-based inhalation anesthesia on postoperative quality of recovery in patients undergoing laparoscopic hysterectomy. METHODS: The protocol of this review was registered in PROSPERO (CRD42022379485). Meanwhile, it will be reported follow the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol. We will search 3 foreign electronic databases (Cochrane Library, Embase, Pubmed) and 4 Chinese electronic databases (China National Knowledge Infrastructure, WangFang Database, Chinese Biomedical Literature Database and Chinese Scientific Journal Database) to collect potential studies from their inceptions to December 2022. Only randomized controlled trials will be included. Two reviewers will independently perform study selection, data extraction and risk of bias assessment. Data synthesis and statistical analysis will be performed using the RevMan 5.4 (The Cochrane Collaboration, Copenhagen, Denmark) software. RESULTS: The results of this systematic review and meta-analysis will be publicly available and published in a peer-reviewed journal. CONCLUSION: This study may provide the evidence regarding the efficacy and safety of total intravenous anesthesia and inhalation anesthesia on postoperative quality of recovery after laparoscopic hysterectomy.

Identification of a novel glycolysis-related signature to predict the prognosis of patients with breast cancer.

BACKGROUND: Breast cancer (BC) has a high incidence and mortality rate in females. Its conventional clinical characteristics are far from accurate for the prediction of individual outcomes. Therefore, we aimed to develop a novel signature to predict the survival of patients with BC. METHODS: We analyzed the data of a training cohort from the Cancer Genome Atlas (TCGA) database and a validation cohort from the Gene Expression Omnibus (GEO) database. After the applications of Gene Set Enrichment Analysis (GSEA) and Cox regression analyses, a glycolysis-related signature for predicting the survival of patients with BC was developed; the signature contained AK3, CACNA1H, IL13RA1, NUP43, PGK1, and SDC1. Furthermore, on the basis of expression levels of the six-gene signature, we constructed a risk score formula to classify the patients into high- and low-risk groups. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to assess the predicted capacity of the model. Later, a nomogram was developed to predict the outcomes of patients with risk score and clinical features over a period of 1, 3, and 5 years. We further used Human Protein Atlas (HPA) database to validate the expressions of the six biomarkers in tumor and sample tissues, which were taken as control. RESULTS: We constructed a six-gene signature to predict the outcomes of patients with BC. The patients in the high-risk group showed poor prognosis than those in the low-risk group. The area under the curve (AUC) values were 0.719 and 0.702, showing that the prediction performance of the signature is acceptable. Additionally, Cox regression analysis revealed that these biomarkers could independently predict the prognosis of BC patients with BC without being affected by clinical factors. The expression levels of all six biomarkers in BC tissues were higher than that in normal tissues; however, AK3 was an exception. CONCLUSION: We developed a six-gene signature to predict the prognosis of patients with BC. Our signature has been proved to have the ability to make an accurate prediction and might be useful in expanding the hypothesis in clinical research.

[Application of transcutaneous electrical acupoint stimulation in perioperative period].

Transcutaneous electrical acupoint stimulation (TEAS) has the characteristics of simple operation, non-invasive, and high patient acceptability, and is widely used in clinical practice. This article summarized the effects of TEAS on analgesia, gastrointestinal tract regulation, circulation regulation, postoperative cognitive function improvement, immune function regulation, anti-inflammatory and anti-stress during the perioperative period. At the same time, this article analyzed the problems of the application of TEAS in the perioperative period, and aimed to promote its clinical application.

Advances With Non-coding RNAs in Neuropathic Pain.

Neuropathic pain (NP) is one of the most common types of clinical pain. The common causes of this syndrome include injury to the central or peripheral nervous systems and pathological changes. NP is characterized by spontaneous pain, hyperalgesia, abnormal pain, and paresthesia. Because of its diverse etiology, the pathogenesis of NP has not been fully elucidated and has become one of the most challenging problems in clinical medicine. This kind of pain is extremely resistant to conventional treatment and is accompanied by serious complications. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), contribute to diverse biological processes by regulating the expression of various mRNAs involved in pain-related pathways, at the posttranscriptional level. Abnormal regulation of ncRNAs is closely related to the occurrence and development of NP. In this review, we summarize the current state of understanding of the roles of different ncRNAs in the development of NP. Understanding these mechanisms can help develop novel therapeutic strategies to prevent or treat chronic pain.

The Fault Tolerant Control Design of an Intensified Heat-Exchanger/Reactor Using a Two-Layer, Multiple-Model Structure.

The heat-exchanger/reactor (HEX reactor) is a kind of plug-flow chemical reactor which combines high heat transfer ability with good chemical performances. It was designed under the popular trend of process intensification in chemical engineering. Previous studies have investigated its characteristics and developed its nominal model. This paper is concerned with its fault tolerant control (FTC) applications. To avoid the difficulties and nonlinearities of this HEX reactor under chemical reactions, a two-layer, multiple-model structure is proposed for designing the FTC scheme. The first layer focuses on representing the nonlinear system with a bank of local linear models while the second layer uses model banks for approaching faulty situations. Model banks are achieved by system identification, and the corresponding controller banks are designed using model predictive control (MPC). The unscented Kalman filter (UKF) is introduced to estimate the states and form the fault detection and isolation (FDI) section. Finally, the FTC simulation and validation results are presented. The idea of a two-layer, multiple-model structure presents a general framework for FTC design of complex and highly nonlinear systems, such as the HEX reactor, whose mathematical model has been created. It implements the design process in an unusual way and is also worth trying on other cases.

A new method for the treatment of chromite ore processing residues.

Chromite ore processing residue (COPR), derived from the so-called high-lime processing of chromite ore, contains a significant fraction of a leachable Cr(VI) which is harmful to human being and other organisms. In recent years, the concern over environmental pollution from the waste residue containing Cr(VI) has become a major problem for the chromium chemical industry. The main purpose of this investigation is to evaluate a new method for remediation of Cr(VI) in COPR. COPR was mixed with reductants, sucrose, starch or flour, and was calcinated at elevated temperatures in inertial gas. Effects of temperature, dosages of reductants and time on Cr(VI) reduction were investigated. Above 500 degrees C, Cr(VI) can be completely reduced to Cr(III).