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67 Companies | 59 Products |
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344 Diseases | |
343 Trials |  |
12261 News |  |
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- | quercetin (LY294002) / Eli Lilly
Journal: Estradiol-Induced MMP-9 Expression via PELP1-Mediated Membrane-Initiated Signaling in ERα-Positive Breast Cancer Cells. (Pubmed Central) - Oct 2, 2020
E-bovine serum albumin (BSA), a large molecular membrane-impenetrable conjugate of E, can also upregulate MMP-9 protein expression in MCF-7, and the action of E-BSA can be abolished by PI3K inhibitor LY294002; treating MCF-7 simultaneously with PELP1-shRNA and LY294002 did not show synergetic inhibitory effect on E-BSA-induced MMP-9 expression. Our results indicated that estrogen-induced MMP-9 expression in ER-positive breast cancer cells may be through PELP1-mediated PI3K/Akt signaling pathway.
- | doxorubicin hydrochloride / Generic mfg.
Journal: Investigation of cardiovascular protective effect of Shenmai injection by network pharmacology and pharmacological evaluation. (Pubmed Central) - Oct 2, 2020
Our results indicated that estrogen-induced MMP-9 expression in ER-positive breast cancer cells may be through PELP1-mediated PI3K/Akt signaling pathway. Collectively, the protective effects of SMI on DOX-induced cardiotoxicity are possibly related to the activation of the PI3K/Akt pathway, as the downstream of G protein-coupled receptor signaling pathway.
- | Review, Journal: Drugging the Phosphoinositide 3-Kinase (PI3K) and Phosphatidylinositol 4-Kinase (PI4K) Family of Enzymes for Treatment of Cancer, Immune Disorders, and Viral/Parasitic Infections. (Pubmed Central) - Oct 2, 2020
The first generation of PI3K inhibitors have recently been clinically approved for a number of different cancers, highlighting their therapeutic value. This review will examine the history of the class I PI3Ks, and the type III PI4Ks, their relevance to human disease, and the structural basis for their regulation and inhibition by potent and selective inhibitors.
- | Journal: HPV16 E6/E7 promote the translocation and glucose uptake of GLUT1 by PI3K/AKT pathway via relieving miR-451 inhibitory effect on CAB39 in lung cancer cells. (Pubmed Central) - Oct 2, 2020
More interestingly, we found that CAB39 prompted GLUT1 translocation to the plasma membrane and glucose uptake, and this promotion depended on the PI3K/AKT pathway. Our findings provide new evidence to support the critical roles of miR-451 and CAB39 in the pathogenesis of HPV-related lung cancer.
- |||| 3 active drugs! Vs-6766 Synergistic combo (last pic in the thread) I replace Defactinib (FAKi) with PI3K mTORC1/2 VS-5584 😎 as PI3K is one of the resistance mechanisms to AMG510. https://t.co/VDN8PpYoQW (Twitter) - Oct 1, 2020
- ||| controlling MAP3k/PI3K SHP-2 pathway very important for durable response with Soto.#LCSM (Twitter) - Oct 1, 2020
- | Journal: PIP-Phldb2 is crucial for LTP regulating synaptic NMDA and AMPA receptor density and PSD95 turnover. (Pubmed Central) - Oct 1, 2020
Therefore, PIP-responsive Phldb2 is pivotal for induction and maintenance of LTP. Memory formation was impaired in our Phldb2 mice.
- | Journal: Mechanism of Hydrogen Sulfide Preconditioning-Associated Protection Against Ischemia-Reperfusion Injury Differs in Diabetic Heart That Develops Myopathy. (Pubmed Central) - Oct 1, 2020
Further, to study the HS mode of action, the experimental rats were exposed to a PI3K inhibitor (Wortmannin) and GSK3β inhibitor (SB216763) before HIPC protocol, whose results suggest that unlike in normal and DM, HIPC mediates its cardioprotective effect independent of PI3K/GSK3β pathway. To conclude, HIPC ameliorates I/R injury in DCM rat via an alternative pathway other than existing PI3K pathway, which is required to be probed under disease conditions.
- | Journal, IO Biomarker: MiR-34a inhibits spinal cord injury and blocks spinal cord neuron apoptosis by activating phatidylinositol 3-kinase (PI3K)/AKT pathway through targeting CD47. (Pubmed Central) - Oct 1, 2020
To conclude, HIPC ameliorates I/R injury in DCM rat via an alternative pathway other than existing PI3K pathway, which is required to be probed under disease conditions. MiR-34a can downregulate CD47 expression to activate PI3K/AKT signal pathway, and thus inhibit SCI induced spinal neuron apoptosis.
- | Journal: Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as anticancer agents. (Pubmed Central) - Oct 1, 2020
Meanwhile, western blot assay indicated that 8i inhibited cell proliferation via suppression of PI3K kinase activity and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 8i could inhibit the migration and invasion ability of HCT116 cells and could induce apoptosis of HCT116 cells.
- | Journal: MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis. (Pubmed Central) - Oct 1, 2020
Our studies demonstrated that MAP2K4 has the potential to serve as an oncogene in breast cancer and it activates the phosphorylated PI3K/AKT signaling pathway to activate downstream cycle-associated proteins and EMT signals while interacting with Vimentin to promote breast cancer cells proliferation, migration, and invasion. In our study, MAP2K4 and Vimentin co-expression is confirmed to be an unfavorable factor in breast cancer.
- | Journal: Wnt/β-Catenin, Carbohydrate Metabolism, and PI3K-Akt Signaling Pathway-Related Genes as Potential Cancer Predictors. (Pubmed Central) - Oct 1, 2020
All candidate pathway-related genes yielded areas under the curve exceeding 95.00% for cancer outcomes, and they were most accurate in predicting colorectal cancer. These results suggest that these pathway-related genes are useful and accurate biomarkers for understanding the mechanisms behind cancer development.
- | quercetin (LY294002) / Eli Lilly
Preclinical, Journal: GPR174 suppression attenuates retinopathy in angiotensin II (Ang II)-treated mice by reducing inflammation via PI3K/AKT signaling. (Pubmed Central) - Oct 1, 2020
The in vitro data showed that pre-treatment of PI3 K/AKT specific inhibitor LY294002 remarkably abrogated GPR174 over-expression-accelerated expression levels of Iba-1, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in lipopolysaccharide (LPS)-incubated retinal microglial cells.Furthermore, in LPS-exposed retinal microglial cells, PI3 K/AKT and NF-κB pathways were further promoted by GPR174 over-expression, which were significantlyabolished by LY294002. Thus, GPR174 might be a positive meditator of inflammation, contributing to Ang II-induced retinopathy by activating PI3 K/AKT signaling, and could be considered as a novel therapeutic target for the treatment of hypertensive retinopathy.
- | chloroquine phosphate / Generic mfg.
Journal: Salidroside induces apoptosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway. (Pubmed Central) - Oct 1, 2020
Furthermore, treatment with the autophagy inhibitor chloroquine enhanced salidroside-induced cell apoptosis, indicating that the autophagy mediated by salidroside may protect AGS cells from death...The above findings indicate that salidroside inhibited the growth of gastric cancer and induced apoptosis and protective autophagy through the PI3K/Akt/mTOR pathway. In summary, our study provides novel insights regarding the activity of salidroside against gastric cancer and contributes to the clinical application of salidroside combined with autophagy inhibitors as a chemotherapeutic strategy for human gastric cancer.
- | Journal: SNHG1 promotes proliferation, migration and invasion of bladder cancer cells via the PI3K/AKT signaling pathway. (Pubmed Central) - Oct 1, 2020
Mechanistically, rescue assays identified that SNHG1 activated the PI3K/AKT signaling pathway. Therefore, it was speculated that SNHG1 functioned as a carcinogenic lncRNA in bladder cancer via activation of PI3K/AKT.
- | sirolimus / Generic mfg., doxorubicin hydrochloride / Generic mfg.
Journal: Glutathione S-transferases P1 protects breast cancer cell from adriamycin-induced cell death through promoting autophagy. (Pubmed Central) - Sep 30, 2020
Taken together, our findings demonstrate that high level of GSTP1 maintains resistance of breast cancer cells to ADR through promoting autophagy. These new molecular insights provide an important contribution to our better understanding the effect of GSTP1 on the resistance of tumors to chemotherapy.
- | Preclinical, Journal: Berberine chloride ameliorated PI3K/Akt-p/SIRT-1/PTEN signaling pathway in insulin resistance syndrome induced in rats. (Pubmed Central) - Sep 30, 2020
Hence, these data provide a crucial message that BER-chloride enhanced both hepatic function and insulin signaling pathways that might be of therapeutic importance to insulin resistance with no harmful effect on the liver. BER-chloride is predicted to be a drug of choice for obesity complications cure.
- | KU-55933 / AstraZeneca
Preclinical, Journal: The effect of inhibitors of phosphatidylinositol 3-kinase-related kinases on dibenzo[def,p]chrysene genotoxicity measured by γH2AX levels and neutral comet assay in HepG2 human hepatocellular cancer cells. (Pubmed Central) - Sep 30, 2020
The PIKK inhibitors applied at non-cytotoxic concentrations: caffeine (1 mM) and KU55933 (2.5 μM) had no significant influence on the DBC cytotoxicity, however NU7026 (5 μM) caused significant increase in the cell viability by about 25%...The obtained results confirm that DBC is cytotoxic and causes damage to the genetic material including DSB. The DNA-PK inhibitor, NU7026 increases cell viability after exposure to DBC and reduces DNA damage, what indicates an important role of the sensor kinase in mediating the effect.
- | Review, Journal: PI3K Isoform-Selective Inhibitors in Cancer. (Pubmed Central) - Sep 30, 2020
These combination therapies have shown better results with cancer treatments. Both the monotherapy and dual therapy treatments are still currently being studied and data collected to better understand cancer and other treatment options.
- | Journal, IO Biomarker: Down-Regulation of SREBP via PI3K/AKT/mTOR Pathway Inhibits the Proliferation and Invasion of Non-Small-Cell Lung Cancer Cells. (Pubmed Central) - Sep 30, 2020
Our study indicated that downregulation of SREBP inhibited the growth in NSCLC cells via PI3K/AKT/mTOR signaling pathway. Thus, we suggested SREBP may serve as a potential target for the treatment of patients with NSCLC.
- | quercetin (LY294002) / Eli Lilly
Journal: HSPA12B Secreted by Tumor-Associated Endothelial Cells Might Induce M2 Polarization of Macrophages via Activating PI3K/Akt/mTOR Signaling. (Pubmed Central) - Sep 30, 2020
Based on these findings, we speculated that aberrantly expressed and secreted HSPA12B by TECs could be taken by macrophages partly via OLR1, leading to subsequent activation of the PI3K/Akt/mTOR signaling pathway and elevated expression of M2 markers. This mechanism shows a novel cross-talk between TECs and TAMs, which contributes to the intratumoral immunosuppressive microenvironment.
- | Journal: PRDX1 is a Tumor Suppressor for Nasopharyngeal Carcinoma by Inhibiting PI3K/AKT/TRAF1 Signaling. (Pubmed Central) - Sep 30, 2020
PRDX1 inhibits NPC by inhibiting the activation of PI3K/AKT/TRAF1 signaling. PRDX1 is a tumor suppressor in human NPC and may be a prognostic biomarker for NPC patients.
- | Journal: Ginger Extract Increases GLUT-4 Expression Preferentially Through AMPK Than PI3K Signalling Pathways in C2C12 Muscle Cells. (Pubmed Central) - Sep 30, 2020
The amount of GLUT-4 in membrane fraction of treated cells in the presence of PI3K inhibitor was higher than in the cells treated with this extract in the presence of AMPK inhibitor (P-value < 0.05). Ethyl acetate ginger extract affects the amount of GLUT-4 protein in membrane and cytosolic fractions of C2C12 myoblast cells mostly through AMPK pathway but less via PI3K.
- || Review, Journal: Endocrine-Resistant Breast Cancer: Mechanisms and Treatment. (Pubmed Central) - Sep 30, 2020
Overcoming primary or acquired resistance to endocrine treatment remains a major challenge. Since the molecular mechanisms of endocrine resistance are manifold, optimal combination and sequencing strategies will have to be developed in the future.
- | perifosine (D21266) / AEterna Zentaris
Journal: Facilitating Granule Cell Survival and Maturation in Dentate Gyrus With Baicalin for Antidepressant Therapeutics. (Pubmed Central) - Sep 30, 2020
PI3K inhibitor LY292002 and AKT inhibitor Perifosine were administered to HT-22 cells to explore the relationship between the PI3K/AKT/GSK3β/β-catenin pathway and baicalin...These results demonstrate that baicalin can alleviate chronic CORT-induced depressive-like behaviors through promoting survival and maturation of adult-born hippocampal granule cells and exhibiting protective effect on hippocampal neuron morphology. We propose the underlying mechanisms involve the activation of the PI3K/AKT/GSK3β/β-catenin pathway.
- | Biomarker, Journal, Tumor Mutational Burden, PD(L)-1 Biomarker, IO biomarker: Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer. (Pubmed Central) - Sep 30, 2020
Novel concurrent mutations were identified including CDH1 mutations. Findings from this cohort support further exploration of the clinical benefit of PI3K inhibitors for "off-label" PIK3CA mutations and combination strategies with potential clinical benefit for patients with breast cancer.
- | Journal, IO Biomarker: CD47 Enhances Cell Viability and Migration Ability but Inhibits Apoptosis in Endometrial Carcinoma Cells via the PI3K/Akt/mTOR Signaling Pathway. (Pubmed Central) - Sep 30, 2020
CD47 upregulation contributes to the activation of PI3K/Akt/mTOR signaling pathway in endometrial carcinoma cells. CD47 exerts oncogenic functions in endometrial carcinoma by activating PI3K/Akt/mTOR signaling, suggesting it may be a novel immunotherapeutic target for therapeutic interventions.
- || pictilisib (GDC-0941) / Roche
Clinical, Journal: Protocol for Comprehensive Synthetic Lethality Screens. (Pubmed Central) - Sep 30, 2020
Here, we provide a detailed protocol for synthetic lethality screens in a Jurkat T cell leukemia line using cell death as the readout measuring the combinatorial effect of a pan-PI3K inhibitor (GDC0941) with specific gene depletion by shRNA...We discuss how this protocol resource can be readily adapted by investigators. For complete details on the use and execution of this protocol, please refer to (Mues et al., 2019).
- |||||| umbralisib (TGR-1202) / TG Therap, tenalisib (RP6530) / Rhizen
Clinical: $TGTX partner Rhizen (TGTX bought umbralisib from them) Phase I/Ib Study of Tenalisib (RP6530), a Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma @semodough @SagarLonialMD @Pharmdca @pawcio2009 @TGTherapeutics https://t.co/6vf27Ed5Er (Twitter) - Sep 30, 2020
- |||| Clinical: Can Next-Generation PI3K Inhibitors Unlock the Full Potential of the Class in Patients With B-Cell Lymphoma? cc @TGTherapeutics @SagarLonialMD @chanyooncheah @semodough @Pharmdca @pawcio2009 @BillMiller32 @GileadSciences @ScienceAtBMS .... $TGTX https://t.co/D88r5jY9Ta (Twitter) - Sep 29, 2020
- | Lovely study! Also highly relevant for PI3K inhibitor aficionados.. :-) (Twitter) - Sep 29, 2020
- | Journal: Suppression of PDGF Induces Neuronal Apoptosis after Neonatal Cerebral Hypoxia and Ischemia by Inhibiting P-PI3K and P-AKT signaling pathways. (Pubmed Central) - Sep 27, 2020
In conclusion, PDGF suppression aggravated neuronal dysfunction, and the underlying mechanism is associated with inhibiting the phosphorylation of P-PI3K and P-AKT. Together, PDGF regulating PI3K and AKT may be an important panel in HIE events and therefore may provide possible strategy for the treatment of HIE in future clinic trail.
- | Preclinical, Journal: Salvinorin A attenuates early brain injury through PI3K/Akt pathway after subarachnoid hemorrhage in rat. (Pubmed Central) - Sep 27, 2020
The mechanism might be related to the increased protein expression of p-PI3K/p-Akt, which accompanied by decreased expression of p-IKKα/β, p-NF-κB, FoxO1, Bim, Bax and Cleaved-caspase-3 in the hippocampus. Thus, therapeutic interventions of SA targeting the PI3K/Akt pathway might be a novel approach to ameliorateEBIvia reducing the apoptosis and inflammation afterSAH.
- | Journal: A study on regulatory mechanism of miR-223 in ulcerative colitis through PI3K/Akt-mTOR signaling pathway. (Pubmed Central) - Sep 27, 2020
Thus, therapeutic interventions of SA targeting the PI3K/Akt pathway might be a novel approach to ameliorateEBIvia reducing the apoptosis and inflammation afterSAH. MiR-223 can trigger cell apoptosis and inflammation in UC by up-regulating the PI3K/Akt-mTOR signaling pathway.
- | Preclinical, Journal: Effect of miR-130a on neuronal injury in rats with intracranial hemorrhage through PTEN/PI3K/AKT signaling pathway. (Pubmed Central) - Sep 27, 2020
MiR-130a promotes neuronal growth in brain tissues in ICH rats and alleviates neuronal injury after ICH through the PTEN/PI3K/AKT signaling pathway. Our findings suggest that miR-130a exerts important clinical significance in the treatment of ICH.
- | Preclinical, Journal: Effects of miR-21 on hypertensive rats through PTEN/PI3K/Akt/mTOR signaling pathway. (Pubmed Central) - Sep 27, 2020
Our findings suggest that miR-130a exerts important clinical significance in the treatment of ICH. MiR-21 is involved in regulating the pathological symptoms and myocardial cell apoptosis in hypertensive rats through the PTEN/PI3K/Akt/mTOR signaling pathway.
- | Journal: Downregulated miRNA-26a-5p induces the apoptosis of endothelial cells in coronary heart disease by inhibiting PI3K/AKT pathway. (Pubmed Central) - Sep 27, 2020
MiR-21 is involved in regulating the pathological symptoms and myocardial cell apoptosis in hypertensive rats through the PTEN/PI3K/Akt/mTOR signaling pathway. MiRNA-26a-5p influences the proliferative and apoptotic abilities of endothelial cells isolated from CAD mice by targeting PTEN to activate PI3K/AKT pathway.
- | fluorouracil / Generic mfg.
Journal: A molecular sub-cluster of colon cancer cells with low VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment. (Pubmed Central) - Sep 27, 2020
At last, three or four sub-clusters classification is validated in colon cancer patients. Overall, our results suggest a molecular sub-cluster of colon cancer cells with low CDX2 and VDR expression is sensitive to chemotherapy, BRAF inhibitors and PI3K-mTOR inhibitors treatment and provide an example of translation of cancer classification to subgroup guided therapies.
- | sirolimus / Generic mfg.
Journal: CD146 Regulates Growth Factor-Induced mTORC2 Activity Independent of the PI3K and mTORC1 Pathways. (Pubmed Central) - Sep 27, 2020
The mechanistic target of rapamycin complex 2 (mTORC2) coordinates cell proliferation, survival, and metabolism with environmental inputs, yet how extracellular stimuli such as growth factors (GFs) activate mTORC2 remains enigmatic...This CD146-mediated mTORC2 activation in response to GF stimulation promotes cell proliferation and survival. Therefore, our findings identify a molecular mechanism by which extracellular stimuli regulate mTORC2 activity, linking environmental cues with mTORC2 regulation.
- | Journal: Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant-driven tumor growth. (Pubmed Central) - Sep 27, 2020
The YAP1 protein was up-regulated as an adaptive resistance-inducing response to inRas37 in RAS-dependent colorectal tumors; accordingly, a combination of inRas37 with a YAP1 inhibitor manifested synergistic antitumor effects in vitro and in vivo. Our study offers a promising pan-RAS-targeting antibody and the corresponding therapeutic strategy against RAS tumors.
- | Journal, IO Biomarker: Gallic Acid Inhibits Bladder Cancer T24 Cell Progression Through Mitochondrial Dysfunction and PI3K/Akt/NF-κB Signaling Suppression. (Pubmed Central) - Sep 27, 2020
Briefly, GA can inhibit T24 cells proliferation, metastasis and promote apoptosis, and the pro-apoptotic activity is closely associated with mitochondrial dysfunction and PI3K/Akt/NF-κB signaling suppression. Our study will help in finding a safe and effective treatment for bladder cancer.
- | metformin / Generic mfg.
Journal: Matrix Stiffness-Upregulated MicroRNA-17-5p Attenuates the Intervention Effects of Metformin on HCC Invasion and Metastasis by Targeting the PTEN/PI3K/Akt Pathway. (Pubmed Central) - Sep 27, 2020
Increased matrix stiffness significantly attenuates the inhibitory effect of metformin on HCC invasion and metastasis, and a common pathway of PTEN/PI3K/Akt/MMPs activated by mechanical stiffness signal and inactivated by metformin contributes to matrix stiffness-caused metformin resistance. To the best of our knowledge, this is the first report to clarify the mechanism of metformin intervention resistance from the perspective of tumor biophysical microenvironment.
- | quercetin (LY294002) / Eli Lilly, triciribine phosphate (VQD 002) / VioQuest, Prescient Therap
Journal: Mitochondrial Depolarization Stimulates Vascular Repair-Relevant Functions of CD34 Cells via Reactive Oxygen Species-Induced Nitric Oxide Generation. (Pubmed Central) - Sep 26, 2020
To the best of our knowledge, this is the first report to clarify the mechanism of metformin intervention resistance from the perspective of tumor biophysical microenvironment. Diazoxide stimulates vascular repair-relevant functions of CD34 cells via mitoK -dependent release of NO and ROS.
- ||| VS-5584 / Verastem
Some of the promising therapeutics, such as PI3K mTOR VS-5584, are also potential novel anticoagulant! https://t.co/mLM6xkrLkz (Twitter) - Sep 26, 2020
- | quercetin (LY294002) / Eli Lilly
Journal: miR-365 inhibits duck myoblast proliferation by targeting IGF-Ⅰ via PI3K/Akt pathway. (Pubmed Central) - Sep 26, 2020
Importantly, the enhanced PI3K, Akt, mTOR and S6K expression by miR-365 inhibitor (anti-miR-365) was abrogated by treatment with LY294002, a PI3K inhibitor. Together, our results indicated that miR-365 may target IGF-Ⅰ to inhibit duck myoblast proliferation via PI3K/Akt pathway.
- | Journal: HS mediates apoptosis in response to inflammation through PI3K/Akt/NFκB signaling pathway. (Pubmed Central) - Sep 26, 2020
HS regulates LPS-induced inflammation and apoptosis by activating the PI3K/Akt/NFκB signaling pathway. Hence, NaHS may be clinically useful for preventing or treating mastitis.
- | Zydelig (idelalisib) / Gilead
Journal: Design, Synthesis and Biological Evaluation of Quinazolin-4-one Based Hydroxamic Acids as Dual PI3K/HDAC Inhibitors. (Pubmed Central) - Sep 26, 2020
A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via an optimized linker...Target engagement of PI3K and HDAC6 by 48c was demonstrated in MV411 cells using the Cellular Thermal Shift Assay (CETSA). Compound 48c showed good pharmacokinetics properties in mice via intraperitoneal (ip) administration and provides a means to examine the biological effects of inhibiting these two important enzymes with a single molecule, either in vitro or in vivo.
- | sirolimus / Generic mfg., doxorubicin hydrochloride / Generic mfg.
Journal: Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3K/Akt/mTOR-dependent manner. (Pubmed Central) - Sep 26, 2020
Autophagy activator rapamycin cancelled off Cur-induced protective effects. Our finding suggested that Cur rescued against DOX-induced cardiac injury probably through regulation of autophagy and pyroptosis in a mTOR-dependent manner.