Plant-derived natural compounds: A new frontier in inducing immunogenic cell death for cancer treatment.

Immunogenic cell death (ICD) can activate adaptive immune response in the host with normal immune system. Some synthetic chemotherapeutic drugs and natural compounds have shown promising results in cancer treatment by triggering the release of damage-associated molecules (DAMPs) to trigger ICD. However, most chemotherapeutic drugs exhibit non-selective cytotoxicity and may also induce and promote metastasis, thereby significantly reducing their clinical efficacy. Among the natural compounds that can induce ICD, plant-derived compounds account for the largest proportion, which are of increasing value in the treatment of cancer. Understanding which plant-derived natural compounds can induce ICD and how they induce ICD is crucial for developing strategies to improve chemotherapy outcomes. In this review, we focus on the recent findings regarding plant-derived natural compounds that induce ICD according to the classification of flavonoids, alkaloids, glycosides, terpenoids and discuss the potential mechanisms including endoplasmic reticulum (ER) stress, DNA damage, apoptosis, necroptosis autophagy, ferroptosis. In addition, plant-derived natural compounds that can enhance the ICD induction ability of conventional therapies for cancer treatment is also elaborated. The rational use of plant-derived natural compounds to induce ICD is helpful for the development of new cancer treatment methods.

New insights into the chemistry and anticancer activity of Ophiocordyceps xuefengensis.

Ophiocordyceps xuefengensis (O. xuefengensis), the sister taxon of Ophiocordyceps sinensis (O. sinensis), is consumed as a "tonic food" due to its health benefits. However, little is known regarding the chemistry and bioactivity of O. xuefengensis. In this study, we characterized 80 indole-based alkaloids in the ethyl acetate fraction of O. xuefengensis by high performance liquid chromatography-quadrupole time of flight mass spectrometry (HPLC-Q-TOF-MS/MS), of which 54 indole-based alkaloids were identified as possibly new compounds. Furthermore, 29 of these compounds were established as potential anti-cancer compounds by ligand fishing combined with HPLC-Q-TOF-MS/MS. Moreover, molecular docking identified the NH- and OH- groups of these compounds as the key active groups. The present study has expanded the knowledge on the characteristic indole-based alkaloids and anti-cancer activity of O. xuefengensis.

Clinical characteristics and analysis of vestibular-evoked myogenic potentials in patients with sudden sensorineural hearing loss in different ages.

BACKGROUND: Numerous studies have found that patients experiencing sudden sensorineural hearing loss (SSHL), with or without accompanying vertigo, often show impaired vestibular function. However, there is a dearth of studies analyzing vestibular-evoked myogenic potentials (VEMPs) in SSHL patients across various age groups. AIM: To investigate vestibular condition in SSHL patients across various age demographics. METHODS: Clinical data of 84 SSHL patients were investigated retrospectively. Audiometry, cervical vestibular evoked myogenic potentials (c-VEMPs), and ocular vestibular evoked myogenic potentials (o-VEMPs) were conducted on these patients. Parameters assessed included the latencies of P1 and N1 waves, as well as the amplitudes of P1-N1 waves. Moreover, the study evaluated the influence of factors such as sex, affected side, configuration of hearing loss, and presence of accompanying vertigo. RESULTS: Among the 84 SSHL patients, no significant differences were observed among the three groups in terms of gender, affected side, and the presence or absence of vertigo. Group II (aged 41-60 years) had the highest number of SSHL cases. The rates of absent o-VEMPs in the affected ears were 20.83%, 31.58%, and 22.72% for the three age groups, respectively, with no statistically significant difference among them. The rates of absent c-VEMPs in the affected ears were 8.3%, 34.21%, and 18.18% for the three age groups, respectively, with significant differences. In the unaffected ears, there were differences observed in the extraction rates of o-VEMPs in the unaffected ears among the age groups. In the three age groups, no significant differences were noted in the three age groups in the latencies of P1 and N1 waves or in the amplitude of N1-P1 waves for c-VEMPs and o-VEMPs, either on the affected side or on the unaffected side, across the three age groups. CONCLUSION: The extraction rate of VEMPs is more valuable than parameters. Regardless of the presence of vertigo, vestibular organs are involved in SSHL. Notably, SSHL patients aged 41-60 appear more susceptible to damage to the inferior vestibular nerve and saccule.

Approaching the Ideal Linearity in Epitaxial Crystalline-Type Memristor by Controlling Filament Growth.

Brain-inspired neuromorphic computing has attracted widespread attention owing to its ability to perform parallel and energy-efficient computation. However, the synaptic weight of amorphous/polycrystalline oxide based memristor usually exhibits large nonlinear behavior with high asymmetry, which aggravates the complexity of peripheral circuit system. Controllable growth of conductive filaments is highly demanded for achieving the highly linear conductance modulation. However, the stochastic behavior of the filament growth in commonly used amorphous/polycrystalline oxide memristor makes it very challenging. Here, the epitaxially grown Hf0.5Zr0.5O2-based memristor with the linearity and symmetry approaching ideal case is reported. A layer of Cu nanoparticles is inserted into epitaxially grown Hf0.5Zr0.5O2 film to form the grain boundaries due to the breaking of the epitaxial growth. By combining with the local electric field enhancement, the growth of filament is confined in the grain boundaries due to the fact that the diffusion of oxygen vacancy in crystalline lattice is more difficult than that in the grain boundaries. Furthermore, the decimal operation and high-accuracy neural network are demonstrated by utilizing the highly linear and multi-level conductance modulation capacity. This method opens an avenue to control the filament growth for the application of resistance random access memory (RRAM) and neuromorphic computing.

A Biomimetic Fibrous Composite Scaffold with Nanotopography-Regulated Mineralization for Bone Defect Repair.

The effective regeneration of large bone defects via bone tissue engineering is challenging due to the difficulty in creating an osteogenic microenvironment. Inspired by the fibrillar architecture of the natural extracellular matrix, we developed a nanoscale bioengineering strategy to produce bone fibril-like composite scaffolds with enhanced osteogenic capability. To activate the surface for biofunctionalization, self-adaptive ridge-like nanolamellae were constructed on poly(ε-caprolactone) (PCL) electrospinning scaffolds via surface-directed epitaxial crystallization. This unique nanotopography with a markedly increased specific surface area offered abundant nucleation sites for Ca2+ recruitment, leading to a 5-fold greater deposition weight of hydroxyapatite than that of the pristine PCL scaffold under stimulated physiological conditions. Bone marrow mesenchymal stem cells (BMSCs) cultured on bone fibril-like scaffolds exhibited enhanced adhesion, proliferation, and osteogenic differentiation in vitro. In a rat calvarial defect model, the bone fibril-like scaffold significantly accelerated bone regeneration, as evidenced by micro-CT, histological histological and immunofluorescence staining. This work provides the way for recapitulating the osteogenic microenvironment in tissue-engineered scaffolds for bone repair.

MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFß2-Smad2/3 signaling pathway in cervical cancer.

SRY-box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell-cycle-arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFß2-Smad2/3-p53-p21WAF1/CIP1-Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4-MAPK (JNK/ERK/p38)-ATF2 and WT1-ATF2 pathways, which is dependent on its high-mobility group (HMG) domain. In addition, the SOX6-induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT-263 (navitoclax) and ABT-199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6-induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin-resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1-ATF2-TGFß2 axis mediates SOX6-induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.

ECM-inspired calcium/zinc laden cellulose scaffold for enhanced bone regeneration.

Cellulose-based polymer scaffolds are highly diverse for designing and fabricating artificial bone substitutes. However, realizing the multi-biological functions of cellulose-based scaffolds has long been challenging. In this work, inspired by the structure and function of the extracellular matrix (ECM) of bone, we developed a novel yet feasible strategy to prepare ECM-like scaffolds with hybrid calcium/zinc mineralization. The 3D porous structure was formed via selective oxidation and freeze drying of bacterial cellulose. Following the principle of electrostatic interaction, calcium/zinc hybrid hydroxyapatite nucleated, crystallized, and precipitated on the 3D scaffold in simulated physiological conditions, which was well confirmed by morphology and composition analysis. Compared with alternative scaffold cohorts, this hybrid ion-loaded cellulose scaffold exhibited a pronounced elevation in alkaline phosphatase (ALP) activity, osteogenic gene expression, and cranial defect regeneration. Notably, the hybrid ion-loaded cellulose scaffold effectively fostered an M2 macrophage milieu and had a strong immune effect in vivo. In summary, this study developed a hybrid multifunctional cellulose-based scaffold that appropriately simulates the ECM to regulate immunomodulatory and osteogenic differentiation, setting a measure for artificial bone substitutes.

Effective electrical manipulation of a topological antiferromagnet by orbital torques.

The electrical control of the non-trivial topology in Weyl antiferromagnets is of great interest for the development of next-generation spintronic devices. Recent studies suggest that the spin Hall effect can switch the topological antiferromagnetic order. However, the switching efficiency remains relatively low. Here, we demonstrate the effective manipulation of antiferromagnetic order in the Weyl semimetal Mn3Sn using orbital torques originating from either metal Mn or oxide CuOx. Although Mn3Sn can convert orbital current to spin current on its own, we find that inserting a heavy metal layer, such as Pt, of appropriate thickness can effectively reduce the critical switching current density by one order of magnitude. In addition, we show that the memristor-like switching behaviour of Mn3Sn can mimic the potentiation and depression processes of a synapse with high linearity-which may be beneficial for constructing accurate artificial neural networks. Our work paves a way for manipulating the topological antiferromagnetic order and may inspire more high-performance antiferromagnetic functional devices.

Range adaptation in schizophrenia: A one-year longitudinal study.

Range adaptation refers to the representation of a stimulus value based on its relative position in the range of pre-experienced values. Altered range adaptation in value representation may be related to motivation and pleasure (MAP) deficit in schizophrenia (SCZ). This follow-up study examined the relationship between range adaptation performance and MAP symptoms in SCZ patients. We recruited 26 schizophrenia patients and followed them for 1 year. They completed an experimental task for estimating their range adaptation to outcome value (OV) and expected value (EV) at baseline and after 1 year. At baseline, we found a marginally significant and negative correlation between OV adaptation and avolition symptoms in SCZ patients. Moreover, the 1-year change of EV adaptation was significantly and negatively correlated with the change of self-report pleasure experience. Our results suggest that range adaptation may track the variations of MAP symptoms in SCZ.

Highly Energy-Efficient Spin Current Generation in SrIrO3 by Manipulating the Octahedral Rotation.

Materials with strong spin-orbit coupling (SOC) have been continuously attracting intensive attention due to their promising application in energy-efficient, high-density, and nonvolatile spintronic devices. Particularly, transition-metal perovskite oxides with strong SOC have been demonstrated to exhibit efficient charge-spin interconversion. In this study, we systematically investigated the impact of epitaxial strain on the spin-orbit torque (SOT) efficiency in the SrIrO3(SIO)/Ni81Fe19(Py) bilayer. The results reveal that the SOT efficiency is strongly related to the octahedral rotation around the in-plane axes of the single-crystal SIO. By modulating the epitaxial strain using different substrates, the SOT efficiency can be remarkably improved from 0.15 to 1.45. This 10-fold enhancement of SOT efficiency suggests that modulating the epitaxial strain is an efficient approach to control the SOT efficiency in complex oxide-based heterostructures. Our work may have the potential to advance the application of complex oxides in energy-efficient spintronic devices.

Tetrahedral Framework Nuclear Acids Can Regulate Interleukin-17 Pathway to Alleviate Inflammation and Inhibit Heterotopic Ossification in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease that leads to serious spinal deformity and ankylosis. Persistent inflammation and progressive ankylosis lead to loss of spinal flexibility in patients with AS. Tetrahedral framework nucleic acids (tFNAs) have emerged as a one kind of nanomaterial composed of four specially designed complementary DNA single strands with outstanding biological properties. Results from in vivo experiments demonstrated that tFNAs treatment could inhibit inflammatory responses and heterotopic ossification to halt disease progression. In vitro, tFNAs were proved to influence the biological behavior of AS primary chondrocytes and inhibit the secretion of pro-inflammatory cytokines through interleukin-17 pathway. The osteogenic process of chondrocytes was as well inhibited at the transcriptional level to regulate the expression of related proteins. Therefore, we believe tFNAs had a strong therapeutic effect and could serve as a nonsurgical remedy in the future to help patients suffering from AS.

Impact of hematological and radiation parameters on the clinical prognosis of esophageal cancer patients treated with definitive chemoradiotherapy.

This study aimed to conduct a survival analysis of thoracic esophageal squamous cell carcinoma (ESCC) patients treated with radical chemoradiotherapy and identify prognostic variables from among the hematological and radiation parameters. Cases of patients with ESCC receiving definitive chemoradiotherapy at Jiangsu Cancer Hospital between January 2018 and September 2020 were screened. A Cox proportional hazards model was used to assess the effect of hematological and radiation parameters on the overall survival (OS). The neutrophil-to-lymphocyte ratio (NLR) was calculated by dividing the absolute neutrophil count (ANC) by the absolute lymphocyte count (ALC) in the week prior to radical chemoradiotherapy. Variables associated with radiation were gathered based on dose-volume histograms (DVH). X-tile software was used to determine the optimal cutoff values for pretreatment NLR and posttreatment ALC nadir. Associations between lymphopenia and dose-volume parameters were analyzed using multivariate logistic regression. The study included 104 ESCC patients. The median follow-up of surviving patients was 45.0 months (interquartile range: 40.2-52.2), with 1- and 3-year OS rates of 88.0% and 62.7%, respectively. Multivariate Cox regression analysis demonstrated a significant survival benefit in patients with low baseline NLR (≤ 2.2), high ALC nadir (> 0.24*109/L), and desirable radiation parameters for the heart and thoracic vertebrae. Increased dose-volume parameters of the heart, lungs, and thoracic vertebrae were correlated with a high probability of radiation-induced lymphopenia (RIL) risk (P < 0.05). Baseline NLR and RIL are significantly related to survival outcomes in ESCC patients. Optimization of radiation parameters of cardiopulmonary and thoracic vertebrae can be effective in the prevention of RIL.

Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer.

Glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that negatively regulates ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 µM). Further studies suggested that 31 could induce ferroptosis in colon cancer cells and its cytotoxic activity could be reversed by ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel ferroptosis inducer agent for colon cancer.

S100a9 inhibits Atg9a transcription and participates in suppression of autophagy in cardiomyocytes induced by ß1-adrenoceptor autoantibodies.

BACKGROUND: Cardiomyocyte death induced by autophagy inhibition is an important cause of cardiac dysfunction. In-depth exploration of its mechanism may help to improve cardiac dysfunction. In our previous study, we found that ß1-adrenergic receptor autoantibodies (ß1-AAs) induced a decrease in myocardial autophagy and caused cardiomyocyte death, thus resulting in cardiac dysfunction. Through tandem mass tag (TMT)-based quantitative proteomics, autophagy-related S100a9 protein was found to be significantly upregulated in the myocardial tissue of actively immunized mice. However, whether S100a9 affects the cardiac function in the presence of ß1-AAs through autophagy and the specific mechanism are currently unclear. METHODS: In this study, the active immunity method was used to establish a ß1-AA-induced mouse cardiac dysfunction model, and RT-PCR and western blot were used to detect changes in gene and protein expression in cardiomyocytes. We used siRNA to knockdown S100a9 in cardiomyocytes. An autophagy PCR array was performed to screen differentially expressed autophagy-related genes in cells transfected with S100a9 siRNA and negative control siRNA. Cytoplasmic nuclear separation, co-immunoprecipitation (Co-IP), and immunofluorescence were used to detect the binding of S100a9 and hypoxia inducible factor-1α (HIF-1α). Finally, AAV9-S100a9-RNAi was injected into mice via the tail vein to knockdown S100a9 in cardiomyocytes. Cardiac function was detected via ultrasonography. RESULTS: The results showed that ß1-AAs induced S100a9 expression. The PCR array indicated that Atg9a changed significantly in S100a9siRNA cells and that ß1-AAs increased the binding of S100a9 and HIF-1α in cytoplasm. Knockdown of S100a9 significantly improved autophagy levels and cardiac dysfunction. CONCLUSION: Our research showed that ß1-AAs increased S100a9 expression in cardiomyocytes and that S100a9 interacted with HIF-1α, which prevented HIF-1α from entering the nucleus normally, thus inhibiting the transcription of Atg9a. This resulted in autophagy inhibition and cardiac dysfunction.

[Leukemia Genotype Analysis of Children with Acute Lymphoblastic Leukemia in Yunnan Area].

OBJECTIVE: To analyze 43 leukemia genes in children with acute lymphoblastic leukemia (ALL) in Yunnan province, and provide the basis for the diagnosis and treatment of children with ALL in this area. METHODS: The clinical data of 428 children with newly diagnosed ALL in Yunnan area from January 2015 to December 2020 were retrospectively analyzed. Multiple nested PCR technology was used to detect 43 common leukemia genes. RESULTS: Among the 428 children with ALL, 159 were positive for leukemia genes, with a positive rate of 37.15% (159/428), and a total of 15 leukemia genes were detected. Among the 159 leukemia gene-positive children, ETV6-RUNX1+ accounted for 25.79% (41/159), followed by E2A-PBX1+ and BCR-ABL+, accounting for 24.53% (39/159) and 23.27% (37/159) respectively. MLL+ accounted for 6.29% (10/159), WT1+ accounted for 4.40% (7/159), IKZF1 gene deletion and CRLF2+ accounted for 3.77% (6/159) respectively. The positive rate of MLL (46.15%) was the highest in ＜1-year old group, the positive rate of ETV6-RUNX1 (10.56%) was the highest in 1-10-year old group, and BCR-ABL+ rate (23.65%) was the highest in >10-year old group. The distribution of leukemia genes in different age groups was statistically significant (P <0.05). CONCLUSION: The most common fusion gene of children with ALL in Yunnan is ETV6-RUNX1, followed by E2A-PBX1 and BCR-ABL.

Tetrahedral Framework Nucleic Acids Inhibit Muscular Mitochondria-Mediated Apoptosis and Ameliorate Muscle Atrophy in Sarcopenia.

Sarcopenia is known as age-related muscle atrophy, which influences over a quarter of the elderly population worldwide. It is characterized by a progressive decline in muscle mass, strength, and performance. To date, clinical treatments in sarcopenia are limited to rehabilitative interventions and dietary supplements. Tetrahedral framework nucleic acids (tFNAs) represent a novel kind of DNA-based nanomaterial with superior antiapoptosis capacity in cells, tissues, organs, and systems. In our study, the therapeutic effect of tFNAs treatment on sarcopenia was evaluated both in vivo and in vitro. Results from muscular biophysiological characteristics demonstrated significant improvement in muscle function and endurance in the aged mouse model, and histologic examinations also showed beneficial morphological changes in muscle fibers. In vitro, DEX-induced sarcopenic myotube atrophy was also ameliorated through the inhibition of mitochondria-mediated cell apoptosis. Collectively, tFNAs treatment might serve as an alternative option to deal with sarcopenia in the near future.

Coexistence of Magnon-Induced and Rashba-Induced Unidirectional Magnetoresistance in Antiferromagnets.

Unidirectional magnetoresistance (UMR) has been intensively studied in ferromagnetic systems, which is mainly induced by spin-dependent and spin-flip electron scattering. Yet, UMR in antiferromagnetic (AFM) systems has not been fully understood to date. In this work, we reported UMR in a YFeO3/Pt heterostructure where YFeO3 is a typical AFM insulator. Magnetic-field dependence and temperature dependence of transport measurements indicate that magnon dynamics and interfacial Rashba splitting are two individual origins for AFM UMR, which is consistent with the UMR theory in ferromagnetic systems. We further established a comprehensive theoretical model that incorporates micromagnetic simulation, density functional theory calculation, and the tight-binding model, which explain the observed AFM UMR phenomenon well. Our work sheds light on the intrinsic transport property of the AFM system and may facilitate the development of AFM spintronic devices.

Acupuncture with twirling reinforcing and reducing manipulation shows a control of hypertension and regulation of blood pressure-related target brain regions in spontaneously hypertensive rat: a preliminary resting-state functional MRI study.

Aim: To observe the effects of acupuncture manipulations on blood pressure and brain function in spontaneously hypertensive rats and elucidate the anti-hypertensive effect of the manipulations' central mechanism. Methods: This study used acupuncture twirling reinforcing, acupuncture twirling reducing, and acupuncture twirling uniform reinforcing-reducing manipulations to act on the bilateral TaiChong point of rats. The depth of acupuncture was 1.5-2 mm, and twisting was performed at a frequency of 60 times/min within ±360° for 3 min, followed by the needle being retained for 17 min. Functional magnetic resonance imaging was performed at the end of the intervention. Regional homogeneity and amplitude of low-frequency fluctuations were used to assess the differences in brain regions in each group of rats, and the core brain region (left hypothalamus) among the differential brain regions was selected as the seed for functional connectivity analysis. Results: (1) The anti-hypertensive effect was achieved by acupuncture manipulations, and the anti-hypertensive effect of twirling reducing manipulation on spontaneously hypertensive rats was better than that of twirling uniform reinforcing-reducing and twirling reinforcing manipulations. (2) After regional homogeneity and amplitude of low-frequency fluctuations analyses, the hypothalamus, the brain region related to blood pressure, was activated in the twirling uniform reinforcing-reducing manipulation group; the corpus callosum and cerebellum were activated in the twirling reinforcing manipulation group; and the hypothalamus, olfactory bulb, corpus callosum, brainstem, globus pallidum, and striatum were activated in the twirling reducing manipulation group. (3) According to the functional connectivity analysis, different acupuncture manipulations increased the functional connections between seed points and the brainstem, olfactory bulb, and cerebellum, etc. Conclusion: These results suggest that acupuncture manipulations achieved the hypotensive effect and the twirling reducing manipulation had a better hypotensive effect on spontaneously hypertensive rats than twirling uniform reinforcing-reducing and twirling reinforcing manipulations; the central mechanism of the anti-hypertensive effect of twirling reinforcing and reducing manipulation may be related to the activation of brain regions associated with blood pressure regulation and the functional connections between them. Furthermore, brain regions involved in motor control, cognition, and hearing were also activated. We hypothesize that activation of these brain regions may help prevent or mitigate the onset and progression of hypertensive brain damage.

Epac1 participates in ß1-adrenoreceptor autoantibody-mediated decreased autophagic flux in cardiomyocytes.

Decreased autophagic flux in cardiomyocytes is an important mechanism by which the ß1-adrenoreceptor (ß1-AR) autoantibody (ß1-AA) induces heart failure. A previous study found that ß1-AA imparts its biological effects via the ß1-AR/Gs/AC/cAMP/PKA canonical signaling pathway, but PKA inhibition does not completely reverse ß1-AA-induced reduction in autophagy in myocardial tissues, suggesting that other signaling molecules participate in this process. This study confirmed that Epac1 upregulation is indeed involved ß1-AA-induced decreased cardiomyocyte autophagy through CE3F4 pretreatment, Epac1 siRNA transfection, western blot and immunofluorescence methods. On this basis, we constructed ß1-AR and ß2-AR knockout mice, and used receptor knockout mice, ß1-AR selective blocker (atenolol), and the ß2-AR/Gi-biased agonist ICI 118551 to show that ß1-AA upregulated Epac1 expression through ß1-AR and ß2-AR to inhibit autophagy, and biased activation of ß2-AR/Gi signaling downregulated myocardial Epac1 expression to reverse ß1-AA-induced myocardial autophagy inhibition. This study aimed to test the hypothesis that Epac1 acts as another effector downstream of cAMP on ß1-AA-induced reduction in cardiomyocyte autophagy, and ß1-AA upregulates myocardial Epac1 expression through ß1-AR and ß2-AR, and biased activation of the ß2-AR/Gi signaling pathway can reverse ß1-AA-induced myocardial autophagy inhibition. This study provides new ideas and therapeutic targets for the prevention and treatment of cardiovascular diseases related to dysregulated autophagy.