Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a central feature of stress-related affective disorders, and corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) initiate neuroendocrine stress responses. Although the α7 nicotinic acetylcholine receptor (α7 nAChR) has been implicated in emotional regulation, its role in PVN CREB/CRH signaling and anxiety- and depressive-like behaviors remains unclear. Here, using male C57BL/6 mice, we found that pharmacological activation of α7 nAChR with PNU282987 induced anxiety- and depressive-like behaviors under control conditions and further exacerbated behavioral abnormalities following chronic restraint stress (CRS), without significantly affecting locomotor activity. PNU282987 also increased CREB phosphorylation and CRH expression in the PVN and elevated serum CRH, adrenocorticotropic hormone (ACTH), and corticosterone (CORT) levels. Conversely, in CRS mice, the α7 nAChR-preferring antagonist methyllycaconitine (MLA) increased sucrose preference, OFT center exploration, and EPM open-arm time while reducing TST immobility. These behavioral effects were accompanied by reduced PVN CREB phosphorylation and CRH expression and decreased serum CRH, ACTH, and CORT levels. Notably, α7 nAChR protein abundance in the PVN was not significantly altered by CRS or drug treatment, suggesting that functional receptor activation rather than receptor upregulation may drive downstream signaling. Moreover, the CREB-mediated transcription inhibitor 666-15 attenuated PNU282987-induced behavioral abnormalities, serum CRH elevation, and PVN CRH upregulation. These findings indicate that α7 nAChR activation promotes anxiety- and depressive-like behaviors associated with enhanced PVN CREB phosphorylation, CRH upregulation, and HPA axis hyperactivity. CREB-associated CRH signaling may therefore represent a neuroendocrine mechanism linking α7 nAChR activation to stress-related affective disturbances.

ObjectiveTo investigate the association between serum uric acid （SUA） levels and 30-day mortality in patients with sepsis， clarify the nonlinear relationship and sex-specific thresholds， and provide evidence for early identification of high-risk patients with sepsis.MethodsUsing the Medical Information Mart for Intensive Care IV （MIMIC-IV） database， this retrospective study included 1，466 adult patients with sepsis admitted to the intensive care unit （ICU） between 2008 and 2019. Patients were divided into four groups according to SUA quartiles： Q1 （n=386）， Q2 （n=351）， Q3 （n=367）， and Q4 （n=362）. The primary outcome was 30-day mortality. Cox proportional hazards regression was used to assess the association between SUA levels and 30-day mortality. A restrictive cubic spline （RCS） model was used to explore the nonlinear relationship. Subgroup analyses were performed to examine the influence of sex on this association. Propensity score matching （PSM）， inverse probability of treatment weighting （IPTW）， and sensitivity analyses were conducted to verify the robustness of the findings.ResultsThe 30-day mortality rate among patients with sepsis was 27.1% （398/1466）. Higher SUA levels were significantly associated with an increased risk of 30-day mortality （fully adjusted model： HR=1.122， 95%CI： 1.089-1.156， P<0.001）. Compared with the Q1 group （SUA≤214.1 μmol/L）， the Q3 group （321.2 μmol/L 493.7 μmol/L） had significantly higher 30-day mortality risks （fully adjusted model： HR=1.550 and 3.065， both P<0.01）. RCS analysis confirmed a J-shaped nonlinear relationship between SUA levels and 30-day mortality risk in patients with sepsis （nonlinearity P=0.005）. After sex stratification， the mortality thresholds were 339.0 μmol/L in men and 291.5 μmol/L in women. When SUA exceeded these thresholds， mortality risk increased significantly with rising SUA levels （all P<0.001）. Subgroup analysis showed that the positive association between SUA and 30-day mortality was stronger in women （women： HR=2.820， 95%CI： 1.950-4.060； men： HR=1.700， 95%CI： 1.280-2.280； both P<0.001）. After PSM， IPTW adjustment， and sensitivity analyses， these findings remained consistent.ConclusionIn patients with sepsis， SUA levels show a J-shaped nonlinear association with 30-day mortality， with sex-specific mortality thresholds. In clinical practice， monitoring SUA and assessing risk according to sex-specific thresholds may help identify patients with sepsis at high risk of death at an early stage， thereby supporting early prognostic stratification and providing a potential direction for future urate-lowering intervention studies.

P-glycoprotein (P-gp) substantially affects the pharmacokinetics and effectiveness of several medicines, including statins, by facilitating their efflux. This study employed computational methods to systematically examine the binding mechanisms, conformational dynamics, and binding affinities of nine statin compounds with human P-gp. Molecular docking demonstrated that seven statins effectively attached to the zosuquidar-defined binding site, with atorvastatin displaying the highest docking score. Subsequent molecular dynamics (MD) simulations revealed that statin binding stabilised P-gp, diminishing backbone flexibility and inhibiting long-range correlated motions, as indicated by decreased RMSD and RMSF values and modified dynamics in cross-correlation and principal component analysis. MM/PBSA binding free energy calculations indicated atorvastatin as the most potent binder, succeeded by cerivastatin and simvastatin. Energy decomposition and hydrogen bond analysis revealed that crucial residues (Tyr950, Gln946, His61, and Glu875) are essential for binding stability due to enduring hydrogen bonds and robust electrostatic interactions. Hydrophobic interactions with residues such as Leu65 and Gln347 augmented binding affinity. These findings clarify the molecular factors influencing statin-P-gp interactions and offer insights into the structure-activity link that regulates binding affinity and conformational stability. The results provide a basis for developing statins with enhanced P-gp binding characteristics, potentially augmenting their therapeutic effectiveness and pharmacokinetic profiles.

Background:Metabolic factors play a critical role in the onset of lower limb joint pain, especially in middle-aged and older individuals. TyG and its derivatives, have emerged as promising indicators of insulin resistance, and are linked with several metabolic diseases, yet their relationships with lower limb joint pain remains insufficiently studied. Methods:This study utilized 9-year longitudinal data (2011-2020) from the China Health and Retirement Longitudinal Study (CHARLS). TyG and its derivatives were collected at baseline (2011). Incident lower limb joint pain was recorded during follow-up. The associations were evaluated using Multivariable Cox proportional hazards models, Restricted Cubic Spline (RCS), and Kaplan-Meier curves. The robustness of the findings was assessed by Fine-Gray competing risk model and subgroup analyses. Results:Among 6817 participants, 2909 (42.67%) developed lower limb joint pain. The highest incidence occurred in the fourth quartile of TyG-BMI, TyG-WHtR and TyG-WC, but not TyG alone. There existed significant positive associations of TyG-BMI (p for trend: 0.015) and TyG-WHtR (p for trend: 0.004) with lower limb joint pain risk, especially the fourth quartiles of TyG-BMI (HR: 1.15; 95% CI: 1.02-1.30), TyG-WHtR (1.18 [1.05-1.32]) and TyG-WC (1.14 [1.01-1.27]). The Fine-Gray competing risk model confirmed this robust association, and RCS indicated significant positive linear relationships of TyG-BMI and TyG-WHtR with new-onset lower limb joint pain. Subgroup analysis identified gender as a significant interactive factor for TyG-BMI, with a notable association in females. These results suggested that TyG derivatives, specifically adiposity-integrated indices, were associated with an increased risk of new-onset lower limb joint pain in middle-aged and older individuals, rather than TyG alone. Conclusion:These results highlight the importance of monitoring TyG derivatives, specifically adiposity-integrated indices (TyG-BMI and TyG-WHtR) for early clinical detection and intervention in high-risk individuals, and offer novel perspectives for the assessment and treatment of lower limb joint pain.

Epidemiological studies indicate that Metabolic Associated Fatty Liver Disease (MAFLD) has become the most prevalent chronic liver disease globally. Identifying bioactive molecules from natural plants that can prevent and ameliorate MAFLD is an effective approach to discovering new MAFLD therapeutics. Liupao tea possesses antioxidant and metabolic regulatory properties. This study aimed to identify the active components of Liupao tea polyphenol extract (PLE), and its potential targets and mechanisms of action in the prevention of MAFLD. We performed experiments on MAFLD mice to establish the prevention efficacy of PLE against MAFLD and determine its optimal dosage. Furthermore, network pharmacology, molecular docking, and SPR were performed to predict that PLE's targets for preventing MAFLD concentrate on the hepatic EGFR target. Knockout of EGFR in hepatocytes attenuated the effects of PLE. These findings indicate that PLE inhibits lipid accumulation by downregulating the EGFR/pEGFR-AKT/pAKT-SREBP-1-ACC1 pathway through binding to the EGFR receptor, thereby preventing MAFLD.

OBJECTIVES:Chronic kidney disease (CKD) is a progressive medical condition marked by a gradual decline in kidney function, leading to an accumulation of waste products and fluids in the body. Drug-induced liver injury (DILI) poses a significant clinical challenge in CKD management, with paracetamol being a commonly used medication. Advanced oxidation protein products (AOPPs) are biomarkers of CKD progression and contributors to DILI. However, the mechanisms behind the increased incidence of DILI in CKD remain unclear. METHODS:We developed an adenine-induced CKD mice model, a paracetamol-induced DILI mice model, and an AOPPs-loaded mice model using intraperitoneal injections. KEY FINDINGS:Declining renal function in the CKD model was associated with a significant weight loss and increased the concentration of serum creatinine and blood urea nitrogen. Following paracetamol administration, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and N-acetyl-p-benzoquinoneimine and liver tissue necrosis increased significantly in CKD groups. In addition, the expression of cytochrome P450 2E1 (CYP2E1) and thrombospondin receptor (CD36) were upregulated, while the adenylate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway showed significant changes in protein expression and phosphorylation. In AOPPs-loaded model, AOPPs upregulated AMPK and Akt protein expression, along with reduced mTOR levels. In HepG2 and L0-2 cell lines, AOPPs and paracetamol significantly increased the protein expression and phosphorylation of AMPK and Akt, alongside a decreased mTOR expression and phosphorylation. AOPPs and paracetamol significantly induced the apoptosis in HepG2 and L0-2 cells. Notably, the expression of CYP2E1 induced by AOPPs and paracetamol was inhibited by dorsomorphin and corynoxine B. CONCLUSIONS:These findings suggest that the AMPK-mTOR signaling pathway mediates the worsening of paracetamol-induced liver injury in CKD, with AOPPs potentially serving as key endogenous factors. This study lays the groundwork for identifying crucial molecules involved in exacerbated paracetamol-induced liver injury in CKD, which may serve as new drug targets and improve the safety profile of paracetamol in patients with CKD.

OBJECTIVES:To examine the effects of belimumab on the immune atlas in patients with systemic lupus erythematosus (SLE). METHODS:We present a single-cell RNA-seq profile of peripheral blood mononuclear cells from six patients with active SLE before and after drug treatment initiation. Three of these patients received belimumab combined with conventional therapy, while three received conventional therapy alone, and served as the control group. RESULTS:We found that belimumab significantly decreased the number of CD16+ monocytes after 8 weeks of treatment, whereas the opposite was observed in the control group. Compared to conventional therapy, belimumab elicited a significant reduction in IFN-stimulated gene (ISG) activity in monocytes and low-density granulocytes (LDGs). Notably, the expansion of unique subpopulations enriched among ISGs was inhibited in patients treated with belimumab. Moreover, the transcription and expression of BAFF-R and B-cell maturation antigen, two BAFF receptors, was increased in plasmacytoid dendritic cells (pDCs), B cells and plasma cells. However, the expression of BAFF-R was inhibited in monocytes and T cells in patients with SLE. CONCLUSIONS:These results revealed a novel mechanism of belimumab action, advancing our understanding of the immune atlas in SLE patients before and after belimumab-targeting treatment.

BackgroundIn contrast to previous network meta-analysis using classical frequentist methods, we evaluated the efficacy and safety of six frequently-used biologics through a Bayesian method.MethodsWeb of Science, Scopus, CENTRAL, ClinicalTrials.gov and ICTRP were searched to collect randomized controlled trials (RCTs) in adults with moderate-to-severe Crohn’s disease, comparing Infliximab, Adalimumab, Certolizumab pegol, Ustekinumab, Risankizumab, or Vedolizumab, relative to placebo or an active comparator for induction of clinical response (two different definitions) and maintenance of clinical remission. A random-effects model was performed with rankings according to the surface under cumulative ranking curve (SUCRA) probability. Finally, we completed sensitivity and consistency analyses, and evaluated the certainty of evidence through GRADE working group guidance.ResultsWe identified 22 and 20 RCTs for induction and maintenance therapy, respectively. Infliximab combined with azathioprine was most effective for inducing clinical response in TNF (tumor necrosis factor) antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab (SUCRA 86.19) and Risankizumab (SUCRA 62.56) have the largest SUCRA in induction of clinical response. Risankizumab has the lowest risk of adverse events (SUCRA 84.81), serious adverse events (SUCRA 94.23), and serious infections (SUCRA 79.73) in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab rank highest for maintaining clinical remission.ConclusionThis analysis suggests that Infliximab in combination with azathioprine may be preferred biologic agents for induction therapy in TNF antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab and Risankizumab may be preferred biologic agents for induction therapy. Risankizumab potentially has the lowest safety risk worth exploring in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab have maintenance efficacy benefits for responders to induction therapy.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=458609, Identifier CRD42023458609.

Psoriasis is a chronic, recurrent and systemic inflammatory skin disease which is mediated by immunoreaction. Its pathogenesis is multifactorial, and the exact driving factor remains unclear. Recent studies showed that gut microbiota, which maintain immune homeostasis of our bodies, is closely related with occurrence, development and prognosis of psoriasis. The intestinal microbial abundance and diversity in patients with psoriasis have changed significantly, including intestinal microbiota disorders and reduced production of short chain fatty acids (SCFAs), abnormalities in Firmicutes/Bacteroidetes (F/B), etc. Besides, the intestinal microbiota of psoriasis patients has also changed after treatment of systemic drugs, biologics and small molecule chemical drugs, suggesting that the intestinal microbiota may be a potential response-to-treatment biomarker for evaluating treatment effectiveness. Oral probiotics and prebiotics administration as well as fecal microbial transplantation were also reported to benefit well in psoriasis patients. Additionally, we also discussed the microbial changes from the skin and other organs, which regulated both the onset and treatment of psoriasis together with gut microbiota. Herein, we reviewed recent studies on the psoriasis-related microbiota in an attempt to confidently identify the "core" microbiota of psoriatic patients, understand how microbiota influence psoriasis through the gut-skin axis, and explore potential therapeutic strategies for psoriasis.

ObjectivesThe purpose of this study was to investigate the effect of intestinal dysbiosis on the bioavailability of voriconazole and to explore any underlying mechanisms.MethodSprague-Dawley rats were randomly divided into two groups: a normal control group and a ceftriaxone-associated dysbiotic group. The composition of the intestinal flora was examined using 16S rRNA sequencing analysis. Voriconazole concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Outer membrane vesicles (OMVs) of microbes from the different groups were prepared for in vitro study in Caco-2 cells. The Nrf2 pathway and its related proteins involved in modifying P-glycoprotein (P-gp) expression were clarified by a series of immunoblot analyses.Key findingsThe diversity and richness of intestinal bacteria, especially the abundance of gram-negative bacteria, were significantly decreased after ceftriaxone treatment. The AUC(0-t) and Cmax of voriconazole were reduced, and greater voriconazole clearance were noted in the dysbiotic group. An in vivo study also indicated that the expression of P-glycoprotein was significantly increased after ceftriaxone treatment, which may be due to the absence of gram-negative bacteria in the intestine. Finally, in vitro findings in Caco-2 cells treated with OMVs from the ceftriaxone-associated dysbiotic group suggested that Nrf2 translocation into the nucleus induced high expression of P-gp.ConclusionOMVs from intestinal bacterial in the ceftriaxone-associated dysbiotic group induced high P-gp expression by regulating the Nrf2 signalling pathway, which led to an in vivo reduction in the bioavailability of voriconazole due to ceftriaxone-associated dysbiosis.

Depression is a highly prevalent and disabling psychiatric disorder worldwide, yet current treatments are limited by delayed onset and suboptimal response rates. The α7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated cation channel within the central cholinergic system, is highly expressed in emotion-regulating regions including the hippocampus and prefrontal cortex, where it modulates neurotransmitter release, synaptic plasticity, and neuroinflammation. Accumulating preclinical evidence indicates that α7 nAChR activation may exert antidepressant-like effects by modulating monoaminergic neurotransmission, enhancing brain-derived neurotrophic factor (BDNF) expression, attenuating microglial activation and proinflammatory cytokine release, and engaging gut–brain-axis pathways. Nevertheless, heterogeneous findings, target-engagement hurdles, and a paucity of adequately powered clinical studies have limited translation to the clinic. This review systematically summarizes the structural features, mechanistic insights, and therapeutic advances of α7 nAChR in depression, with the aim of providing a theoretical basis and future directions for targeted interventions and novel drug discovery.

Background and Aims: Voriconazole (VRC), a widely used antifungal drug, often causes hepatotoxicity, which presents a significant clinical challenge. Previous studies demonstrated that Astragalus polysaccharide (APS) can regulate VRC metabolism, thereby potentially mitigating its hepatotoxic effects. In this study, we aimed to explore the mechanism by which APS regulates VRC metabolism. Methods: First, we assessed the association of abnormal VRC metabolism with hepatotoxicity using the Roussel Uclaf Causality Assessment Method scale. Second, we conducted a series of basic experiments to verify the promotive effect of APS on VRC metabolism. Various in vitro and in vivo assays, including cytokine profiling, immunohistochemistry, quantitative polymerase chain reaction, metabolite analysis, and drug concentration measurements, were performed using a lipopolysaccharideinduced rat inflammation model. Finally, experiments such as intestinal biodiversity analysis, intestinal clearance as sessments, and Bifidobacterium bifidum replenishment were performed to examine the ability of B. bifidum to regulate the expression of the VRC-metabolizing enzyme CYP2C19 through the gut-liver axis. Results: The results indicated that APS does not have a direct effect on hepatocytes. However, the assessment of gut microbiota function revealed that APS significantly increases the abundance of B. bifidum, which could lead to an anti-inflammatory response in the liver and indirectly enhance VRC metabolism. The dual-luciferase reporter gene assay revealed that APS can hinder the secretion of pro-inflammatory mediators and reduce the inhibitory effect on CYP2C19 transcription through the nuclear factor-KB signaling pathway. Conclusions: The study offers valuable insights into the mechanism by which APS alleviates VRC-induced liver damage, highlighting its immunomodulatory influence on hepatic tissues and its indirect regulatory control of VRC-metabolizing enzymes within hepatocytes.

Background Coronavirus disease 2019 (COVID-19) is an evolving global pandemic, and nanobodies, as well as other single-domain antibodies (sdAbs), have been recognized as a potential diagnostic and therapeutic tool for infectious diseases. High-throughput screening techniques such as phage display have been developed as an alternative to in vivo immunization for the discovery of antibody-like target-specific binders. Methods We designed and constructed a highly diverse synthetic phage library sdAb-U (single-domain Antibody - Universal library ) based on a human framework. The SARS-CoV-2 receptor-binding domain (RBD) was expressed and purified. The universal library sdAb-U was panned against the RBD protein target for two rounds, followed by monoclonal phage ELISA (enzyme-linked immunosorbent assay) to identify RBD-specific binders (the first stage). High-affinity binders were sequenced and the obtained CDR1 and CDR2 sequences were combined with fully randomized CDR3 to construct a targeted (focused) phage library sdAb-RBD, for subsequent second-stage phage panning (also two rounds) and screening. Then, sequences with high single-to-background ratios in phage ELISA were selected for expression. The binding affinities of sdAbs to RBD were measured by an ELISA-based method. In addition, we conducted competition ELISA (using ACE2 ectodomain S19-D615) and SARS-CoV-2 pseudovirus neutralization assays for the high-affinity RBD-binding sdAb39. Results Significant enrichments were observed in both the first-stage (universal library) and the second-stage (focused library) phage panning. Five RBD-specific binders were identified in the first stage with high ELISA signal-to-background ratios. In the second stage, we observed a much higher possibility of finding RBD-specific clones in phage ELISA. Among 45 selected RBD-positive sequences, we found eight sdAbs can be well expressed, and five of them show high-affinity to RBD (EC 50 < 100nM). We finally found that sdAb39 (EC 50 ~ 4nM) can compete with ACE2 for binding to RBD. Conclusion Overall, this two-stage strategy of synthetic phage display libraries enables rapid selection of SARS-CoV-2 RBD sdAb with potential therapeutic activity, and this two-stage strategy can potentially be used for rapid discovery of sdAbs against other targets.

Purpose: This study aims to investigate the effects of Huang Gan formula (HGF), a Chinese herbal prescription used for chronic kidney disease (CKD), on the regulation of the gut microbiota and colonic microenvironment of CKD.Methods: CKD rats were induced by 150 mg/kg adenine gavage for 4 weeks, then orally treated with or without 3.6 g/kg or 7.2 g/kg of HGF for 8 weeks. The renal function and structure were analyzed by biochemical detection, hematoxylin and eosin, Masson's trichrome, Sirius red and immunochemical staining. Average fecal weight and number in the colon were recorded to assess colonic motility. Further, the changes in the gut microbiota and colonic microenvironment were evaluated by 16S rRNA sequencing, RT-PCR or immunofluorescence. The levels of inflammatory cytokines, uremic toxins, and NF-kappa B signaling pathway were detected by RTPCR, ELISA, chloramine-T method or Western blotting. Redundancy analysis biplot and Spearman's rank correlation coefficient were used for correlation analysis.Results: HGF significantly improved renal function and pathological injuries of CKD. HGF could improve gut microbial dysbiosis, protect colonic barrier and promote motility of colonic lumens. Further, HGF inhibited systemic inflammation through a reduction of TNF-alpha, IL-6, IL-113, TGF-131, and a suppression of NF-kappa B signaling pathway. The serum levels of the selected uremic toxins were also reduced by HGF treatment. Spearman correlation analysis suggested that high-dose HGF inhibited the overgrowth of bacteria that were positively correlated with inflammatory factors (eg, TNF-alpha) and uremic toxins (eg, indoxyl sulfate), whereas it promoted the proliferation of bacteria belonging to beneficial microbial groups and was positively correlated with the level of IL-10.Conclusion: Our results suggest that HGF can improve adenine-induced CKD via suppressing systemic inflammation and uremia, which may associate with the regulations of the gut microbiota and colonic microenvironment.

Drug-induced liver injury (DILI) is prevalent in the treatment of chronic kidney disease (CKD). Advanced oxidation protein products (AOPPs) are markers of CKD progression and participate in the occurrence and development of liver diseases. However, the mechanisms underlying the regulation of DILI in CKD have not been established. Herein, we demonstrate the involvement of Cytochrome p450 2E1 (CYP2E1) in DILI induced by AOPPs is exacerbated by exposure to acetaminophen (APAP). We used a adenine-induced CKD model, a model of DILI induced by APAP, and the AOPPs model was generated by intraperitoneal injection. The decline in renal function was associated with a significantly increased concentration of Scr, BUN and AOPPs, and renal tissue fibrosis. The ALT, AST, and AOPPs levels and liver tissue necrosis increased significantly in CKD model group compared with the sodium carboxymethyl cellulose (CMCNa) group. In the AOPPs model, compared to the PBS controls, ALT, AST, and AOPP levels, and liver tissue necrosis increased significantly. In HepG2 or L0-2 cell lines, cell survival was significantly reduced in the AOPP + APAP treatment and CYP2E1 protein expression was increased. FPS-ZM1 or NAC attenuated the hepatocyte toxicity induced by AOPP + APAP and suppression of CYP2E1 expression. AOPPs exacerbated APAP-induced DILI through CYP2E1 signaling pathways. Protein uremic toxins, such as AOPPs, can modify drug toxicity in patients with CKD. This study provides new a rationale to reduce the generation of DILIs in clinical treatment in patients with CKD. AOPPs targeting may present a novel approach to reduce the occurrence of DILI.

Purpose: Voriconazole (VOR) is combined with atorvastatin (ATO) to treat fungal infections in patients with dyslipidemia in clinical practice. However, the pharmacokinetic interactions and potential mechanisms between them are unknown. Therefore, this study aimed to investigate the pharmacokinetic interactions and potential mechanisms between ATO and VOR.Patients and methods: We collected plasma samples from three patients using ATO and VOR. Rats were administered either VOR or normal saline for 6 days, followed by a single dose of 2 mg/kg ATO, and then plasma samples were collected at different time points. The incubation models of human liver microsomes or HepG2 cells were constructed in vitro. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) system was developed to determine the concentration of ATO, 2-hydroxy-ATO, 4-hydroxy-ATO, and VOR.Results: In patients, VOR significantly reduced the metabolism of ATO and slowed the formation of 2-hydroxy- and 4-hydroxy-ATO. In rats pretreated with orally administered VOR for 6 days or normal saline given a single dose of 2 mg/kg ATO administered orally on Day 6, the t1/2 of ATO was significantly prolonged from 3.61 to 6.43 h, and the area under the concentration-time curve (AUC0–24h) values of ATO increased from 53.86 to 176.84 h μg.L−1. However, the pharmacokinetic parameters of VOR (20 mg/kg) with or without pretreatment with ATO (2 mg/kg) only slightly changed. In vitro studies indicated that VOR inhibited the metabolism of ATO and testosterone, and the IC50 values were 45.94 and 49.81 μM. However, no significant change in transporter behaviors of ATO was observed when VOR or transporter inhibitors were co-administered.Conclusion: Our study demonstrated that VOR has significant interactions with ATO, probably due to VOR’s inhibition of the CYP3A4-mediated metabolism of ATO. Based on the clinical cases and potential interactions, the basic data obtained in our study are expected to help adjust the dose of ATO and promote the design of rational dosage regimens for pharmacotherapy for fungal infections in patients with dyslipidemia.

AIM:To assess the potential heterogeneity in cardiovascular (CV), renal and safety outcomes of canagliflozin between Whites and Asians, as well as these outcomes in each subgroup. MATERIALS AND METHODS:The CANVAS Program enrolled 10 142 patients with type 2 diabetes, comprising 78.34% Whites and 12.66% Asians. CV, renal and safety outcomes were comprehensively analysed using Cox regression models, while intermediate markers were assessed using time-varying mixed-effects models. Racial heterogeneity was evaluated by adding a treatment-race interacion term. RESULTS:Canagliflozin showed no significant racial disparities in the majority of the CV, renal and safety outcomes. The heterogeneity (p = .04) was observed on all-cause mortality, with reduced risk in Whites (hazard ratio 0.84; 95% confidence interval 0.71-0.99) and a statistically non-significant increased risk in Asians (hazard ratio 1.64; 95% confidence interval 0.94-2.90). There was a significant racial difference in acute kidney injury (p = .04) and a marginally significant racial heterogeneity for the composite of hospitalization for heart failure and CV death (p = .06) and serious renal-related adverse events (p = .07). CONCLUSION:Canagliflozin reduced CV and renal risks similarly in Whites and Asians; however, there was a significant racial discrepancy in all-cause mortality. This distinction may be attributed to the fact that Asian patients exhibited diminished CV protection effects and more renal adverse events with canagliflozin, potentially resulting from the smaller reductions in weight and uric acid. These findings highlight the importance of investigating the impact of race on treatment response to sodium-glucose cotransporter-2 inhibitors and provide more precise treatment strategies.

Image, graphical abstractAs an accelerators of the progress of CKD, AOPPs significantly prolong the t1/2 and MRT0-∞ and increase the AUC0-∞ of aloe-emodin, emodin, rhein and chrysophanol by increasing inflammatory cytokine production. Studies of aloe-emodin, emodin, rhein and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.

Coronavirus disease 2019 (COVID-19) is an evolving global pandemic, and nanobody (Nb) is recognized as a potential diagnostic and therapeutic tool for infectious disease. Here, we designed and synthesized a humanized and highly diverse phage Nbs library hsNb-U (Humanized synthetic Nbs Library - Universal). We expressed and purified the SARS-CoV-2 receptor-binding domain (RBD), and screened this univeral library against the RBD protein target. Then, the CDR1 and CDR2 sequences of five leads obtained from the hsNb-U phage panning were combined with randomly mutated CDR3 to construct a targeted (focused) phage display library, hsNb-RBD, for subsequent phage panning and screening. From the obtained sequences, we expressed 45 unique anti-RBD candidate Nbs. Among the selected Nbs, eight were found to be highly expressed, and five of these show high-affinity to RBD (EC 50 less than 100nM). Finally, we found that Nb39 can compete with angiotensin converting enzyme 2 (ACE2) for binding to RBD. Overall, this two-step strategy of synthetic phage display libraries enables rapid selection of SARS-CoV-2 RBD nanobodies with potential therapeutic activity, and this two-step strategy can potentially be used for rapid discovery of Nbs against other targets.

Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1–3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body’s response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body’s local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.