2D Tantalum Disulfide Reduction Strategy Customized Ta2O5/rGO Heterointerface Aerogel Toward Boosting Electromagnetic Wave Absorption and Flame Retardancy.

The exceptional and substantial electron affinity, as well as the excellent chemical and thermal stability of transition metal oxides (TMOs), infuse infinite vitality into multifunctional applications, especially in the field of electromagnetic wave (EMW) absorption. Nonetheless, the suboptimal structural mechanical properties and absence of structural regulation continue to hinder the advancement of TMOs-based aerogels. Herein, a novel 2D tantalum disulfide (2H-TaS2) reduction strategy is demonstrated to synthesize Ta2O5/reduced graphene oxide (rGO) heterointerface aerogels with unique characters. As the prerequisite, the defects, interfaces, and configurations of aerogels are regulated by varying the concentration of 2H-TaS2 to ensure the Ta2O5/rGO heterointerface aerogels with appealing EMW absorption properties such as a minimum reflection loss (RLmin) of -61.93 dB and an effective absorption bandwidth (EAB) of 8.54 GHz (7.80-16.34 GHz). This strategy provides valuable insights for designing advanced EMW absorbers. Meanwhile, the aerogel exhibits favorable thermal insulation performance with a value of 36 mW m-1 K-1, outstanding fire resistance capability, and exceptional mechanical energy dissipation performance, making it promising for applications in the aerospace industry and consumer electronics devices.

Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial.

Importance: Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. Objective: To assess the efficacy of argatroban plus alteplase for AIS. Design, Setting, and Participants: This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Interventions: Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 µg/kg bolus over 3-5 minutes followed by an infusion of 1.0 µg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Conclusions and Relevance: Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03740958.

Microparticles from Hyperphosphatemia-Stimulated Endothelial Cells Promote Vascular Calcification Through Astrocyte-Elevated Gene-1.

Endothelial microparticles (EMPs) can be released in chronic kidney disease (CKD). Plasma concentration of high inorganic phosphate (HP) is considered as a decisive determinant of vascular calcification in CKD. We therefore explored the role of HP-induced EMPs (HP-EMPs) in the vascular calcification and its potential mechanism. We observed the shape of HP-EMPs captured by vascular smooth muscle cells (VSMCs) dynamically changed from rare dots, rosettes, to semicircle or circle. Our results demonstrated that HP-EMPs could directly promote VSMC calcification, or accelerate HP-induced calcification through signal transducers and activators of transcription 3 (STAT3)/bone morphogenetic protein-2 (BMP2) signaling pathway. AEG-1 activity was increased through HP-EMPs-induced VSMC calcification, in arteries from uremic rats, or from uremic rats treated with HP-EMPs. AEG-1 deficiency blocked, whereas AEG-1 overexpression exacerbated, the calcium deposition of VSMCs. AEG-1, a target of miR-153-3p, could be suppressed by agomiR-153-3p. Notably, VSMC-specific enhance of miR-153-3p by tail vein injection of aptamer-agomiR-153-3p decreased calcium deposition in both uremia rats treated with HP-EMPs or not. HP-EMPs could directly induce VSMCs calcification and accelerate Pi-induced calcification, and AEG-1 may act as crucial regulator of HP-EMPs-induced vascular calcification. This study sheds light on the therapeutic agents that influence HP-EMPs production or AEG-1 activity, which may be of benefit to treat vascular calcification.

RNA-seq analysis of extracellular vesicles from hyperphosphatemia-stimulated endothelial cells provides insight into the mechanism underlying vascular calcification.

BACKGROUND: Hyperphosphatemia (HP) is associated with vascular calcification (VC) in chronic kidney disease (CKD). However, relationship between HP-induced-endothelial extracellular vesicles (HP-EC-EVs) and VC is unclear, and miR expression in HP-EC-EVs has not been determined. METHODS: We isolated HP-EC-EVs from endothelial cells with HP and observed that HP-EC-EVs were up-taken by vascular smooth muscle cells (VSMCs). HP-EC-EVs inducing calcium deposition was characterized by Alizarin Red S, colourimetric analysis and ALP activity. To investigate the mechanism of HP-EC-EVs-induced VSMC calcification, RNA-sequencing for HP-EC-EVs was performed. RESULTS: We first demonstrated that HP-EC-EVs induced VSMC calcification in vitro. RNA-seq analysis of HP-EC-EVs illustrated that one known miR (hsa-miR-3182) was statistically up-regulated and twelve miRs were significantly down-regulated, which was verified by qRT-PCR. We predicted 58,209 and 74,469 target genes for those down- and up-regulated miRs respectively through miRDB, miRWalk and miRanda databases. GO terms showed that down- and up-regulated targets were mostly enriched in calcium-dependent cell-cell adhesion via plama membrane cell-adhesion molecules (GO:0,016,338, BP) and cell adhesion (GO:0,007,155, BP), plasma membrane (GO:0,005,886, CC), and metal ion binding (GO:0,046,914, MF) and ATP binding (GO:0,005,524, MF) respectively. Top-20 pathways by KEGG analysis included calcium signaling pathway, cAMP signaling pathway, and ABC transporters, which were closely related to VC. CONCLUSION: Our results indicated that those significantly altered miRs, which were packaged in HP-EC-EVs, may play an important role in VC by regulating related pathways. It may provide novel insight into the mechanism of CKD calcification.

Causes and predictors of mortality from lupus nephritis in Southern Hunan, China.

OBJECTIVES: The objective of the study was to explore the causes and predictors of mortality in a cohort of LN with LN in southern Hunan, China. METHODS: We analyzed 236 patients with biopsy-proven LN during 2010-2018. Demographic data, laboratory data, SLEDAI scores, treatment strategies, and comorbidity were collected. Cox regression analysis was carried out to determine the independent predictors of mortality. RESULTS: The patients had mean disease duration of 67.9 ± 28.2 months. Class IV LN was the predominant biopsy class within the cohort (38.1%). After 1 year therapy, the majority of patients achieved complete remission (72.9%) and 44 (18.6%) patients achieved partial remission. The 5- and 10-years survival rates for our cohort were 94.4 and 85.2%, respectively. There were 18 deaths (7.6%), of which the main causes were infection (50%) alone and cardiovascular diseases (27.8%). Independent predictors of mortality in our cohort were: platelet-to-neutrophil ratio (PNR) [hazard ratio (HR) 5.910; confidence interval (CI) 1.253-27.875], onset age (HR 1.090; CI 1.035-1.147), and SLEDAI scores (HR 1.258; CI 1.068-1.482). CONCLUSION: We firstly revealed that PNR might be a promising predictor of mortality and reported the causes and prognostic predictors of mortality in LN from southern Hunan, China.

Afatinib Decreases P-Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells.

We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P-glycoprotein (P-gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P-gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P-gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR-induced apoptosis and autophagy in A549T cells. Meanwhile, the co-treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase-3, PARP, LC3B-II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P-gp, ADR-induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414-423, 2018. © 2017 Wiley Periodicals, Inc.

Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury.

Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.

High-sensitivity, ultrawide linear range, antibacterial textile pressure sensor based on chitosan/MXene hierarchical architecture.

It is still a great challenge for the flexible piezoresistive pressure sensors to simultaneously achieve wide linearity and high sensitivity. Herein, we propose a high-performance textile pressure sensor based on chitosan (CTS)/MXene fiber. The hierarchical "point to line" architecture enables the pressure sensor with high sensitivity of 1.16 kPa-1 over an ultrawide linear range of 1.5 MPa. Furthermore, the CTS/MXene pressure sensor possesses a low fatigue over 1000 loading/unloading cycles under 1.5 MPa pressure load, attributed to the strong chemical bonding between CTS fiber and MXene and excellent mechanical stability. Besides, the proposed sensor shows good antibacterial effect benefiting from the strong interaction between polycationic structure of CTS/MXene and the predominantly anionic components of bacteria surface. The sensor is also applied to detect real-time human action, an overall classification accuracy of 98.61% based on deep neural network-convolutional neural network (CNN) for six human actions is realized.

Tenecteplase Plus Butyphthalide for Stroke Within 4.5-6 Hours of Onset (EXIT-BT): a Phase 2 Study.

To date, the benefit of intravenous thrombolysis is confined to within 4.5 h of onset for acute ischemic stroke (AIS) without advanced neuroimaging selection. The current trial aimed to investigate the safety and efficacy of intravenous tenecteplase (TNK) plus Dl-3-n-Butylphthalide (NBP) in AIS within 4.5 to 6 h of onset. In this randomized, multicenter trial, eligible AIS patients were randomly assigned to receive intravenous TNK (0.25 mg/kg) plus NBP or NBP within 4.5 to 6 h of onset. The primary endpoint was symptomatic intracranial hemorrhage (sICH). Secondary endpoints included excellent functional outcome defined as a modified Rankin Scale score of 0 to 1 at 90 days. 100 patients diagnosed by non-contrast CT (NCCT) were enrolled, including 50 in TNK group and 50 in control group. sICH occurred in 2.0% (1/50) in TNK group and 0.0% (0/49) in control group with no difference (unadjusted P = 0.998). The proportion of excellent functional outcome was 77.6% (38/49) in TNK group and 69.4% (34/49) in control group with non-significance (absolute difference 8.2%, P = 0.36). A significant decrease in NIHSS score at 24 h (P = 0.004) and more early neurological improvement (20.4% vs 4.1%; P = 0.026) was observed in TNK vs control group, but there was no difference in other secondary outcomes. This phase 2 study suggests that intravenous TNK with adjuvant NBP seems safe, feasible and may improve early neurological function in AIS patients within 4.5 to 6 h of symptom onset selected using NCCT.Clinical Trials Registration: This trial was registered with ClinicalTrials.gov (NCT05189509).

Clopidogrel Plus Aspirin vs Aspirin Alone in Patients With Acute Mild to Moderate Stroke: The ATAMIS Randomized Clinical Trial.

Importance: Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking. Objective: To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke. Design, Setting, and Participants: This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome. Interventions: Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio. Main Outcomes and Measures: The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points. Results: Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups. Conclusions and Relevance: Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT02869009.

Extracellular vesicles in atherosclerosis and vascular calcification: the versatile non-coding RNAs from endothelial cells and vascular smooth muscle cells.

Atherosclerosis (AS) is characterized by the accumulation of lipids, fibrous elements, and calcification in the innermost layers of arteries. Vascular calcification (VC), the deposition of calcium and phosphate within the arterial wall, is an important characteristic of AS natural history. However, medial arterial calcification (MAC) differs from intimal calcification and cannot simply be explained as the consequence of AS. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are directly involved in AS and VC processes. Understanding the communication between ECs and VSMCs is critical in revealing mechanisms underlying AS and VC. Extracellular vesicles (EVs) are found as intercellular messengers in kinds of physiological processes and pathological progression. Non-coding RNAs (ncRNAs) encapsulated in EVs are involved in AS and VC, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). The effects of ncRNAs have not been comprehensively understood, especially encapsulated in EVs. Some ncRNAs have demonstrated significant roles in AS and VC, but it remains unclear the functions of the majority ncRNAs detected in EVs. In this review, we summarize ncRNAs encapsulated in EC-EVs and VSMC-EVs, and the signaling pathways that are involved in AS and VC.

VX-765 ameliorates CKD VSMC calcification by regulating STAT3 activation.

BACKGROUND: Recent clinical evidences show that caspase-1 inhibitor-VX-765 attenuates atherosclerosis in ApoE deficient mice. However, there is rarely information about the effect of VX-765 on hyperphosphatemia-induced vascular smooth muscle cells (VSMCs) calcification or vascular calcification in chronic kidney disease (CKD) rats. Here we investigate the effect of VX-765 on vascular calcification in uremia circumstances. METHODS: Hyperphosphatemia-induced VSMC calcification were evaluated by Alizarin Red S. Aortas from CKD rats which were gavaged with VX-765 were examined for calcification signal using micro-CT. Levels of NLRP3, caspase-1, and GSDMD were measured by quantitative real-time PCR, western blotting, immunofluorescence assay, and immunohistochemistry. RESULTS: We demonstrated for the first time that the levels of NLRP3, caspase-1, GSDMD, IL-1ß, and IL-18 were up-regulated in hyperphosphatemia-induced calcifying VSMCs. Blockade of caspase-1 activation by VX-765 inhibited pyroptosis-related molecules and VSMC calcification in a concentration-dependent manner in vitro. Further analysis of aortas from calcified CKD rats showed an up-regulation of caspase-1 and GSDMD expression compared with those non-calcified vascular tissue from control rats or with those decreased-calcified vascular tissue from CKD rats treated with 50 mg/kg/d, which indicated that pyroptotic indicators were tightly correlated with CKD arterial calcification. In vitro studies further demonstrated that VX-765 ameliorated hyperphosphatemia-induced VSMCs calcification through inhibiting the STAT3 activation. CONCLUSIONS: Our findings indicated that VX-765 could inhibit hyperphosphatemia-induced calcifying VSMCs and ameliorate vascular calcification in CKD rats. VX-765 might be a potential treatment strategy for CKD vascular calcification.

Intravenous Tenecteplase for Acute Ischemic Stroke Within 4.5-24 Hours of Onset (ROSE-TNK): A Phase 2, Randomized, Multicenter Study.

BACKGROUND AND PURPOSE: Intravenous tenecteplase (TNK) efficacy has not been well demonstrated in acute ischemic stroke (AIS) beyond 4.5 hours after onset. This study aimed to determine the effect of intravenous TNK for AIS within 4.5 to 24 hours of onset. METHODS: In this pilot trial, eligible AIS patients with diffusion-weighted imaging (DWI)-fluid attenuated inversion recovery (FLAIR) mismatch were randomly allocated to intravenous TNK (0.25 mg/kg) or standard care within 4.5-24 hours of onset. The primary endpoint was excellent functional outcome at 90 days (modified Rankin Scale [mRS] score of 0-1). The primary safety endpoint was symptomatic intracranial hemorrhage (sICH). RESULTS: Of the randomly assigned 80 patients, the primary endpoint occurred in 52.5% (21/40) of TNK group and 50.0% (20/40) of control group, with no significant difference (unadjusted odds ratio, 1.11; 95% confidence interval 0.46-2.66; P=0.82). More early neurological improvement occurred in TNK group than in control group (11 vs. 3, P=0.03), but no significant differences were found in other secondary endpoints, such as mRS 0-2 at 90 days, shift analysis of mRS at 90 days, and change in National Institutes of Health Stroke Scale score at 24 hours and 7 days. There were no cases of sICH in this trial; however, asymptomatic intracranial hemorrhage occurred in 3 of the 40 patients (7.5%) in the TNK group. CONCLUSION: This phase 2, randomized, multicenter study suggests that intravenous TNK within 4.5-24 hours of onset may be safe and feasible in AIS patients with a DWI-FLAIR mismatch.

Association between subclinical left ventricular ejection fraction and platelet-to-lymphocyte ratio in patients with peritoneal dialysis.

Background: Reduced left ventricular ejection function (LVEF) was associated with increased mortality in patients with peritoneal dialysis (PD) in Asia and the United States of America. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were correlated with LVEF in PD. However, little information is available regarding the relationship between monocyte-to-lymphocyte ratio (MLR), left ventricular ejection fraction (LVEF), and the use of NLR, PLR, and MLR in predicting left ventricular systolic dysfunction (LVSD) in patients with PD. Methods: All 181 patients with PD were enrolled between 2014 and 2021 from the Nephrology Department of the First Affiliated Hospital of the University of South China. Demographic features, clinical characteristics, laboratory values, and echocardiographic parameters were collected. Results: The mean age of patients with PD was 47.4 ± 12.6, and 90 (49.7%) of the patients were men. LVEF showed a negative correlation with PLR (r = -0.200, p = 0.007) and MLR (r = -0.146, p = 0.049). The levels of NLR, PLR, and MLR were elevated in patients with PD with LVSD compared with those without (all p < 0.05). PLR (OR 4.331, 95% CI: 1.223, 15.342) and albumin (OR 13.346, 95% CI: 3.928, 45.346) were significantly associated with LVSD patients with PD in the multivariate logistic analysis. For differentiating patients with PD with LVSD, optimal cutoffs of NLR, PLR, MLR, and albumin were 4.5 (sensitivity: 76.7%, specificity: 55.0%, and overall accuracy: 58%), 202.6 (sensitivity: 66.7%, specificity: 69.5%, and overall accuracy: 69%), 0.483 (sensitivity: 53.3%, specificity: 72.8%, and overall accuracy: 30%), and 34.6 (sensitivity: 72.2%), respectively. Conclusions: Our results revealed that PLR was better than NLR, MLR, and albumin in predicting LVSD in PD.

OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam.

This study aimed to demonstrate that organic anion transporters (OATs) mediate the drug-drug interaction (DDI) between piperacillin and tazobactam. After co-administration with piperacillin in rats, the AUC of tazobactam in plasma was significantly increased, and t1/2ß was prolonged with significant reduction in plasma clearance, renal clearance and cumulative urinary excretion. In rat and human kidney slices, probenecid, p-aminohippurate and benzylpenicillin inhibited the uptake of piperacillin and tazobactam. Piperacillin significantly inhibited the uptake of tazobactam. Moreover, the uptakes of piperacillin, tazobactam and sulbactam in hOAT1/3-HEK293 cells were significantly higher compared with mock-HEK293 cells, respectively. Piperacillin significantly inhibited the uptake of tazobactam in hOAT1/3-HEK293 cells. The Km values of tazobactam (431 ±â€¯67 µM for hOAT1, 377 ±â€¯63 µM for hOAT3) were significantly higher than those of piperacillin (37 ±â€¯5 µM for hOAT1, 172 ±â€¯28 µM for hOAT3). This suggested that piperacillin has a stronger affinity to hOAT1/3 than tazobactam. Meanwhile, the Km values of tazobactam were increased in the presence of piperacillin with unchanged Vmax. This indicated that piperacillin inhibited the uptake of tazobactam in a competitive manner. In conclusion, piperacillin and tazobactam are the substrates of hOAT1/3, and OAT1/3 mediate the DDI between piperacillin and tazobactam.