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BACKGROUND: Increased prevalence of hepatocellular carcinoma (HCC) remains a global health challenge. HCC chemoresistance is a clinical obstacle for its management. Aberrant miRNA expression is a hallmark for both cancer progression and drug resistance. However, it is unclear which miRNAs are involved in HCC chemoresistance. METHODS: MicroRNA microarray analysis revealed a differential expression profile of microRNAs between the hepatocellular carcinoma HA22T cell line and the HDACi-R cell line, which was validated by quantitative real-time PCR (qRT-PCR). To determine the biological function of miR-342-5p and the mechanism of the microRNA-342-5p/CFL1 axis in hepatocellular carcinoma HDACi resistance, loss- and gain-of-function studies were conducted in vitro. RESULTS: Here we demonstrated the molecular mechanism of histone deacetylase inhibitor (HDACi) resistance in HCC. Differential miRNA expression analysis showed significant down regulation of miR-342-5p in HDACi-R cells than in parental HA22T cells. Mimics of miR-342-5p enhanced apoptosis through upregulation of Bax, cyto-C, cleaved-caspase-3 expressions with concomitant decline in anti-apoptotic protein (Bcl-2) in HDACi-R cells. Although HDACi did not increase cell viability of HDACi-R, overexpression of miR-342-5p decreased cofilin-1 expression, upregulated reactive oxygen species (ROS) mediated apoptosis, and sensitized HDACi-R to HDACi in a dose-dependent manner. CONCLUSION: Our findings demonstrated the critical role of miR-342-5p in HDACi resistance of HCC and that this mechanism might be attributed to miR-342-5p/cofilin-1 regulation.
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Quantum error correction is an essential tool for reliably performing tasks for processing quantum information on a large scale. However, integration into quantum circuits to achieve these tasks is problematic when one realizes that nontransverse operations, which are essential for universal quantum computation, lead to the spread of errors. Quantum gate teleportation has been proposed as an elegant solution for this. Here, one replaces these fragile, nontransverse inline gates with the generation of specific, highly entangled offline resource states that can be teleported into the circuit to implement the nontransverse gate. As the first important step, we create a maximally entangled state between a physical and an error-correctable logical qubit and use it as a teleportation resource. We then demonstrate the teleportation of quantum information encoded on the physical qubit into the error-corrected logical qubit with fidelities up to 0.786. Our scheme can be designed to be fully fault tolerant so that it can be used in future large-scale quantum technologies.
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High sperm cryotolerance is crucial to the successful cryopreservation of boar sperm. Evaluating the cryotolerance of boar sperm by using a rapid and convenient technique can enhance the commercial viability of these sperm. This study investigated the correlation between sperm parameters for three sample subsets-fresh sperm, sperm with H2O2-induced oxidative damage (hereinafter referred to as H2O2-induced sperm), and frozen-thawed sperm-to identify the potential of these correlations to predict cryotolerance. A total of 64 sperm samples were obtained from 64 Duroc boars. The sperm parameters of the three subsets, where the frozen-thawed sperm were analysed at 30 or 180 min after thawing, were determined, and the coefficients of correlation between these parameters were calculated. The results indicated that H2O2-induced oxidative stress resulted in decreases in various sperm parameters-including total motility (TM), viability (VIA), mitochondrial membrane potential (MMP), and live sperm with MMP (LMP)-but increased their coefficients of variation. Receiver operating characteristic (ROC) curve analysis revealed that the kinematic parameters of the H2O2-induced sperm effectively predicted those of the frozen-thawed boar sperm at 30 min after thawing; the corresponding area under the ROC curve (AUC) was 0.8667 for TM and 0.8733 for progressive motility in the H2O2-induced sperm. For measurement at 180 min after thawing, the sperm membrane and mitochondrial parameters of the H2O2-induced sperm effectively predicted the LMP of the frozen-thawed boar sperm; the corresponding AUC was 0.8489 for VIA, 0.8289 for MMP, and 0.8444 for LMP. To our knowledge, this is the first study to directly establish a strong correlation between post-thaw boar sperm quality and H2O2-induced oxidative stress before freezing. Our proposed technique can serve as a valuable reference for the development of practical applications aimed at enhancing techniques for cryopreserving boar sperm.
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Antioxidantes , Preservação do Sêmen , Suínos , Masculino , Animais , Antioxidantes/farmacologia , Sêmen , Peróxido de Hidrogênio/farmacologia , Preservação do Sêmen/veterinária , Preservação do Sêmen/métodos , Espermatozoides , Criopreservação/veterinária , Criopreservação/métodos , Motilidade dos EspermatozoidesRESUMO
Resistance to chemotherapy is the deadlock in cancer treatment. In this study, we used wild-type LOVO (LOVOWT ), a human colon cancer cell line, and the oxaliplatin-resistant sub-clone LOVOOR cells to investigate the molecular mechanisms of the development of drug resistance in colon cancer. Compared with LOVOWT cells, LOVOOR cells had a high proliferation capacity and a high percentage on the G2/M phase. The expression and activation of Aurora-A, a critical kinase in G2/M phase, were higher in LOVOOR cells than in LOVOWT cells. The results from immunofluorescence indicated an irregular distribution of Aurora-A in LOVOOR cells. To evaluate the importance of Aurora-A in oxaliplatin-resistant property of LOVOOR cells, overexpression of Aurora-A in LOVOWT cells and otherwise knockdown of Aurora-A in LOVOOR cells were performed and followed by administration of oxaliplatin. The results indicated that Aurora-A might contribute to the resistance of LOVOOR cells to oxaliplatin treatment by depressing p53 signaling. The specific findings in this study provide a possibility that targeting Aurora-A might be a solution for patients who have failed oxaliplatin treatment.
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Antineoplásicos , Neoplasias do Colo , Humanos , Oxaliplatina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Resistencia a Medicamentos AntineoplásicosRESUMO
Recent breakthroughs have opened the possibility of intermediate-scale quantum computing with tens to hundreds of qubits, and shown the potential for solving classical challenging problems, such as in chemistry and condensed matter physics. However, the high accuracy needed to surpass classical computers poses a critical demand on the circuit depth, which is severely limited by the non-negligible gate infidelity, currently around 0.1%-1%. The limited circuit depth places restrictions on the performance of variational quantum algorithms (VQA) and prevents VQAs from exploring desired nontrivial quantum states. To resolve this problem, we propose a paradigm of Schrödinger-Heisenberg variational quantum algorithms (SHVQA). Using SHVQA, the expectation values of operators on states that require very deep circuits to prepare can now be efficiently measured by rather shallow circuits. The idea is to incorporate a virtual Heisenberg circuit, which acts effectively on the measurement observables, into a real shallow Schrödinger circuit, which is implemented realistically on the quantum hardware. We choose a Clifford virtual circuit, whose effect on the Hamiltonian can be seen as efficient classical processing. Yet, it greatly enlarges the state's expressivity, realizing much larger unitary t designs. Our method enables accurate quantum simulation and computation that otherwise are only achievable with much deeper circuits or more accurate operations conventionally. This has been verified in our numerical experiments for a better approximation of random states, higher-fidelity solutions to the XXZ model, and the electronic structure Hamiltonians of small molecules. Thus, together with effective quantum error mitigation, our work paves the way for realizing accurate quantum computing algorithms with near-term quantum devices.
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Nonlocality arising in networks composed of several independent sources gives rise to phenomena radically different from that in standard Bell scenarios. Over the years, the phenomenon of network nonlocality in the entanglement-swapping scenario has been well investigated and demonstrated. However, it is known that violations of the so-called bilocality inequality used in previous experimental demonstrations cannot be used to certify the nonclassicality of their sources. This has put forward a stronger concept for nonlocality in networks, called full network nonlocality. Here, we experimentally observe full network nonlocal correlations in a network where the source-independence, locality, and measurement-independence loopholes are closed. This is ensured by employing two independent sources, rapid setting generation, and spacelike separations of relevant events. Our experiment violates known inequalities characterizing nonfull network nonlocal correlations by over 5 standard deviations, certifying the absence of classical sources in the realization.
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Quantum metrology employs quantum resources to enhance the measurement sensitivity beyond that can be achieved classically. While multiphoton entangled N00N states can in principle beat the shot-noise limit and reach the Heisenberg limit, high N00N states are difficult to prepare and fragile to photon loss which hinders them from reaching unconditional quantum metrological advantages. Here, we combine the idea of unconventional nonlinear interferometers and stimulated emission of squeezed light, previously developed for the photonic quantum computer Jiuzhang, to propose and realize a new scheme that achieves a scalable, unconditional, and robust quantum metrological advantage. We observe a 5.8(1)-fold enhancement above the shot-noise limit in the Fisher information extracted per photon, without discounting for photon loss and imperfections, which outperforms ideal 5-N00N states. The Heisenberg-limited scaling, the robustness to external photon loss, and the ease-of-use of our method make it applicable in practical quantum metrology at a low photon flux regime.
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Gaussian boson sampling (GBS) is not only a feasible protocol for demonstrating quantum computational advantage, but also mathematically associated with certain graph-related and quantum chemistry problems. In particular, it is proposed that the generated samples from the GBS could be harnessed to enhance the classical stochastic algorithms in searching some graph features. Here, we use JiÇzhang, a noisy intermediate-scale quantum computer, to solve graph problems. The samples are generated from a 144-mode fully connected photonic processor, with photon click up to 80 in the quantum computational advantage regime. We investigate the open question of whether the GBS enhancement over the classical stochastic algorithms persists-and how it scales-with an increasing system size on noisy quantum devices in the computationally interesting regime. We experimentally observe the presence of GBS enhancement with a large photon-click number and a robustness of the enhancement under certain noise. Our work is a step toward testing real-world problems using the existing noisy intermediate-scale quantum computers and hopes to stimulate the development of more efficient classical and quantum-inspired algorithms.
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We report new Gaussian boson sampling experiments with pseudo-photon-number-resolving detection, which register up to 255 photon-click events. We consider partial photon distinguishability and develop a more complete model for the characterization of the noisy Gaussian boson sampling. In the quantum computational advantage regime, we use Bayesian tests and correlation function analysis to validate the samples against all current classical spoofing mockups. Estimating with the best classical algorithms to date, generating a single ideal sample from the same distribution on the supercomputer Frontier would take â¼600 yr using exact methods, whereas our quantum computer, JiÇzhang 3.0, takes only 1.27 µs to produce a sample. Generating the hardest sample from the experiment using an exact algorithm would take Frontierâ¼3.1×10^{10} yr.
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Lung cancer is one of the most common cancers in the world. Chemotherapy is a standard clinical treatment. However, tumor cells often develop multidrug resistance after chemotherapy, an inevitable bottleneck in cancer treatment. Therefore, this study used gemcitabine-resistant (GEM-R) CL1-0 lung cancer cells. First, we used flow cytometry and western blot analysis to examine differences in performance between resistant and parental cells. The results showed that compared with parental cells, GEM-R CL1-0 cells significantly enhanced the activation of the AKT pathway, which promoted survival and growth, and decreased the activation of the reactive oxygen species-extracellular signal-regulated kinase (ROS)-ERK pathway. Next, the AKT and ERK pathways' role in tumor growth was further explored in vivo using a xenograft model. The results showed that enhancing AKT and inhibiting ERK activation reduced GEM-induced inhibition of tumor growth. Finally, combining the above results, we found that GEM-R CL1-0 cells showed reduced sensitivity to GEM by activating the phosphatidylinositol 3-kinase/AKT/NF-kB pathway and inhibiting the ROS-ERK pathway leading to resistance against GEM. Therefore, the AKT and ERK pathways are potential targets for improving the sensitivity of cancer cells to anticancer drugs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gencitabina , NF-kappa B/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Linhagem Celular Tumoral , ApoptoseRESUMO
The most common cancer-related death in the world is non-small cell lung cancer (NSCLC). Gemcitabine (GEM) is a common and effective first-line chemotherapeutic drug for the treatment of NSCLC. However, the long-term use of chemotherapeutic drugs in patients usually induces cancer cell drug resistance, leading to poor survival, and prognosis. In this study, to observe and explore the key targets and potential mechanisms of NSCLC resistance to GEM, we first cultured lung cancer CL1-0 cells in a GEM-containing medium to induce CL1-0 cells to develop GEM resistance. Next, we compared protein expression between the parental and GEM-R CL1-0 cell groups. We observed significantly lower expression of autophagy-related proteins in GEM-R CL1-0 cells than in parental CL1-0 cells, indicating that autophagy is associated with GEM resistance in CL1-0 cells. Furthermore, a series of autophagy experiments revealed that GEM-R CL1-0 cells had significantly reduced GEM-induced c-Jun N-terminal kinase phosphorylation, which further affected the phosphorylation of Bcl-2, thereby reducing the dissociation of Bcl-2 and Beclin-1 and ultimately reducing the generation of GEM-induced autophagy-dependent cell death. Our findings suggest that altering the expression of autophagy is a promising therapeutic option for drug-resistant lung cancer.
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Morte Celular Autofágica , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gencitabina , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fosforilação , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Autofagia , ApoptoseRESUMO
Lung cancer is the most common malignant cancer worldwide. Combination therapies are urgently needed to increase patient survival. Calycosin is a phytoestrogen isoflavone that has been reported previously to inhibit tumor cell growth, although its effects on lung cancer remain unclear. The aim of this study was to investigate the effects of calycosin on cell proliferation and apoptosis of gemcitabine-resistant lung cancer cells. Using calycosin to treat human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) and examine the effects on the cells. Cultured human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) were treated with increasing concentrations of calycosin. Cell viability and apoptosis were studied by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, flow cytometry, and TUNEL assays. Western blots were used to measure the expression levels of proliferation-related proteins and cancer stem cell proteins in CL1-0 GEMR cells. The results showed that calycosin treatment inhibited cell proliferation, decreased cell migration ability, and suppressed cancer stem cell properties in CL1-0 GEMR cells. Interestingly, in CL1-0 GEMR cells, calycosin treatment not only increased LDOC1 but also decreased GNL3L/NFκB protein levels and mRNA levels, in concentration-dependent manners. We speculate that calycosin inhibited cell proliferation of the gemcitabine-resistant cell line through regulating the LDOC1/GNL3L/NFκB pathway.
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Isoflavonas , Neoplasias Pulmonares , Humanos , Gencitabina , Neoplasias Pulmonares/tratamento farmacológico , Linhagem Celular Tumoral , NF-kappa B , Isoflavonas/farmacologia , Proliferação de Células , Apoptose , Proteínas Nucleares/farmacologia , Proteínas Supressoras de Tumor/farmacologia , Proteínas de Ligação ao GTP/farmacologiaRESUMO
Nonlocality captures one of the counterintuitive features of nature that defies classical intuition. Recent investigations reveal that our physical world's nonlocality is at least tripartite; i.e., genuinely tripartite nonlocal correlations in nature cannot be reproduced by any causal theory involving bipartite nonclassical resources and unlimited shared randomness. Here, by allowing the fair sampling assumption and postselection, we experimentally demonstrate such genuine tripartite nonlocality in a network under strict locality constraints that are ensured by spacelike separating all relevant events and employing fast quantum random number generators and high-speed polarization measurements. In particular, for a photonic quantum triangular network we observe a locality-loophole-free violation of the Bell-type inequality by 7.57 standard deviations for a postselected tripartite Greenberger-Horne-Zeilinger state of fidelity (93.13±0.24)%, which convincingly disproves the possibility of simulating genuine tripartite nonlocality by bipartite nonlocal resources with globally shared randomness.
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Standard quantum theory was formulated with complex-valued Schrödinger equations, wave functions, operators, and Hilbert spaces. Previous work attempted to simulate quantum systems using only real numbers by exploiting an enlarged Hilbert space. A fundamental question arises: are the complex numbers really necessary in the standard formalism of quantum theory? To answer this question, a quantum game has been developed to distinguish standard quantum theory from its real-number analog, by revealing a contradiction between a high-fidelity multiqubit quantum experiment and players using only real-number quantum theory. Here, using superconducting qubits, we faithfully realize the quantum game based on deterministic entanglement swapping with a state-of-the-art fidelity of 0.952. Our experimental results violate the real-number bound of 7.66 by 43 standard deviations. Our results disprove the real-number formulation and establish the indispensable role of complex numbers in the standard quantum theory.
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Quantum mechanics is commonly formulated in a complex, rather than real, Hilbert space. However, whether quantum theory really needs the participation of complex numbers has been debated ever since its birth. Recently, a Bell-like test in an entanglement-swapping scenario has been proposed to distinguish standard quantum mechanics from its real-valued analog. Previous experiments have conceptually demonstrated, yet not satisfied, the central requirement of independent state preparation and measurements and leave several loopholes. Here, we implement such a Bell-like test with two separated independent sources delivering entangled photons to three separated parties under strict locality conditions that are enforced by spacelike separation of the relevant events, rapid random setting generation, and fast measurement. With the fair-sampling assumption and closed loopholes of independent source, locality, and measurement independence simultaneously, we violate the constraints of real-valued quantum mechanics by 5.30 standard deviations. Our results disprove the real-valued quantum theory to describe nature and ensure the indispensable role of complex numbers in quantum mechanics.
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First proposed by Mayers and Yao, self-testing provides a certification method to infer the underlying physics of quantum experiments in a black-box scenario. Numerous demonstrations have been reported to self-test various types of entangled states. However, all the multiparticle self-testing experiments reported so far suffer from both detection and locality loopholes. Here, we report the first experimental realization of multiparticle entanglement self-testing closing the locality loophole in a photonic system, and the detection loophole in a superconducting system, respectively. We certify three-party and four-party GHZ states with at least 0.84(1) and 0.86(3) fidelities in a device-independent way. These results can be viewed as a meaningful advance in multiparticle loophole-free self-testing, and also significant progress on the foundations of quantum entanglement certification.
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Urothelial bladder cancer is rapidly spreading across Western countries, and therapy has shown little-to-moderate effects on bladder cancer. Thus, focusing on curbing cancer incidence has become crucial. The aim of the present study was to investigate the anticancer effects of Tannic acid (TA) in human bladder cancer. UMUC3 bladder cancer cells were treated with different concentrations of TA (0-100 µM) and tested for cell viability, colony formation, and apoptosis. The involvement of the phosphoinositide-3 kinase (PI3K)/Akt pathway in the action of TA was examined. TA treatment significantly inhibited the viability and increased percentage of apoptotic cells, thereby decreasing antiapoptotic proteins (BCL2, MCL-1, and BCL-XL) expression, resulting in the Caspase-3 activation. TA treatment decreased stem cell markers expression such as SOX2, OCT4, and NANOG. Additionally, TA treatment significantly reduced the phosphorylation levels of Akt in bladder cancer cells. Our study demonstrates the growth inhibitory effects of TA in bladder cancer cells, and highlights its potential as an anticancer agent for bladder cancer.
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Proteínas Proto-Oncogênicas c-akt , Neoplasias da Bexiga Urinária , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosforilação , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Taninos/farmacologia , Taninos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , ApoptoseRESUMO
We experimentally demonstrate that when three single photons transmit through two polarization channels, in a well-defined pre- and postselected ensemble, there are no two photons in the same polarization channel by weak-strength measurement, a counterintuitive quantum counting effect called the quantum pigeonhole paradox. We further show that this effect breaks down in second-order measurement. These results indicate the existence of the quantum pigeonhole paradox and its operating regime.
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Porcine reproductive and respiratory syndrome virus (PRRSV) infects placental and lung macrophages, causing a global epidemic with economic loss. Attempts to develop an effective vaccine to control the disease have not been effective. Currently, developing PRRSV disease-resistant pigs via a gene editing (GE) strategy to mutate the PRRSV receptor or to delete the binding domain on the macrophage appears promising. In this study, we used the strategy of Edinburg University to construct two guide RNAs (gRNAs) located on the proximal front and post sites of exon 7. Directive microinjection of two gRNAs and Cas9 mRNA into the cytoplasm of pronuclear zygotes efficiently generated four piglets confirmed as CD163 knockout (KO) and/or CD163 exon 7 deleted (CD163ΔE7). In four GE piglets, three pigs carried two chromosome CD163 KO or ΔE7. Peripheral blood mononuclear cells (PBMCs) from three GE and wild-type (WT) pigs were activated into macrophages for in vitro transfection. The results showed that the activated macrophages from all GE pigs were significantly more viable than those from WT pig. Current results suggest that we have successfully generated PRRSV-resistant pigs, although in vivo challenge is needed to validate that the pigs are PRRSV resistant.
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This study reports the effect of cardiac-specific insulin-like growth factor-II receptor α (IGF-IIRα) overexpression on the development of liver dysfunction in transgenic rats via STZ-induced diabetic hepatocyte damage. The cardio-hepatic syndrome comprises a number of heart and liver illnesses in which an acute or chronic disease in one organ can lead to acute or chronic disease in the other. However, the molecular mechanism involved in such a set of conditions is unclear. In this study, we developed a transgenic rat model with cardiac-specific overexpression of IGF-IIRα, which is a supplementary splicing variant of insulin-like growth factor-II receptor (IGF-IIR), expressed in pathological hearts, to investigate the relationship between late fetal gene expression in diabetic hearts and their influence on diabetic hepatopathy. STZ (55 mg/kg) was intraperitoneally delivered into IGF-IIR overexpressed transgenic (TG) and non-transgenic (NTG) animal models developed in Sprague-Dawley (SD) rats after an overnight fast. The relationship among IGF-IIRα overexpression and hepatocyte damages have been determined based on the complexity of damage in the liver. Our findings revealed that overexpression of the cardiac-specific IGF-IIRα enhances diabetes-induced morphological alterations and hepatic inflammation in the livers. The diabetic transgenic rats demonstrated the development of pathological conditions such as thick collagen fiber deposition, bridging fibrosis, and elevation of α-SMA and MMP1 related liver fibrosis mechanisms. Our data suggest that IGF-IIRα overexpression in the heart during a pathological state may worsen diabetic hepatopathy in rats.