A high dose of estradiol (10 μM-6 h, showed a promotion of AMPK activation in a previous study) significantly inhibited SC ultrastructure, mitochondrial function, and proliferation-related pathways, while these adverse effects were weakened by Compound C treatment or miR-1285 mimic transfection. Our findings suggest that the activation and inhibition of AMPK induced by specific drugs or synthesized targeted miRNA fragments could regulate immature boar SC proliferative activity by influencing the CDK4/Cyclin D3 pathway and mitochondrial function; this helps to provide a basis for the prevention and treatment of male sterility in clinical practice.

Specifically, S100P inhibition significantly enhanced the growth of HL-60 tumor xenografts and increased the expression of microtubule-associated protein 1 light chain 3 and p-AMPK in nude mice. Consequently, it can be concluded that S100P plays a regulatory role in the chemosensitivity of leukemia cells by modulating the p53/AMPK/mTOR pathway, which controls autophagy in leukemia cells.

BH3 mimetics, including the BCL2/BCLXL/BCLw inhibitor navitoclax and MCL1 inhibitors S64315 and tapotoclax, have undergone clinical testing for a variety of neoplasms...Building on the observation that BH3 mimetic monotherapy induces AMP kinase (AMPK) activation in multiple acute leukemia cell lines, we report that the AMPK inhibitors (AMPKis) dorsomorphin and BAY-3827 sensitize these cells to navitoclax or MCL1 inhibitors...Conversely, dorsomorphin synergizes with navitoclax or the MCL1 inhibitor S63845 to induce cell death in primary acute leukemia samples ex vivo and increases the antitumor effects of navitoclax or S63845 in several xenograft models in vivo with little or no increase in toxicity in normal tissues. These results suggest that AMPK inhibition can sensitize acute leukemia to multiple BH3 mimetics, potentially allowing administration of lower doses while inducing similar antineoplastic effects.

P2, N=90, Not yet recruiting, Glaceum

P1, N=36, Completed, Glaceum | Recruiting --> Completed

P2, N=81, Completed, Glaceum | Active, not recruiting --> Completed | Phase classification: P2a --> P2 | Trial completion date: Dec 2022 --> Apr 2023

Importantly, potential drugs such as salermide, celestrol, cercosporin, dorsomorphin dihydrochloride, and LDN-193189 monohydrochloride that can reverse the aging-associated signatures in HSCs from healthy elderly were identified. The analysis of RNA-seq data based on NGKD techniques revealed a plethora of differentially regulated pathways, gene ontologies, and drugs with anti-aging potential to promote healthspan in the elderly.

Additionally, SRE was found to increase p-AMPKT172 , but had no effect on total AMPK expression, after administration of the AMPK inhibitor Compound C, the inhibitory effect of SRE on M1 macrophages was partially reversed. The results indicate that SRE has an inhibitory effect on AD, making it a potential therapeutic agent for this atopic disorder.

Furthermore, inhibition of the AMPK/SIRT1 signaling pathway by Compound C, an AMPK inhibitor, significantly reversed the protective effect of wogonin on OGD/R-induced NLRP3 inflammasome. Meanwhile, the protective effect of wogonin against brain IR injury was also reversed in the presence of compound C. These results suggest that wogonin ameliorates cerebral IR injruy-induced inflammation by inhibiting NLRP3 inflammasome through the AMPK/SIRT1 signaling pathway.

Surprisingly, the two inhibitors appear to promote Thr172 phosphorylation by different mechanisms: BAY-3827 primarily protects against Thr172 dephosphorylation, while SBI-0206965 also promotes phosphorylation by LKB1 at low concentrations, while increasing cellular AMP:ATP ratios at higher concentrations. Due to its greater potency and fewer off-target effects, BAY-3827 is now the inhibitor of choice for cell studies, although its low bioavailability may limit its use in vivo.

Four-week purslane treatment ameliorated aortic relaxations, ER stress, and oxidative stress in diabetic obese mice. This study supported that purslane protected endothelial function, and inhibited ER stress and oxidative stress in vasculature through AMPK/eNOS activation, revealing its therapeutic potential against vascular complications in diabetes.

AMPK inhibitor dorsomorphin reversed this effect of SN-4, confirming that the effect is mediated by AMPK activation...Although lactic acidosis is a serious side effect of biguanides such as metformin, SN-4 did not affect lactate production...In diabetes treatment, it is important to not only regulate blood sugar levels but also prevent complications. Our findings reveal the therapeutic potential of SN-4 as a new antidiabetic drug that can also help prevent future complications.

BMP signalling pathway is important for CML cell survival. Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone, the combination efficacy importantly being demonstrated in both 2D and 3D cell cultures highlighting the need for combinatorial therapies in contrast to standard of care single agents. Our study provides justification to target multiple kinases in CML to combat LSC persistence.

In a further study, after inhibiting AMPK with dorsomorphin, the anti-inflammatory effects of catalpol were significantly reduced. Therefore, catalpol ameliorates LPS-induced inflammatory response by activating AMPK/mTOR signaling pathway in IEC-6 cells.

Osthole has a radiosensitizing effect on subcutaneous transplanted hepatocellular carcinoma, and its mechanism may be related to inhibition of GSK-3β/AMPK/mTOR pathway-controlled glycolysis.

Dorsomorphin, the selective inhibitor on AMPK was introduced to study the downstream signaling through which the GPNMB works...GPNMB treatment significantly magnified the expression of p-AMPK while p-NFκB, IL-1β, IL-6 and TNF-α were suppressed; in the meantime, the combined administration of GPNMB and AMPK inhibitor could decrease the intensity of p-AMPK and reverse the quantity of p-NFκB and the above inflammatory cytokines. GPNMB has the potential of ameliorating the brain edema and neuroinflammation, protecting the BBB and improving the neurological outcome, possibly via the AMPK/NFκB signaling pathway.

All these protective effects of GMET on lipid accumulation and inflammation in vivo and in vitro were largely abolished by co-treatment with dorsomorphin, an AMPK inhibitor. In conclusion, GMET alleviated lipid accumulation and inflammation to preserve normal hepatocyte function in steatohepatitis. Thus, GMET is a novel potential multi-targeting compound to improve steatohepatitis.

Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells. In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53.

Molecular docking results showed that BML-275 can bind to the FKRP12-rapamycin binding site on mTOR protein, and thereby may have the same inhibitory activity on mTOR as rapamycin. Thus, these findings indicated that BML-275 induces mitochondrial-mediated apoptosis and autophagy in PCa by targeting mTOR inhibition. BML-275 may be a potential candidate for the treatment of PCa.

Six main gene clusters and 27 significant hub genes mainly involved in cell cycle regulation have been identified. By assessing the interaction between 3 drugs and hub genes and information gained from previous clinical investigations, we suggested the three possible repurposed drug combinations, Vorinostat - Dorsomorphin, PP-110 - Dorsomorphin, and Puromycin - Vorinostat with a high chance of success in clinical trials.

Overexpressed GLIS3 promoted proliferation, migration, invasion, TGF-β1 expression and Smad1/5 phosphorylation in GAC cells, with SB505124 reversing the effects of overexpressed GLIS3 on proliferation, migration, invasion and Smad1/5 phosphorylation whereas dorsomorphin exhibiting no influence on GLIS3-induced effects. GLIS3 facilitated the malignant phenotype of GAC cells via regulating TGF-β1/TGFβR1/Smad1/5 pathway, which may be a novel prognostic indicator of GAC and provided a target for GAC treatment.

The effects of AMPK-modulation on cell viability and proliferation in UM cell lines with different molecular profiles (i.e., 92-1, MP46, OMM2.5 and Mel270) were investigated via XTT cell viability and proliferation assays after treating the cells with varying concentrations of A-769662 (AMPK-activator) or dorsomorphin (AMPK-inhibitor)...We propose a new perspective in the treatment of UM. Targeting AMPK pathway may open up new avenues in developing novel therapeutic approaches to improve overall-survival in UM.

It is noteworthy that GW9662 (a PPARγ inhibitor) and Compound C (an AMPK inhibitor) partially reversed the anti-proliferation and anti-metastasis effects of XLLX in TNBC cells. Therefore, XLLX may effectively inhibit the growth and metastasis of TNBC by activating the PPARγ/AMPK signaling pathway.

The protumorigenic effects of BMP13 on HCC cells were almost completely abrogated by the small molecule dorsomorphin 1 (DMH1), which selectively blocks the intracellular kinase domain of ALK2 and ALK3, indicating that BMP13 acts via these BMP type I receptors on HCC cells. In summary, this study newly identifies stroma-derived BMP13 as a potential new tumor promotor in HCC and indicates this secreted growth-factor as a possible novel therapeutic target in HCC.

Our results suggest that FFAR2 signaling antagonized TLR2- and TLR3-induced lung cancer progression via the suppression of the cAMP-AMPK-TAK1 signaling axis for the activation of NF-κB, and its agonist might be a potential therapeutic agent for the treatment of lung cancer.

In addition, the expression of β-catenin, COX-2, and HMGB1 were upregulated, as well as the expression of p16 was downregulated. These findings suggest that changes in the AMPK signaling pathway exacerbate the deterioration of disrupted energy metabolism, chronic inflammation, hypoxia, and cellular aging in the tumor microenvironment, promoting the development of fatty liver into liver cancer.

AMPK signaling was inhibited by the application of a pharmacological agent, Dorsomorphin, and the therapeutic effects of their conditioned medium (CM) were evaluated using in vitro cell cultures, ex vivo breast cancer tissues, and a mouse model of mammary tumors and tumor-induced osteolysis...In a mouse model of breast cancer, the application of AMPK-inhibited lymphocyte-derived CM reduced mammary tumors additively to a chemotherapeutic agent, Taxol... We demonstrated that PBMCs can be used to generate tumor-suppressive proteomes, and extracellular tumor-suppressing proteins such as MSN, ENO1, and PABPC1 are converted from tumor-promoting factors inside cancer cells. The results support the possibility of developing autologous blood-based therapy, in which tumor-suppressing proteins are enriched in engineered PBMC-derived CM by the inhibition of AMPK signaling.

Furthermore, Compound C synergistically enhanced the cytotoxicity of BCR-ABL inhibitors and the BCL2 inhibitor ABT-199. Collectively, this study indicates that Compound C induces MCL1 downregulation through the AMPK/p38 MAPK/miR-22/HuR pathway, thereby inducing apoptosis of KU812 and MEG-01 cells. Furthermore, our findings suggest that AMPK inhibition is a promising strategy for improving CML therapy.

PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higher phosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis via PHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as the potential epigenetic target in cancer metastasis.

Multiple transcription factors regulate SESN2 expression, including hypoxia-inducible factor 1 (HIF-1), p53, nuclear factor E2-related factor 2 (Nrf2), activating transcription factor 4 (ATF4), ATF6, etc. Upon induction, SESN2 generally leads to activation of adenosine monophosphate-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1)...However, the role of SESN2 in HCC is controversial due to its paradoxical pro-autophagic and anti-apoptotic effects. In conclusion, this review summarizes the biological functions of SESN2 in hypoxia, genotoxic stress, oxidative stress, ER stress, and inflammation, and specifically emphasizes the pathophysiological significance of SESN2 in liver diseases, aiming to providing a comprehensive understanding for SESN2 as a potential therapeutic target in liver diseases.

Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Overall, our study was the first to demonstrate that IC2 induced cytoprotective autophagy by SCD1 inhibition in breast cancer cells and that the autophagy inhibitor markedly enhanced the anticancer activity of IC2. Therefore, IC2 was a potential candidate compound in combination therapy for breast cancer.

Furthermore, knockdown of MCT4 led to the significant increase of ROS and MDA levels in 5637 cells and ferroptosis in 5637 cells induced by ferroptosis inducers including RSL3 (APExBIO) and erastin (APExBIO) via inhibition of AMPK-related proteins. Moreover, knockdown of MCT4 inhibited autophagy in 5637 cells, while siMCT4 promoted inhibition of autophagy by CQ (an autophagy inhibitor), which increased the level of apoptosis. This study confirmed that knockdown of MCT4 could affect oxidative stress and induce ferroptosis and inhibition of autophagy, thus suggesting that MCT4 may be a potential target for the treatment of bladder cancer.

The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion.

When autophagy was inhibited by 3-methyladenine (3-MA), ALR-induced proliferation inhibition, invasion, and migration capabilities, as well as apoptosis rate and G2/M phase arrest, were all reversed, and the activities of key proteins in the AMPK/mTOR pathway were all constrained. In summary, the results presented here indicate that ALR may be effective as a natural antitumor agent by activating AMPK and inhibiting the mTOR autophagy pathway in HepG2 cells.

And the pharmacological effects of calycosin in PTC cells were related to Sestrin2 activation, increased p-AMPK and inhibited p-mTOR and p-p70S6Kinase; these alterations were reversed when silencing Sestrin2. In conclusion, calycosin has an inhibitory effect on PTC via promoting apoptosis and autophagy through the Sestrin2/AMPK/mTOR pathway.

Furthermore, the level of phosphorylated (p-)AMPK, an energy sensor molecule, was upregulated when FH was knocked down in lung cancer cells, and the inhibition of p-AMPK led to an increase in the expression of disabled homolog 2, a tumor suppressor protein. These findings suggest that FH may serve as an effective biomarker for predicting the prognosis of lung cancer and as a therapeutic mediator.

Moreover, clinically available VEGFR-TKIs were found to regulate AMPK differently that, apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. This study discovered AMPK as an important off-target of apatinib, and elucidated different effects of this cluster of VEGFR-TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic, and highlights the subset of VEGFR-TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1-mutant NSCLC.

Simultaneously increased fatty acid synthesis and degradation would have "wasted" ATP in Hepa-1c4 cells, thus raising the [AMP]:[ATP] ratio, and further contributing to the upregulation of the AMPK pathway. Since these tumour cells can proliferate without the HIF-1/2 pathways, combinations of HIF1/2 inhibitors with PGC-1α or AMPK inhibitors should be explored.

Here, we investigated the therapeutic effects and molecular mechanisms of docetaxel, which is a paclitaxel antitumor agent, on the cell growth of a human tongue SCC-derived SAS cell line. The docetaxel-induced increases in p-JNK, p-ERK, and p-AMPKα protein expression could also be reversed by treatment with either SP600125, PD98059, or compound c. These results indicate that docetaxel induces human tongue SCC cell apoptosis via interdependent MAPK-JNK, MAPK-ERK1/2, and AMPKα signaling pathways. Our results show that docetaxel could possibly exert a potent pharmacological effect on human oral tongue SCC cell growth.

Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.

Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs.