Transition metal complex-incorporated polyaniline as a platform for an enzymatic uric acid electrochemical sensor.

Uric acid (UA) is the primary waste product from purine metabolism in humans. Excessive UA levels in the body will accumulate in joints and form crystals that cause a wide range of health problems. An enzymatic electrochemical biosensor for UA based on the transition metal complex-incorporated polyaniline PANI-RC functionalized with both urate oxidase (UOx) as a specific bioreceptor and horseradish peroxidase (HRP) as a signal enhancer was developed. The transition metal complex being used herein is the commonly used redox couple (RC) in electrochemical biosensors, [Fe(CN)6]3-/4-, which plays the pivotal role of electron acceptors. This PANI-RC platform then becomes a conducive environment not only for enzyme immobilization but also for signal transfer improvement. The synergistic combination of HRP near UOx and RC anchored on the backbone of PANI helps in electron transfer from the enzymatic reaction to the current collector. The resulting PANI-RC-based UA sensor demonstrates high sensitivity with a detection limit of 11.4 µM, wide linear range, good stability, and excellent selectivity even in the presence of the most problematic interference in UA assays (e.g., ascorbic acid and urea). The recovery tests using artificial biofluid-spiked UA samples also showed promising results for practical usage of the PANI-RC-based UA sensor.

Sensitive Detection of BVDV Using Gold Nanoparticle-Modified Few-Layer Black Phosphorus with Affinity Peptide-Based Electrochemical Sensor.

The lethality of the bovine viral diarrhea virus (BVDV) in cattle involves inapparent infection and various, typically subclinical, syndromes. Cattle of all ages are vulnerable to infection with the virus. It also causes considerable economic losses, primarily due to reduced reproductive performance. In the absence of treatment that can completely cure infected animals, detection of BVDV relies on highly sensitive and selective diagnosis methods. In this study, an electrochemical detection system was developed as a useful and sensitive system for the detection of BVDV to suggest the direction of diagnostic technology through the development of conductive nanoparticle synthesis. As a countermeasure, a more sensitive and rapid BVDV detection system was developed using the synthesis of electroconductive nanomaterials black phosphorus (BP) and gold nanoparticle (AuNP). To increase the conductivity effect, AuNP was synthesized on the BP surface, and the stability of BP was improved by using dopamine self-polymerization. Moreover, its characterizations, electrical conductivity, selectivity, and sensitivity toward BVDV also have been investigated. The BP@AuNP-peptide-based BVDV electrochemical sensor exhibited a low detection limit of 0.59 copies mL-1 with high selectivity and long-term stability (retaining 95% of its initial performance over 30 days).

Investigation of Anti-Liver Cancer Activity of the Herbal Drug FDY003 Using Network Pharmacology.

Globally, liver cancer (LC) is the sixth-most frequently occurring and the second-most fatal malignancy, responsible for 0.83 million deaths annually. Although the application of herbal drugs in cancer therapies has increased, their anti-LC activity and relevant mechanisms have not been fully studied from a systems perspective. To address these issues, we conducted a system-perspective network pharmacological investigation into the activity and mechanisms underlying the action of the herbal drug. FDY003 reduced the viability of human LC treatment. FDY003 reduced the viability of human LC cells and elevated their chemosensitivity. There were a total of 16 potential bioactive chemical components in FDY003 and they had 91 corresponding targets responsible for the pathological processes in LC. These FDY003 targets were functionally involved in regulating the survival, proliferation, apoptosis, and cell cycle of LC cells. Additionally, we found that FDY003 may target key signaling cascades connected to diverse LC pathological mechanisms, namely, PI3K-Akt, focal adhesion, IL-17, FoxO, MAPK, and TNF pathways. Overall, this study contributed to integrative mechanistic insights into the anti-LC potential of FDY003.

Associations between local acidosis induced by renal LDHA and renal fibrosis and mitochondrial abnormalities in patients with diabetic kidney disease.

During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms' tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD.

Exploration of the System-Level Mechanisms of the Herbal Drug FDY003 for Pancreatic Cancer Treatment: A Network Pharmacological Investigation.

Pancreatic cancer (PC) is the most lethal cancer with the lowest survival rate globally. Although the prescription of herbal drugs against PC is gaining increasing attention, their polypharmacological therapeutic mechanisms are yet to be fully understood. Based on network pharmacology, we explored the anti-PC properties and system-level mechanisms of the herbal drug FDY003. FDY003 decreased the viability of human PC cells and strengthened their chemosensitivity. Network pharmacological analysis of FDY003 indicated the presence of 16 active phytochemical components and 123 PC-related pharmacological targets. Functional enrichment analysis revealed that the PC-related targets of FDY003 participate in the regulation of cell growth and proliferation, cell cycle process, cell survival, and cell death. In addition, FDY003 was shown to target diverse key pathways associated with PC pathophysiology, namely, the PIK3-Akt, MAPK, FoxO, focal adhesion, TNF, p53, HIF-1, and Ras pathways. Our network pharmacological findings advance the mechanistic understanding of the anti-PC properties of FDY003 from a system perspective.

Rapid Screening of Glucocorticoid Receptor (GR) Effectors Using Cortisol-Detecting Sensor Cells.

Cortisol, a stress hormone, plays key roles in mediating stress and anti-inflammatory responses. As abnormal cortisol levels can induce various adverse effects, screening cortisol and cortisol analogues is important for monitoring stress levels and for identifying drug candidates. A novel cell-based sensing system was adopted for rapid screening of cortisol and its functional analogues under complex cellular regulation. We used glucocorticoid receptor (GR) fused to a split intein which reconstituted with the counterpart to trigger conditional protein splicing (CPS) in the presence of targets. CPS generates functional signal peptides which promptly translocate the fluorescent cargo. The sensor cells exhibited exceptional performance in discriminating between the functional and structural analogues of cortisol with improved sensitivity. Essential oil extracts with stress relief activity were screened using the sensor cells to identify GR effectors. The sensor cells responded to peppermint oil, and L-limonene and L-menthol were identified as potential GR effectors from the major components of peppermint oil. Further analysis indicated L-limonene as a selective GR agonist (SEGRA) which is a potential anti-inflammatory agent as it attenuates proinflammatory responses without causing notable adverse effects of GR agonists.

A Network Pharmacology Study on the Molecular Mechanisms of FDY003 for Breast Cancer Treatment.

Herbal medicines have drawn considerable attention with regard to their potential applications in breast cancer (BC) treatment, a frequently diagnosed malignant disease, considering their anticancer efficacy with relatively less adverse effects. However, their mechanisms of systemic action have not been understood comprehensively. Based on network pharmacology approaches, we attempted to unveil the mechanisms of FDY003, an herbal drug comprised of Lonicera japonica Thunberg, Artemisia capillaris Thunberg, and Cordyceps militaris, against BC at a systemic level. We found that FDY003 exhibited pharmacological effects on human BC cells. Subsequently, detailed data regarding the biochemical components contained in FDY003 were obtained from comprehensive herbal medicine-related databases, including TCMSP and CancerHSP. By evaluating their pharmacokinetic properties, 18 chemical compounds in FDY003 were shown to be potentially active constituents interacting with 140 BC-associated therapeutic targets to produce the pharmacological activity. Gene ontology enrichment analysis using g:Profiler indicated that the FDY003 targets were involved in the modulation of cellular processes, involving the cell proliferation, cell cycle process, and cell apoptosis. Based on a KEGG pathway enrichment analysis, we further revealed that a variety of oncogenic pathways that play key roles in the pathology of BC were significantly enriched with the therapeutic targets of FDY003; these included PI3K-Akt, MAPK, focal adhesion, FoxO, TNF, and estrogen signaling pathways. Here, we present a network-perspective of the molecular mechanisms via which herbal drugs treat BC.

Uncovering the Anti-Lung-Cancer Mechanisms of the Herbal Drug FDY2004 by Network Pharmacology.

With growing evidence on the therapeutic efficacy and safety of herbal drugs, there has been a substantial increase in their application in the lung cancer treatment. Meanwhile, their action mechanisms at the system level have not been comprehensively uncovered. To this end, we employed a network pharmacology methodology to elucidate the systematic action mechanisms of FDY2004, an anticancer herbal drug composed of Moutan Radicis Cortex, Persicae Semen, and Rhei Radix et Rhizoma, in lung cancer treatment. By evaluating the pharmacokinetic properties of the chemical compounds present in FDY2004 using herbal medicine-associated databases, we identified its 29 active chemical components interacting with 141 lung cancer-associated therapeutic targets in humans. The functional enrichment analysis of the lung cancer-related targets of FDY2004 revealed the enriched Gene Ontology terms, involving the regulation of cell proliferation and growth, cell survival and death, and oxidative stress responses. Moreover, we identified key FDY2004-targeted oncogenic and tumor-suppressive pathways associated with lung cancer, including the phosphatidylinositol 3-kinase-Akt, mitogen-activated protein kinase, tumor necrosis factor, Ras, focal adhesion, and hypoxia-inducible factor-1 signaling pathways. Overall, our study provides novel evidence and basis for research on the comprehensive anticancer mechanisms of herbal medicines in lung cancer treatment.

An Investigation of the Molecular Mechanisms Underlying the Analgesic Effect of Jakyak-Gamcho Decoction: A Network Pharmacology Study.

Herbal drugs have drawn substantial interest as effective analgesic agents; however, their therapeutic mechanisms remain to be fully understood. To address this question, we performed a network pharmacology study to explore the system-level mechanisms that underlie the analgesic activity of Jakyak-Gamcho decoction (JGd; Shaoyao-Gancao-Tang in Chinese and Shakuyaku-Kanzo-To in Japanese), an herbal prescription consisting of Paeonia lactiflora Pallas and Glycyrrhiza uralensis Fischer. Based on comprehensive information regarding the pharmacological and chemical properties of the herbal constituents of JGd, we identified 57 active chemical compounds and their 70 pain-associated targets. The JGd targets were determined to be involved in the regulation of diverse biological activities as follows: calcium- and cytokine-mediated signalings, calcium ion concentration and homeostasis, cellular behaviors of muscle and neuronal cells, inflammatory response, and response to chemical, cytokine, drug, and oxidative stress. The targets were further enriched in various pain-associated signalings, including the PI3K-Akt, estrogen, ErbB, neurotrophin, neuroactive ligand-receptor interaction, HIF-1, serotonergic synapse, JAK-STAT, and cAMP pathways. Thus, these data provide a systematic basis to understand the molecular mechanisms underlying the analgesic activity of herbal drugs.

Alcohol consumption before pregnancy causes detrimental fetal development and maternal metabolic disorders.

Alcohol consumption before or during pregnancy poses serious health risks to the fetus; however, the underlying mechanisms involved remain obscure. Here, we investigated whether ethanol consumption before pregnancy affects maternal or fetal health and whether pharmacological inhibition of CYP2E1, a major ethanol oxidation enzyme, by 4-methylpyrazole (4-MP) has therapeutic effects. We found that ethanol consumption (5%) 2 weeks before pregnancy resulted in a decrease in the number of viable fetuses and abnormal fetal development, and these effects were accompanied by impaired maternal glucose homeostasis and hepatic steatosis during pregnancy. Neonates of ethanol-fed mice had postnatal macrosomia and significantly decreased growth rates during the lactation period. However, treatment with 4-MP, a CYP2E1 inhibitor, markedly ameliorated the reduction in insulin action and glucose disposal responsiveness in the livers of ethanol-fed mice. Blockage of CYP2E1 significantly reduced the alteration in hepatic lipid deposition, fatty acid oxidation, mitochondrial energy status, and macrophage infiltration observed in ethanol-fed mice. Finally, there was a positive correlation between postnatal macrosomia or growth retardation and increased inflammatory responses. Collectively, our study suggests that even moderate ethanol intake may be detrimental to fetal development and may cause growth retardation through maternal metabolic disorders.

Network Pharmacology-Based Investigation of the System-Level Molecular Mechanisms of the Hematopoietic Activity of Samul-Tang, a Traditional Korean Herbal Formula.

Hematopoiesis is a dynamic process of the continuous production of diverse blood cell types to meet the body's physiological demands and involves complex regulation of multiple cellular mechanisms in hematopoietic stem cells, including proliferation, self-renewal, differentiation, and apoptosis. Disruption of the hematopoietic system is known to cause various hematological disorders such as myelosuppression. There is growing evidence on the beneficial effects of herbal medicines on hematopoiesis; however, their mechanism of action remains unclear. In this study, we conducted a network pharmacological-based investigation of the system-level mechanisms underlying the hematopoietic activity of Samul-tang, which is an herbal formula consisting of four herbal medicines, including Angelicae Gigantis Radix, Rehmanniae Radix Preparata, Paeoniae Radix Alba, and Cnidii Rhizoma. In silico analysis of the absorption-distribution-metabolism-excretion model identified 16 active phytochemical compounds contained in Samul-tang that may target 158 genes/proteins associated with myelosuppression to exert pharmacological effects. Functional enrichment analysis suggested that the targets of Samul-tang were significantly enriched in multiple pathways closely related to the hematopoiesis and myelosuppression development, including the PI3K-Akt, MAPK, IL-17, TNF, FoxO, HIF-1, NF-kappa B, and p53 signaling pathways. Our study provides novel evidence regarding the system-level mechanisms underlying the hematopoiesis-promoting effect of herbal medicines for hematological disorder treatment.

Differences of the ankle plantar flexor length in typically developing children and children with spastic hemiplegic cerebral palsy.

The purpose of this study is to analyze the lengths of the medial and lateral gastrocnemius and soleus muscles in children with spastic hemiplegic cerebral palsy to quantitatively assess the structural differences in skeletal muscles. This study included 10 children with spastic cerebral palsy and 10 children with typically development. To assess the changes in the length of the ankle plantar flexor due to cerebral palsy, we utilized both gait analysis and software for interactive musculoskeletal modeling to model skeletal muscle length. With this model, the differences in the lengths of the medial and lateral gastrocnemius and soleus muscles were assessed at different knee (0°, 45°, and 90°) and ankle (-10°, 0°, 15°, and 30°) angles. Muscle length on the paretic group was shorter than the typically developing and nonparetic group for all three muscles (medial and lateral gastrocnemius and soleus muscles) for knee and ankle angles. These results were not statistically significant. Normalized muscle lengths in the dynamic/static status revealed a significant difference in the length of the lateral gastrocnemius muscle between the cerebral palsy and typically developing group. I observed muscle shortening on the paretic side of the children with cerebral palsy. This finding suggests that the recovery of plantar flexor length is the most important issue that must be resolved for normal gait and motor function.

Association between alcohol consumption pattern and the incidence risk of type 2 diabetes in Korean men: A 12-years follow-up study.

Moderate alcohol consumption is generally associated with reduced risk of type 2 diabetes. However, this beneficial effects of alcohol intake remains controversial due to inconsistent results across studies. The analysis was performed using data from the Ansung-Ansan cohort study. We categorized the participants into four groups-based on the baseline (one-point measure; non-drinking, <5 g/day, ≥5, <30 g/day, and ≥30 g/day) and follow-up (consumption pattern; never-drinking, light, moderate, and heavy drinking) measurement. At baseline, ≥30 g/day alcohol consumption increased the risk of incident diabetes (HR: 1.42; 95% CI, 1.10-1.85), but ≥5, <30 g/day alcohol consumption had no effects on the incident diabetes. Meanwhile, when using the alcohol consumption pattern, a heavy-drinking pattern increased the risk of incident diabetes (HR = 1.32, 1.01-1.73), but the light and moderate consumption pattern was associated with a reduced risk of type 2 diabetes (HR: 0.66; 0.50-0.87 and HR: 0.74; 0.57-0.95, respectively). At the end point of follow-up, the insulinogenic index (IGI), but not the insulin sensitivity index (ISI), differed among the groups. Alcohol consumption pattern had a J-shaped association with the incident type 2 diabetes in Korean men. The IGI showed an inverted J-shaped association according to alcohol drinking pattern, but the ISI was not a J-shape.

Analysis of muscle activation in each body segment in response to the stimulation intensity of whole-body vibration.

[Purpose] The purpose of this study was to investigate the effects of a whole-body vibration exercise, as well as to discuss the scientific basis to establish optimal intensity by analyzing differences between muscle activations in each body part, according to the stimulation intensity of the whole-body vibration. [Subjects and Methods] The study subjects included 10 healthy men in their 20s without orthopedic disease. Representative muscles from the subjects' primary body segments were selected while the subjects were in upright positions on exercise machines; electromyography electrodes were attached to the selected muscles. Following that, the muscle activities of each part were measured at different intensities. No vibration, 50/80 in volume, and 10/25/40 Hz were mixed and applied when the subjects were on the whole-vibration exercise machines in upright positions. After that, electromyographic signals were collected and analyzed with the root mean square of muscular activation. [Results] As a result of the analysis, it was found that the muscle activation effects had statistically meaningful differences according to changes in exercise intensity in all 8 muscles. When the no-vibration status was standardized and analyzed as 1, the muscle effect became lower at higher frequencies, but became higher at larger volumes. [Conclusion] In conclusion, it was shown that the whole-body vibration stimulation promoted muscle activation across the entire body part, and the exercise effects in each muscle varied depending on the exercise intensities.

Asynchronous Alterations of Muscle Force and Tendon Stiffness Following 8 Weeks of Resistance Exercise with Whole-Body Vibration in Older Women.

This study aimed to examine whether muscle force and tendon stiffness in a muscle-tendon complex alter synchronously following 8-week whole-body vibration (WBV) training in older people. Forty older women aged 65 years and older were randomly assigned into control (CON, n = 15) and whole-body vibration (WBV) training groups (exposure time, n = 13; vibration intensity, n = 12). For the training groups, a 4-week detraining period was completed following the training period. Throughout the training/detraining period, force of the medial gastrocnemius (MG) muscle and stiffness of the Achilles tendon were assessed four times (0, 4, 8, and 12 weeks) using a combined system of dynamometer and ultrasonography. While muscle force gradually increased throughout the training period (p < .05), a significant increase in tendon stiffness was observed after 8 weeks (p < .05). These findings indicated that, during the early phase of WBV training, muscle force and tendon stiffness changed asynchronously, which might be a factor in possible musculotendinous injuries.

The acute effect of neuromuscular activation in resistance exercise on human skeletal muscle with the interpolated twitch technique.

[Purpose] The purpose of this study was to perform a quantitative assessment of neuromechanical adaptation in skeletal muscles and to propose the scientific underpinnings of the acute effects induced by resistance exercise. [Subjects] The subjects in this study were 11 healthy adult men in their 20s who had no orthopedic history at the time of the study. To examine any signs of resistance exercise-induced changes in the ankle plantar flexor, the subjects were directed to perform a standing barbell calf raise routine. [Methods] Subjects were to carry a load equal to their weights and to perform five sets of ten repetitions. The maximal voluntary isometric contraction torque, resting twitch torque, muscle inhibition, root mean square of muscular activation, contraction time, and half relaxation time were analyzed by synchronizing a dynamometer, an electrical stimulator, and an electromyography system. [Results] The maximal voluntary isometric contraction torque appeared to decline, but the change was not statistically significant. The decline of resting twitch torque, on the other hand, was found to be statistically significant. Muscle inhibition and root mean square of muscular activation were both reduced, but both changes were not statistically significant. Lastly, contraction time and half relaxation time both statistically decreased significantly after resistance exercise. [Conclusion] These results indicate that the acute effects of resistance exercise have a greater impact on the peripheral mechanical system itself, rather than on neurological factors, in terms of the generation of muscle force.

Chronic alcohol consumption potentiates the development of diabetes through pancreatic ß-cell dysfunction.

Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic ß-cell and the exact mechanisms associated with ethanol-mediated ß-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic ß-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic ß-cell dysfunction and metabolic syndrome.

Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.

Chronic ethanol consumption induces pancreatic ß-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic ß-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from -287 to -158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and ß-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters ß-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis.

Acute effect of heel-drop exercise with varying ranges of motion on the gastrocnemius aponeurosis-tendon's mechanical properties.

The objectives of this study was to investigate the acute effects of various magnitudes of tendon strain on the mechanical properties of the human medial gastrocnemius (MG) in vivo during controlled heel-drop exercises. Seven male and seven female volunteers performed two different exercises executed one month apart: one was a heel-drop exercise on a block (HDB), and the other was a heel-drop exercise on level floor (HDL). In each regimen, the subjects completed a session of 150 heel-drop exercises (15 repetitions×10 sets; with a 30 s rest following each set). Before and immediately after the heel-drop exercise, the ankle plantar flexor torque and elongation of the MG were measured using a combined measurement system of dynamometry and ultrasonography and then the MG tendon strain and stiffness were evaluated in each subject. The tendon stiffness measured prior to the exercises was not significantly different between the two groups 23.7±10.6N/mm and 24.1±10.0N/mm for the HDB and HDL, respectively (p>.05). During the heel-drop exercise, it was found that the tendon strain during the heel-drop exercise on a block (8.4±3.7%) was significantly higher than the strain measured on the level floor (5.4±3.8%) (p<.05). In addition, the tendon stiffness following the heel-drop exercise on a block (32.3±12.2N/mm) was significantly greater than the tendon stiffness measured following the heel-drop exercise on the level floor (25.4±11.4N/mm) (p<.05). The results of this study suggest that tendon stiffness immediately following a heel-drop exercise depends on the magnitude of tendon strain.

In vivo activating transcription factor 3 silencing ameliorates the AMPK compensatory effects for ER stress-mediated ß-cell dysfunction during the progression of type-2 diabetes.

In obese Zucker diabetic fatty (ZDF) rats, ER stress is associated with insulin resistance and pancreatic ß-cell dysfunction; however the exact mechanisms by which ER stress drives type-2 diabetes remain uncertain. Here, we investigated the role of ATF3 on the preventive regulation of AMPK against ER stress-mediated ß-cell dysfunction during the end-stage progression of hyperglycemia in ZDF rats. The impaired glucose metabolism and ß-cell dysfunction were significantly increased in late-diabetic phase 19-week-old ZDF rats. Although AMPK phosphorylation reduced in 6- and 12-week-old ZDF rats was remarkably increased at 19weeks, the increases of lipogenice genes, ATF3, and ER stress or ROS-mediated ß-cell dysfunction were still remained, which were attenuated by in vivo-injection of chemical chaperon tauroursodeoxycholate (TUDCA), chronic AICAR, or antioxidants. ATF3 did not directly affect AMPK phosphorylation, but counteracts the preventive effects of AMPK for high glucose-induced ß-cell dysfunction. Moreover, knockdown of ATF3 by delivery of in vivo-jetPEI ATF3 siRNA attenuated ER stress-mediated ß-cell dysfunction and enhanced the beneficial effect of AICAR. Our data suggest that ATF3 may play as a counteracting regulator of AMPK and thus promote ß-cell dysfunction and the development of type-2 diabetes and could be a potential therapeutic target in treating type-2 diabetes.