BackgroundRoflumilast, a highly selective phosphodiesterase 4 inhibitor, is used to treat with chronic obstructive pulmonary disease and psoriasis. We aim to determine potential roflumilast-associated adverse events (AEs) and the differences in AE signals among diverse populations.MethodsRoflumilast’s AE reports between the first quarter of 2011 and the fourth quarter of 2024 were obtained from the FDA Adverse Event Reporting System (FAERS) and Canada Vigilance Adverse Reaction Database (CVARD). The signal strength was measured by four disproportionality analysis methods, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).ResultsIn FAERS, population aged ≥65 years and oral medication users accounted for a predominant proportion in the reported cases. FDA-unlabeled respiratory, thoracic and mediastinal disorders was the only one signal categorized by system organ class met all four algorithms. Newly identified AEs such as dyspnea, condition aggravated, cough, and tachycardia could contribute valuable safety considerations for clinical practice. The analysis of the available time-to-onset data suggested that cases often occurred within the first 30 days post-treatment. These results were externally validated in CVARD, suggesting consistent findings. Notably, headache was more frequently reported among users of topical formulations and female patients, while suicidal ideation and weight loss were more commonly reported in male patients and oral medications, respectively.ConclusionThis study confirmed established adverse reactions and identified novel AEs in real-world clinical practice by dual-database pharmacovigilance analysis. Clinicians should remain vigilant for AEs that differ by gender and route to enable early intervention and improve prognosis. The findings highlight personalized safety management, while underscoring the necessity of prospective studies to validate results and further characterize roflumilast’s safety profile.

Tacrolimus-induced chronic nephrotoxicity (TICN) limits its clinical application without prevention strategies. Identifying a specific target and finding corresponding drug are critical for its prevention. We previously found that transcription factor EB (TFEB), a substrate of calcineurin, is key to TICN. Further exploration of drugs targeting TFEB without compromising tacrolimus efficacy holds promise for preventing TICN. Astragaloside IV (AS-IV), the major bioactive component of Astragali Radix, can alleviate various renal diseases. However, its regulatory effect on TFEB and the underlying mechanism remain unknown. Herein, we found that AS-IV significantly reactivated TFEB and restored tacrolimus-impaired renal function and pathology, autophagy flux and DNA repair. These effects were reversed upon TFEB knockdown. Further studies revealed that AS-IV did not affect calcineurin but activated TFEB by inhibiting mTOR, which dominantly phosphorylated TFEB Ser211. Altogether, this study suggested that AS-IV mitigated TICN via mTOR-TFEB without affecting calcineurin, making it a promising therapeutic agent for TICN.

Intestinal mucositis is one of the most common toxicities of 5-fluorouracil (5-FU)-based chemotherapy, occurring in up to 80% of treated patients. Clinically, it presents as abdominal pain, watery or bloody diarrhea, malabsorption and body-weight loss, often forcing chemotherapy dose reduction or discontinuation, thereby aggravating the psychological burden of patients, prolonging hospital stay and potentially increasing mortality. Histologically, 5-FU-induced intestinal mucositis (FIM) is characterized by villus atrophy, crypt apoptosis, disruption of epithelial barrier and pronounced inflammatory infiltration. In this review, we delineate the mechanisms of FIM, a multi-stage pathogenesis that integrates direct epithelial cell apoptosis, oxidative stress, inflammation signal cascades, intestinal barrier disruption, dysbiosis, as well as more recently recognized factors such as impaired intestinal neuroregulation and intestinal senescence. Additionally, we summarize the potential pharmacological interventions, aiming to offer a reference for future basic and clinical research on FIM.

Tacrolimus-induced chronic nephrotoxicity (TICN) limits its clinical application without prevention strategies. Identifying a specific target and finding corresponding drug are critical for its prevention. We previously found that transcription factor EB (TFEB), a substrate of calcineurin, is key to TICN. Further exploration of drugs targeting TFEB without compromising tacrolimus efficacy holds promise for preventing TICN. Astragaloside IV (AS-IV), the major bioactive component of Astragali Radix, can alleviate various renal diseases. However, its regulatory effect on TFEB and the underlying mechanism remain unknown. Herein, we found that AS-IV significantly reactivated TFEB and restored tacrolimus-impaired renal function and pathology, autophagy flux and DNA repair. These effects were reversed upon TFEB knockdown. Further studies revealed that AS-IV did not affect calcineurin but activated TFEB by inhibiting mTOR, which dominantly phosphorylated TFEB Ser211. Altogether, this study suggested that AS-IV mitigated TICN via mTOR-TFEB without affecting calcineurin, making it a promising therapeutic agent for TICN.

Tacrolimus-induced chronic nephrotoxicity (TICN) hinders long-term use of tacrolimus, but its mechanism remains unclear. Tacrolimus exerts its pharmacological effect by inhibiting calcineurin and its substrate nuclear factor of activated T cells. Whether the inhibition of other calcineurin substrates is related to TICN remains to be explored. Transcription factor EB (TFEB), a substrate of calcineurin, plays a crucial role in homeostasis. Herein, we found that tacrolimus inhibited TFEB nuclear translocation and activity in mouse kidneys and HK-2 cells. Then, TFEB gain and loss of function rescued and exacerbated, respectively, the effect of tacrolimus in HK-2 cells. Furthermore, TFEB activation by both phosphorylation site mutation and agonist rescued TICN in mice. To elucidate the mechanism of TFEB, we analyzed ChIP-Seq data. We identified growth arrest and DNA damage-inducible 45α (GADD45α) as a transcriptional target of TFEB via ChIP and dual-luciferase reporter assays. Then we revealed that GADD45α overexpression rescued DNA damage and kidney injury caused by tacrolimus or TFEB knockdown in vitro and vice versa. The protective effect of GADD45α against TICN and DNA damage was further demonstrated by overexpressing it in mice. In conclusion, the persistent inhibition of the TFEB/GADD45α pathway by tacrolimus contributes to TICN. This study identifies a specific target for intervention in TICN.

[This corrects the article DOI: 10.3389/fphar.2020.610102.].

This study was to investigate the mechanism of Changma Xifeng tablet, a traditional Chinese medicine in the treatment of Tourette syndrome. Network pharmacology was utilized to pinpoint blood-entering constituents of Changma Xifeng and explore their potential targets. Additionally, differential microRNA expression analysis was conducted to predict Tourette syndrome-associated targets, complemented by molecular docking and dynamics simulations to support the interactions of the active compounds with these targets. The study identified 98 common targets between Changma Xifeng and Tourette syndrome, which may be involved in the treatment process. A protein-protein interaction network and a drug-active ingredient-disease target network highlighted the formulation’s multi-component, multi-target therapeutic approach. Eight pivotal targets-AR, GRM5, MET, RORA, HTR2A, CNR1, PDE4B, and TOP1-were identified at the intersection of microRNA and drug targets. Molecular docking revealed 12 complexes with favorable binding energies below − 7 kcal/mol, specifically: AR with Alfacalcidol, TOP1 with Albiflorin, GRM5 with Arachidic Acid, GRM5 with Palmitic Acid, AR with Arachidic Acid, AR with 2-Hydroxyoctadecanoic Acid, RORA with Pinellic Acid, RORA with Palmitic Acid, AR with Acoronene, AR with Epiacoronene, AR with 4,4’-Methylenediphenol, and HTR2A with Calycosin. Our molecular docking and molecular dynamics simulations suggest potential stable interactions between the formulation’s active components and target proteins. These computational methods provide a preliminary theoretical framework that will guide our future experimental work. The study provides a scientific rationale for the use of traditional Chinese medicine in Tourette syndrome management and offers new insights for drug development.

The trough concentration (C0) of tacrolimus in children with nephrotic syndrome (NS) has rarely been explored, so its target level was based on transplant research. This study aimed to determine the optimal tacrolimus C0 in NS children. Data from primary NS children treated with tacrolimus at Wuhan Children's Hospital in the last 10 years were retrospectively collected. According to the cutoff C0 analyzed by receiver-operator characteristics (ROC) analysis, patients were divided into very low- (< 4 ng/mL), low- (4-5 ng/mL), medium- (5-7 ng/mL), and high-concentration (7-10 ng/mL) groups. A total of 196 patients were enrolled for primary outcome analysis. Compared to medium-concentration group, only the very low-concentration group obtained significant inferior primary outcomes, including overall remission rate, relapse-free survival rate, and relapse rate at 6 months. For secondary outcomes, the very low-concentration group experienced more frequent treatment failure in 12 months, whereas the high-concentration group suffered a higher risk of adverse events than the medium-concentration group. For steroid-resistant NS, very low- and low-concentration groups required longer time to achieve remission compared to medium-concentration group. For steroid-sensitive NS, the very low-concentration group suffered a higher relapse frequency than medium-concentration group. Lastly, the dose of tacrolimus required for children with different CYP3A5 genotypes with or without Wuzhi capsules was analyzed. In conclusion, tacrolimus may be targeted to C0 of 4-7 ng/mL during the first 6 months in children with NS. For steroid-resistant NS, C0 of 5-7 ng/mL can achieve a rapid remission.

BackgroundGuselkumab is an IL-23 inhibitor widely used for the treatment of moderate-to-severe plaque psoriasis. Our study aimed to characterize the profile of adverse events (AEs) associated with guselkumab from the FDA adverse event reporting system (FAERS).MethodsDisproportionality analysis including the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the Bayesian confidence propagation neural network (BCPNN), and the multiitem gamma Poisson shrinker (MGPS) algorithms were used to assess the signals of guselkumab related AE.ResultsA total of 22,950,014 reports were collected from the FAERS database, of which 24,312 reports regarding guselkumab as the 'primary suspected (PS)' AEs were identified. AEs induced by guselkumab were distributed in 27 organ systems. In this study, 205 significant disproportionality preferred terms (PTs) that matched four algorithms simultaneously were obtained for analysis. Unexpected significant AEs such as onychomadesis, malignant melanoma in situ, endometrial cancer, and erectile dysfunction were observed.ConclusionThe clinical observed AEs, along with potential new AE signals associated with guselkumab were identified based on the analysis of FAERS data, which could provide valuable evidence for clinical monitoring, risk identification, and further safety studies of identification.

ObjectiveThere is a lack of effective and long-term safe drugs for the treatment of osteoarthritis (OA). Tetrandrine (Tet) has been approved and used to treat rheumatoid arthritis for several decades, but its effect on OA has not been investigated. Herein, we explored the effect of Tet on OA and its underlying mechanism.MethodsOA was induced using destabilization of the medial meniscus (DMM) in C57BL/6J mice. The animals were randomly divided into sham, DMM, Tet, celecoxib (CXB), and indomethacin (INDO) groups. Each group was given solvent or corresponding drugs by gavage for 7 weeks after convalescence. Pathological staining, OARSI scores, micro-computed tomography and behavior tests were performed to evaluate the effects of Tet.ResultsTet remarkably alleviated cartilage injury in the knee joint, limited bone remodeling in the subchondral bone, and delayed progression of OA. Tet also significantly relieved joint pain and maintained function. Further mechanistic studies revealed that Tet lowered inflammatory cytokine levels and selectively suppressed gene and protein expression of cyclooxygenase (COX)-2 but not COX-1 (P<0.01). Tet also reduced the production of prostaglandin E2 without damaging the gastric mucosa.ConclusionWe found that Tet could selectively inhibit COX-2 gene expression and decrease cytokine levels in mice, thus reducing inflammation and improving OA without obvious gastric adverse events. These results provide a scientific basis for the clinical application of Tet in the treatment of OA.

Background and Aims:We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1. Methods:IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p. Results:Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33-deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent. Conclusions:IL-33-ST2-GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.

The authors examined the original data of their work and noticed misuse of images in fig. 1 and fig. 3 (as shown below on the upper panels, red box). The correct images are shown on the lower panels (red box). The authors sincerely apologize for the mistake and confirm the change does not affect the scientific conclusion of the published work.

Hepatic sinusoidal obstruction syndrome (HSOS) is a serious side effect of oxaliplatin (OXA) treatment. The present study aimed to establish a reproducible mouse model of OXA-induced HSOS and to preliminarily explore the underlying molecular mechanisms using mRNA microarray analysis. A total of 45 C57BL/6 male mice were randomly divided into five groups: Control, 5 mg/kg OXA, 10 mg/kg OXA, 15 mg/kg OXA and 20 mg/kg OXA. The mice were respectively injected intraperitoneally with 5% glucose solution, or 5, 10, 15 or 20 mg/kg OXA solution once a week for 6 consecutive weeks. The body weight of the mice was recorded every day. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Hematoxylin and eosin staining, Sirius red staining and scanning electron microscopy were used to identify pathological changes. mRNA microarray was used to analyze changes in the gene expression profiles mainly from the functional aspects of Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The oxidation mechanism was verified by measuring oxidative stress-related markers and reactive oxygen species with dihydroethidium probe technology, according to the microarray results. Among all of the OXA groups, 10 mg/kg OXA resulted in an acceptable survival rate of 78%. The mice showed obvious splenomegaly, increases in serum levels of ALT and AST, aggravation of liver pathological injuries and hepatic sinusoidal injuries. The microarray results suggested that mRNA expression changes after OXA treatment were associated with 'oxidative stress', 'coagulation function', 'steroid anabolism' and 'pro-inflammatory responses'. The results confirmed that OXA aggravated oxidative damage in the livers of the mice. The present study successfully established a mouse model of OXA-induced HSOS and preliminarily analyzed the underlying molecular mechanisms involved, thus laying a foundation for a subsequent in-depth study.

Aim Clinical utility of doxorubicin (DOX) is limited by its cardiotoxic side effect, and the underlying mechanism still needs to be fully elucidated. This research aimed to examine the role of (pro)renin receptor (PRR) in DOX-induced heart failure (HF) and its underlying mechanism. Main Methods Sprague Dawley (SD) rats were injected with an accumulative dosage of DOX (15 mg/kg) to induce HF. Cardiac functions were detected by transthoracic echocardiography examination. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum were detected, and oxidative stress related injuries were evaluated. Furthermore, the mRNA expression of PRR gene and its related genes were detected by real-time PCR (RT-PCR), and protein levels of PRR, RAC1, NOX4 and NOX2 were determined by Western blot. Reactive oxygen species (ROS) were determined in DOX-treated rats or cells. Additionally, PRR and RAC1 were silenced with their respective siRNAs to validate the in vitro impacts of PRR/RAC1 on DOX-induced cardiotoxicity. Moreover, inhibitors of PRR and RAC1 were used to validate their effects in vivo. Key Findings PRR and RAC1 expressions increased in DOX-induced HF. The levels of CK and LDH as well as oxidative stress indicators increased significantly after DOX treatment. Oxidative injury and apoptosis of cardiomyocytes were attenuated both in vivo and in vitro upon suppression of PRR or RAC1. Furthermore, the inhibition of PRR could significantly down-regulate the expressions of RAC1 and NOX4 but not that of NOX2, while the inhibition of RAC1 did not affect PRR. Significance Our findings showed that PRR inhibition could weaken RAC1-NOX4 pathway and alleviate DOX-induced HF via decreasing ROS production, thereby suggesting a promising target for the treatment of DOX-induced HF.

Tacrolimus-induced chronic nephrotoxicity (TIN) hinders its long-term use in patients. However, there are no drugs available in the clinic to relieve it at present. Astragaloside IV (AS-IV) is a saponin extract of the Astragalus which is widely used in the treatment of kidney disease. This study aimed to investigate the effect of AS-IV on TIN and its underlying mechanism. Herein, C57BL/6 mice were treated with tacrolimus and/or AS-IV for 4 weeks, and then the renal function, fibrosis, oxidative stress and p62-Keap1-Nrf2 pathway were evaluated to ascertain the contribution of AS-IV and p62-Keap1-Nrf2 pathway to TIN. Our results demonstrated that AS-IV significantly improved renal function and alleviated tubulointerstitial fibrosis compared with the model group. The expression of fibrosis-related proteins, including TGF-β1, Collagen I and α-SMA, were also decreased by AS-IV. Furthermore, AS-IV relieved the inhibition of tacrolimus on antioxidant enzymes. The data in HK-2 cells also proved that AS-IV reduced tacrolimus-induced cell death and oxidative stress. Mechanistically, AS-IV markedly promoted the nuclear translocation of Nrf2 and the renal protective effects of AS-IV were abolished by Nrf2 inhibitor. Further researches showed that phosphorylated p62 was significantly increased after AS-IV pretreatment. Moreover, AS-IV failed to increase nuclear translocation of Nrf2 and subsequent anti-oxidative stress in HK-2 cells transfected with p62 siRNA. Collectively, these findings indicate that AS-IV relieve TIN by enhancing p62 phosphorylation, thereby increasing Nrf2 nuclear translocation, and then alleviating ROS accumulation and renal fibrosis.

Children with kidney insufficiency are susceptible to vancomycin-induced acute kidney injury (VIAKI), but there is a lack of compelling clinical data. We conducted a nested case-control study to evaluate the relationship between kidney insufficiency and incidence of VIAKI in children. Patients were considered to have VIAKI if they met the criteria for eGFR change according to pRIFLE-I or p-RIFLE-F. Case group comprised patients who developed VIAKI. Case-control ratio was 1:3; patients were matched for age, severity, and nature of illness and initial vancomycin dose. Primary endpoint was incidence of VIAKI at three levels of kidney function, calculated using Kaplan-Meier curve and log-rank test. Secondary endpoint was treatment-related in-hospital mortality amongst case and control groups. Amongst 386 children who fit study criteria, 31 developed VIAKI (8.03%). Thirty-one cases and 93 controls were selected from the observed cohort. Three risk factors were identified for VIAKI: moderate kidney insufficiency (OR 8.8, 2.4–32.8), vancomycin trough concentration ≥ 15 μg/mL (OR 7.7, 1.7–34.4), and furosemide use (OR 24.8, 6.4–98.2). A significant difference in time to VIAKI was noted between patients with moderate kidney insufficiency and patients with mild kidney insufficiency or normal kidney function (p < 0.001). In-hospital mortality rate in case group was 45.2%, compared to 18.3% in control group (p < 0.01). Children with moderate kidney insufficiency are more likely to develop VIAKI than those with normal and mild kidney insufficiency. Patients who develop VIAKI have higher in-hospital mortality than those who do not develop VIAKI.

BACKGROUND:At present, coronavirus disease 2019 (COVID-19) has spread in many countries. We conducted this study to help pediatricians understand the conditions of COVID-19 in children. METHODS:We retrospectively summarized the characteristics, treatment and outcomes of pediatric cases in Wuhan Children's Hospital which was the only designated hospital for children with COVID-19 in Hubei Province. A Cox proportional hazards regression analysis was used to evaluate factors associated with clinical outcomes. RESULTS:As of February 29, 75 children had been discharged, of which only one was has severe pneumonia and one was critical cases. Children younger than 2 years were more susceptible to COVID-19. All patients have received interferon-α nebulization, and eight cases including the severe and critical cases were co-administrated ribavirin. Five patients with mild pneumonia were given arbidol. Twenty-three patients were given traditional Chinese medicine (TCM). The average length of stay (LOS) and the time of SARS-CoV-2 clearance were 10.57 and 6.39 days, respectively. None of the factors was associated with LOS or time of SARS-CoV-2 clearance. CONCLUSIONS:The severity of COVID-19 in pediatric cases were milder than adults. The efficacy of the antiviral therapy in children with COVID-19 remains to be evaluated.

目的:筛选黄芪改善他克莫司慢性肾毒性的活性组分,并初步阐明其作用机制.方法:将48只C57BL/6小鼠随机分为6组:空白对照组、模型组、黄芪总提取物组、黄芪总黄酮组、黄芪多糖组和黄芪总皂苷组,每组8只.除空白对照组外,其余各组采用他克莫司诱导慢性肾毒性模型,各治疗组同时灌胃给予相应的治疗药物,qd,连续28d.末次给药后,检测各组小鼠尿量、体质量、血肌酐(SCr)、尿素氮(BUN);HE和Masson染色观察肾组织病理改变,Western blot检测肾组织转化生长因子β1(TGF-β1)、Ⅰ型胶原蛋白(Collagen Ⅰ)和α-平滑肌肌动蛋白(α-SMA)的表达,应用试剂盒测定超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GSH-Px)和丙二醛(MDA)水平.结果:与模型组相比,黄芪总提取物组、黄芪多糖和黄芪总皂苷可显著降低小鼠SCr、BUN、肾小管间质纤维化程度、TGF-β1 、Collagen Ⅰ和α-SMA的蛋白表达(P＜0.05或P＜0.01),增加抗氧化酶SOD、CAT和GSH-Px的活性(P＜0.05或P＜0.01),显著降低MDA水平(P＜0.05或P＜0.01),而黄芪总黄酮无明显作用(P＞0.05).结论:黄芪多糖和黄芪总皂苷可能是黄芪发挥肾毒性保护作用的活性组分,其作用机制可能与减少氧化应激相关.

Today, an increase in vancomycin dose has been proposed to ensure efficacy. However, the risk of nephrotoxicity will increase with the dose. The aim of this study was to evaluate the dosage regimens of vancomycin in pediatric patients based on pharmacokinetics/pharmacodynamics (PK/PD) and to optimize dosage individualization. Population pharmacokinetics analysis was performed on 155 Chinese children (aged 1 month to 16 years), which were divided into various renal function subpopulations. Monte Carlo simulation was carried to evaluate the efficacy and safety of vancomycin dosage regimens on each subpopulation. Compared with children with normal renal function as glomerular filtration rate (GFR) ≥ 90 mL/min·1.73 m2, the clearance of vancomycin decreased by 39.4% and the half life increased 1.74 fold respectively in children with moderate renal inadequacy (30 ≤ GFR < 60 mL/min·1.73 m2). When vancomycin was administered as conventional dosage (40-60mg·kg-1·d-1) to against methicillin-resistant staphylococcus aureus (MRSA) with higher MICs of 1-2 mg·L-1 for children with normal renal function, the probability of efficacy target attainment ( PTA) at AUC0-24h/MIC ≥ 400 (where AUC is the area under curve and MIC is the minimum inhibitory concentration) achieved ≤ 63.64%. While vancomycin dosage exceeded 70mg·kg-1·d-1 for children with normal renal function, 50mg·kg-1·d-1 for mild renal inadequacy (60 ≤ GFR < 90 mL/min·1.73 m2), 30 mg·kg-1·d-1 for moderate renal inadequacy respectively, the PTA at trough concentration above 20 mg·L-1 achieved > 20%, that not to be suggested for high risk of nephrotoxicity. Considering both efficacy and safety, the conventional vancomycin dosage is not enough and adjustable interval is narrow for pediatric patients with MIC 1-2 mg·L-1 MRSA infection and normal renal function.