The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis.

Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.

Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. METHODS: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. RESULTS: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. CONCLUSIONS: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.

Blood lipids mediate the effects of gut microbiome on endometriosis: a mendelian randomization study.

BACKGROUND: There is evidence for an association between the gut microbiome and endometriosis. However, their causal relationship and the mediating role of lipid metabolism remain unclear. METHODS: Using genome-wide association study (GWAS) data, we conducted a bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between gut microbiome and endometriosis. The inverse variance weighted (IVW) method was used as the primary model, with other MR models used for comparison. Sensitivity analysis based on different statistical assumptions was used to evaluate whether the results were robust. A two-step MR analysis was further conducted to explore the mediating effects of lipids, by integrating univariable MR and the multivariate MR method based on the Bayesian model averaging method (MR-BMA). RESULTS: We identified four possible intestinal bacteria genera associated with the risk of endometriosis through the IVW method, including Eubacterium ruminantium group (odds ratio [OR] = 0.881, 95% CI: 0.795-0.976, P = 0.015), Anaerotruncus (OR = 1.252, 95% CI: 1.028-1.525, P = 0.025), Olsenella (OR = 1.110, 95% CI: 1.007-1.223, P = 0.036), and Oscillospira (OR = 1.215, 95% CI: 1.014-1.456, P = 0.035). The further two-step MR analysis identified that the effect of Olsenella on endometriosis was mediated by triglycerides (proportion mediated: 3.3%; 95% CI = 1.5-5.1%). CONCLUSION: This MR study found evidence for specific gut microbiomes associated with the risk of endometriosis, which might partially be mediated by triglycerides.

Improving the performance of reference-frame-independent quantum key distribution with advantage distillation technology.

The reference-frame-independent quantum key distribution (RFI-QKD) has the advantage of tolerating reference frames that slowly vary. It can generate secure keys between two remote users with slowly drifted and unknown reference frames. However, the drift of reference frames may inevitably compromise the performance of QKD systems. In the paper, we employ the advantage distillation technology (ADT) to the RFI-QKD and the RFI measurement-device-independent QKD (RFI MDI-QKD), and we then analyze the effect of ADT on the performance of decoy-state RFI-QKD and RFI MDI-QKD in both asymptotic and nonasymptotic cases. The simulation results show that ADT can significantly improve the maximum transmission distance and the maximum tolerable background error rate. Furthermore, the performance of RFI-QKD and RFI MDI-QKD in terms of the secret key rate and maximum transmission distance are still greatly improved when statistical fluctuations are taken into account. Our work combines the merits of the ADT and RFI-QKD protocols, which further enhances the robustness and practicability of QKD systems.

Sideband cooling of a trapped ion in strong sideband coupling regime.

Conventional theoretical studies on the ground-state laser cooling of a trapped ion have mostly focused on the weak sideband coupling (WSC) regime, where the cooling rate is inverse proportional to the linewidth of the excited state. In a recent work [New J. Phys.23, 023018 (2021)10.1088/1367-2630/abe273], we proposed a theoretical framework to study the ground state cooling of a trapped ion in the strong sideband coupling (SSC) regime, under the assumption of a vanishing carrier transition. Here we extend this analysis to more general situations with nonvanishing carrier transitions, where we show that by properly tuning the coupling lasers a cooling rate proportional to the linewidth can be achieved. Our theoretical predictions closely agree with the corresponding exact solutions in the SSC regime, which provide an important theoretical guidance for sideband cooling experiments.

Field test of quantum key distribution over aerial fiber based on simple and stable modulation.

We have developed a simple time-bin phase encoding quantum key distribution system, using the optical injection locking technique. This setup incorporates both the merits of simplicity and stability in encoding, and immunity to channel disturbance. We have demonstrated the field implementation of quantum key distribution over long-distance deployed aerial fiber automatically. During the 70-day field test, we achieved approximately a 1.0 kbps secure key rate with stable performance. Our work takes an important step toward widespread implementation of QKD systems in diverse and complex real-life scenarios.

Time-bin phase-encoding quantum key distribution using Sagnac-based optics and compatible electronics.

In this work, we present a new time-bin phase-encoding quantum key distribution (QKD), where the transmitter utilizes an inherently stable Sagnac-type interferometer, and has comparable electrical requirements to existing polarization or phase encoding schemes. This approach does not require intensity calibration and is insensitive to environmental disturbances, making it both flexible and high-performing. We conducted experiments with a compact QKD system to demonstrate the stability and secure key rate performance of the presented scheme. The results show a typical secure key rate of 6.2 kbps@20 dB and 0.4 kbps@30 dB with channel loss emulated by variable optical attenuators. A continuous test of 120-km fiber spool shows a stable quantum bit error rate of the time-bin basis within 0.4%∼0.6% over a consecutive 9-day period without any adjustment. This intrinsically stable and compatible scheme of time-bin phase encoding is extensively applicable in various QKD experiments, including BB84 and measurement-device-independent QKD.

Perioperative experiences and needs of patients who undergo colorectal cancer surgery and their family caregivers: a qualitative study.

PURPOSE: Colorectal cancer (CRC) surgeries are major, complex, and often associated with debilitating symptoms or significant deconditioning that may impair patients' quality of life. Little is known about how patients and family caregivers cope and their unmet needs during this daunting perioperative phase. This study aimed to explore the experiences and needs of CRC patients who undergo surgery and their family caregivers. METHODS: An exploratory qualitative design was adopted. A total of 27 participants comprising fifteen outpatients who had undergone colorectal cancer surgery and twelve family caregivers were recruited through purposive sampling from a public tertiary hospital in Singapore between December 2019 and November 2020. Individual, audio-recorded, semi-structured interviews were conducted, transcribed verbatim, and analyzed using thematic analysis. RESULTS: Four themes emerged: initial reactions to the diagnosis, impact of the illness and surgery, personal coping, and external support. The lack of apparent assessments on the psychological well-being of patients was found despite several participants exhibiting early signs of distress. Access to psychological support provided by healthcare professionals or peers was selective, and knowledge deficit was prevalent, especially in the preoperative stage. CONCLUSION: Psychological priming and strengthening are important for CRC patients' and their caregivers' adaptive coping throughout the treatment continuum. Technology-based, dyadic psychoeducation should be offered preoperatively to ease CRC patients' acceptance of their diagnosis and adjustment to life after surgery while at the same time reduce the burden of family carers.

A systematic review and meta-analysis on the effectiveness of web-based psychosocial interventions among patients with colorectal cancer.

AIMS: To synthesize the effectiveness of web-based psychosocial interventions on self-efficacy, anxiety, depression, quality of life (QoL), non-specific psychological and cancer-specific distress among patients with colorectal cancer (CRC). DESIGN: A systematic review and meta-analysis. DATA SOURCES: Six databases (PubMed, PsycINFO, Embase, Scopus, CINAHL and CNKI) were searched from inception to December 2021. REVIEW METHODS: Experimental/quasi-experimental studies involving patients with CRC for the improvement of aforementioned outcomes were included. Two reviewers screened and extracted the data, and assessed studies' methodological quality using risk of bias tools. Meta-analyses and narrative syntheses were performed. RESULTS: Nineteen studies consisting of 1386 participants were identified. Cognitive-behavioural therapy delivered online was the most common trialled web-based psychosocial intervention. Meta-analyses revealed no positive effect for self-efficacy (standardized mean difference 0.93, 95% CI: 0.52 to 1.35, p < .01) and minimal benefit for QoL (mean difference [MD] 2.83, 95% CI: -0.31 to 5.98, p = .08) but significant positive effects for anxiety (MD -2.23, 95% CI: -3.31 to -1.14, p < .01) and depression (MD -2.84, 95% CI: -4.09 to -1.59, p < .01) among CRC survivors in the intervention group as compared with the control group. Narrative synthesis suggested possible benefits in reducing distress. CONCLUSION: Web-based psychosocial interventions are promising alternatives to conventional delivery methods in reducing patients' anxiety, depression and distress. However, evidence on self-efficacy and QoL remains inconsistent. More adequately powered, well-designed trials with targeted and theory-based interventions are required to ascertain findings. IMPACT: By highlighting the potential of web-based psychosocial interventions in reducing anxiety and depression among CRC survivors, this review has put forth beneficial information supporting the use and acceptance of web-based care delivery in light of COVID-19 restrictions and nationwide lockdowns. Meanwhile, the paucity of empirical support reflects the necessity of more extensive research to test and improve other health outcomes. PROSPERO registration number: CRD42021261396.

Security Analysis of Sending or Not-Sending Twin-Field Quantum Key Distribution with Weak Randomness.

Sending-or-not sending twin-field quantum key distribution (SNS TF-QKD) has the advantage of tolerating large amounts of misalignment errors, and its key rate can exceed the linear bound of repeaterless quantum key distribution. However, the weak randomness in a practical QKD system may lower the secret key rate and limit its achievable communication distance, thus compromising its performance. In this paper, we analyze the effects of the weak randomness on the SNS TF-QKD. The numerical simulation shows that SNS TF-QKD can still have an excellent performance under the weak random condition: the secret key rate can exceed the PLOB boundary and achieve long transmission distances. Furthermore, our simulation results also show that SNS TF-QKD is more robust to the weak randomness loopholes than the BB84 protocol and the measurement-device-independent QKD (MDI-QKD). Our results emphasize that keeping the randomness of the states is significant to the protection of state preparation devices.

Practical Security of High-Dimensional Quantum Key Distribution with Intensity Modulator Extinction.

Quantum key distribution (QKD) has attracted much attention due to its unconditional security. High-dimensional quantum key distribution (HD-QKD) is a brand-new type of QKD protocol that has many excellent advantages. Nonetheless, practical imperfections in realistic devices that are not considered in the theoretical security proof may have an impact on the practical security of realistic HD-QKD systems. In this paper, we research the influence of a realistic intensity modulator on the practical security of HD-QKD systems with the decoy-state method and finite-key effects. We demonstrate that there is a certain impact in the secret key rate and the transmission distance when taking practical factors into security analysis.

Strong Quantum Computational Advantage Using a Superconducting Quantum Processor.

Scaling up to a large number of qubits with high-precision control is essential in the demonstrations of quantum computational advantage to exponentially outpace the classical hardware and algorithmic improvements. Here, we develop a two-dimensional programmable superconducting quantum processor, Zuchongzhi, which is composed of 66 functional qubits in a tunable coupling architecture. To characterize the performance of the whole system, we perform random quantum circuits sampling for benchmarking, up to a system size of 56 qubits and 20 cycles. The computational cost of the classical simulation of this task is estimated to be 2-3 orders of magnitude higher than the previous work on 53-qubit Sycamore processor [Nature 574, 505 (2019)NATUAS0028-083610.1038/s41586-019-1666-5. We estimate that the sampling task finished by Zuchongzhi in about 1.2 h will take the most powerful supercomputer at least 8 yr. Our work establishes an unambiguous quantum computational advantage that is infeasible for classical computation in a reasonable amount of time. The high-precision and programmable quantum computing platform opens a new door to explore novel many-body phenomena and implement complex quantum algorithms.

A Theory-Based, Multidisciplinary Approach to Cocreate a Patient-Centric Digital Solution to Enhance Perioperative Health Outcomes Among Colorectal Cancer Patients and Their Family Caregivers: Development and Evaluation Study.

BACKGROUND: Elective colorectal cancer (CRC) surgeries offer enhanced surgical outcomes but demand high self-efficacy in prehabilitation and competency in self-care and disease management postsurgery. Conventional strategies to meet perioperative needs have not been pragmatic, and there remains a pressing need for novel technologies that could improve health outcomes. OBJECTIVE: The aim of this paper was to describe the development of a smartphone-based interactive CRC self-management enhancement psychosocial program (iCanManage) in order to improve health outcomes among patients who undergo elective CRC surgeries and their family caregivers. METHODS: A multidisciplinary international team comprising physicians, specialist nurses, a psychologist, software engineers, academic researchers, cancer survivors, patient ambassadors, and ostomy care medical equipment suppliers was formed to facilitate the development of this patient-centric digital solution. The process occurred in several stages: (1) review of current practice through clinic visits and on-site observations; (2) review of literature and findings from preliminary studies; (3) content development grounded in an underpinning theory; (4) integration of support services; and (5) optimizing user experience through improving interface aesthetics and customization. In our study, 5 participants with CRC performed preliminary assessments on the quality of the developed solution using the 20-item user version of the Mobile App Rating Scale (uMARS), which had good psychometric properties. RESULTS: Based on the collected uMARS data, the smartphone app was rated highly for functionality, aesthetics, information quality, and perceived impact, and moderately for engagement and subjective quality. Several limiting factors such as poor agility in the adoption of digital technology and low eHealth literacy were identified despite efforts to promote engagement and ensure ease of use of the mobile app. To overcome such barriers, additional app-training sessions, an instruction manual, and regular telephone calls will be incorporated into the iCanManage program during the trial period. CONCLUSIONS: This form of multidisciplinary collaboration is advantageous as it can potentially streamline existing care paths and allow the delivery of more holistic care to the CRC population during the perioperative period. Should the program be found to be effective and sustainable, hospitals adopting this digital solution may achieve better resource allocation and reduce overall health care costs in the long run. TRIAL REGISTRATION: ClinicalTrials.gov NCT04159363; https://clinicaltrials.gov/ct2/show/NCT04159363.

Thiol-Responsive Gold Nanodot Swarm with Glycol Chitosan for Photothermal Cancer Therapy.

Photothermal therapy (PTT) is one of the most promising cancer treatment methods because hyperthermal effects and immunogenic cell death via PTT are destructive to cancer. However, PTT requires photoabsorbers that absorb near-infrared (NIR) light with deeper penetration depth in the body and effectively convert light into heat. Gold nanoparticles have various unique properties which are suitable for photoabsorbers, e.g., controllable optical properties and easy surface modification. We developed gold nanodot swarms (AuNSw) by creating small gold nanoparticles (sGNPs) in the presence of hydrophobically-modified glycol chitosan. The sGNPs assembled with each other through their interaction with amine groups of glycol chitosan. AuNSw absorbed 808-nm laser and increased temperature to 55 °C. In contrast, AuNSw lost its particle structure upon exposure to thiolated molecules and did not convert NIR light into heat. In vitro studies demonstrated the photothermal effect and immunogenic cell death after PTT with AuNSW. After intratumoral injection of AuNSw with laser irradiation, tumor growth of xenograft mouse models was depressed. We found hyperthermal damage and immunogenic cell death in tumor tissues through histological and biochemical analyses. Thiol-responsive AuNSw showed feasibility for PTT, with advanced functionality in the tumor microenvironment.

Sending or Not-Sending Twin-Field Quantum Key Distribution with Flawed and Leaky Sources.

Twin-field quantum key distribution (TF-QKD) has attracted considerable attention and developed rapidly due to its ability to surpass the fundamental rate-distance limit of QKD. However, the device imperfections may compromise its practical implementations. The goal of this paper is to make it robust against the state preparation flaws (SPFs) and side channels at the light source. We adopt the sending or not-sending (SNS) TF-QKD protocol to accommodate the SPFs and multiple optical modes in the emitted states. We analyze that the flaws of the phase modulation can be overcome by regarding the deviation of the phase as phase noise and eliminating it with the post-selection of phase. To overcome the side channels, we extend the generalized loss-tolerant (GLT) method to the four-intensity decoy-state SNS protocol. Remarkably, by decomposing of the two-mode single-photon states, the phase error rate can be estimated with only four parameters. The practical security of the SNS protocol with flawed and leaky source can be guaranteed. Our results might constitute a crucial step towards guaranteeing the practical implementation of the SNS protocol.

Improvement of stem cell-derived exosome release efficiency by surface-modified nanoparticles.

BACKGROUND: Mesenchymal stem cells (MSCs) are pluripotent stromal cells that release extracellular vesicles (EVs). EVs contain various growth factors and antioxidants that can positively affect the surrounding cells. Nanoscale MSC-derived EVs, such as exosomes, have been developed as bio-stable nano-type materials. However, some issues, such as low yield and difficulty in quantification, limit their use. We hypothesized that enhancing exosome production using nanoparticles would stimulate the release of intracellular molecules. RESULTS: The aim of this study was to elucidate the molecular mechanisms of exosome generation by comparing the internalization of surface-modified, positively charged nanoparticles and exosome generation from MSCs. We determined that Rab7, a late endosome and auto-phagosome marker, was increased upon exosome expression and was associated with autophagosome formation. CONCLUSIONS: It was concluded that the nanoparticles we developed were transported to the lysosome by clathrin-mediated endocytosis. additionally, entered nanoparticles stimulated that autophagy related factors to release exosome from the MSC. MSC-derived exosomes using nanoparticles may increase exosome yield and enable the discovery of nanoparticle-induced genetic factors.

Critical role for arginase II in osteoarthritis pathogenesis.

OBJECTIVE: Osteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. METHODS: Expression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2-/- mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II). RESULTS: The gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2-/-) abolished all manifestations of DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.

General-Purpose Quantum Circuit Simulator with Projected Entangled-Pair States and the Quantum Supremacy Frontier.

Recent advances on quantum computing hardware have pushed quantum computing to the verge of quantum supremacy. Here, we bring together many-body quantum physics and quantum computing by using a method for strongly interacting two-dimensional systems, the projected entangled-pair states, to realize an effective general-purpose simulator of quantum algorithms. The classical computing complexity of this simulator is directly related to the entanglement generation of the underlying quantum circuit rather than the number of qubits or gate operations. We apply our method to study random quantum circuits, which allows us to quantify precisely the memory usage and the time requirements of random quantum circuits. We demonstrate our method by computing one amplitude for a 7×7 lattice of qubits with depth (1+40+1) on the Tianhe-2 supercomputer.

Enhanced Homing Technique of Mesenchymal Stem Cells Using Iron Oxide Nanoparticles by Magnetic Attraction in Olfactory-Injured Mouse Models.

Intranasal delivery of mesenchymal stem cells (MSCs) to the olfactory bulb is a promising approach for treating olfactory injury. Additionally, using the homing phenomenon of MSCs may be clinically applicable for developing therapeutic cell carriers. Herein, using superparamagnetic iron oxide nanoparticles (SPIONs) and a permanent magnet, we demonstrated an enhanced homing effect in an olfactory model. Superparamagnetic iron oxide nanoparticles with rhodamine B (IRBs) had a diameter of 5.22 ± 0.9 nm and ζ-potential of +15.2 ± 0.3 mV. IRB concentration of 15 µg/mL was injected with SPIONs into MSCs, as cell viability significantly decreased when 20 μg/mL was used (p ≤ 0.005) compared to in controls. The cells exhibited magnetic attraction in vitro. SPIONs also stimulated CXCR4 (C-X-C chemokine receptor type 4) expression and CXCR4-SDF-1 (Stromal cell-derived factor 1) signaling in MSCs. After injecting magnetized MSCs, these cells were detected in the damaged olfactory bulb one week after injury on one side, and there was a significant increase compared to when non-magnetized MSCs were injected. Our results suggest that SPIONs-labeled MSCs migrated to injured olfactory tissue through guidance with a permanent magnet, resulting in better homing effects of MSCs in vivo, and that iron oxide nanoparticles can be used for internalization, various biological applications, and regenerative studies.

Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans.

It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the Tmax changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h → 0.75 h). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CLint,BCRP,intestine of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction).