Emetine treatment also increased cellular and mitochondrial reactive oxygen species, and emetine-induced apoptosis in KG-1a cells was partially prevented by the antioxidant N-acetylcysteine, indicating that emetine induces apoptosis, at least in part, by inducing oxidative stress. Overall, these studies indicate that emetine is a novel potential anti-AML agent with promising activity against stem/progenitor cells, encouraging the development of further studies aimed at its clinical application.

BTZ also increased mitochondrial superoxide levels in KG-1a cells, and BTZ-induced apoptosis was partially prevented by pretreatment with the antioxidant N-acetylcysteine, indicating that BTZ induces oxidative stress-mediated apoptosis in KG-1a cells. At a dosage of 0.1 mg/kg every other day for 2 weeks, BTZ significantly reduced the percentage of hCD45-positive cells in the bone marrow and peripheral blood of NSG mice engrafted with KG-1a cells with tolerable toxicity. Taken together, these data indicate that the anti-LSC potential of BTZ appears to be an important strategy for AML treatment.

Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias...Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/β, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib...Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.

These results implied that EGCG could inhibit the expression of PD-1 in T cells, thereby promoting anti-tumor effects of T cells. EGCG will be a promising candidate in anti-tumor therapy.

Pip ameliorates NASH progression, and the therapeutical effect was associated with inhibition of hepatocyte pyroptosis induced by NF-κB.

By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway's inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.

The mechanism of action of TSG-6 was attributed to its interaction with CD44. These findings reveal novel mechanisms by which DPSCs counter inflammation and provide a basis for the treatment of pulpitis.

In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs.

P2, N=103, Completed, AJU Pharm Co., Ltd.

P1, N=7, Terminated, Roswell Park Cancer Institute | N=36 --> 7 | Trial completion date: Aug 2024 --> Jan 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2024 --> Jan 2024; low accrual

Taken together, our findings show that GLA has a protective impact on cartilage throughout OA progression, implying that GLA could be employed as a possible therapeutic agent for OA, thus giving a new therapeutic method for the treatment of OA.

P1, N=12, Suspended, Fox Chase Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Recruiting --> Suspended | Trial primary completion date: Mar 2024 --> Mar 2025

Meanwhile, TLR4 inhibitor BAY11-7082 might overturn the repression effect of TLR4 on M.tb-infected HTP-1 cell damage. YY1-activated TLR4 might aggravate mycobacterial injury in human macrophages after M.tb infection by the NF-kB pathway, providing a promising therapeutic target for TB treatment.

Findings elucidate that VD mediates the modulation of stemness in CD133+/CD44 + breast cancer stem cells through the regulation of NLRP3 expression. The research represents novel insights on the implications for the application of VD in cancer therapies.

P2, N=60, Recruiting, University of Colorado, Denver | Trial completion date: Jan 2029 --> Jan 2030 | Trial primary completion date: Nov 2028 --> Nov 2029

P3, N=396, Recruiting, AJU Pharm Co., Ltd.

P1, N=64, Recruiting, Geistlich Pharma AG | Trial completion date: Aug 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Sep 2024

P1/2, N=52, Active, not recruiting, Golden Biotechnology Corporation | Trial completion date: Dec 2023 --> Mar 2024

In contrast, ZNG suppressed neuro-inflammation, activated Akt2/FOXO1 signaling, and repaired histological irregularities. In general, SA caused oxidative stress, inflammation, ER stress, and apoptosis in the sciatic nerves of rats, causing damage to the tissues, however, ZNG suppressed these pathways and protected the sciatic nerves from the destructive effect of SA.

Mechanistically, immunofluorescence staining and western blotting were used to measure the protein levels of TLR4, phosphorylated NF-κB, phosphorylated IκBα, and phosphorylated MAPKs, showing that tomatidine inactivated NF-κB and MAPK signaling in lung tissues of CLP-induced ALI mice. In conclusion, tomatidine exerts protective effects against sepsis-induced severe damage to the lungs by inhibiting inflammation and activating autophagy in CLP-treated mice through inactivating the NF-κB and MAPK pathways, which may be an effective candidate for treating septic ALI.

Our findings suggest that O. fragrans, particularly its triterpenoid-rich EtOAc fraction, holds promise as a novel therapeutic agent for CRC prevention and therapy. These results provide valuable insights into the potential application of O. fragrans and its bioactive compounds in combating CRC.

P1, N=33, Terminated, Reata, a wholly owned subsidiary of Biogen | Phase classification: P1/2 --> P1

P2, N=80, Completed, Reata, a wholly owned subsidiary of Biogen | Phase classification: P2a --> P2

P2, N=227, Completed, Reata, a wholly owned subsidiary of Biogen | Phase classification: P2b --> P2

These results demonstrate that ruxolitinib attenuates the neuroinflammatory responses both in vivo and in vitro, at least in part by inhibiting MAPK/NF-κB signaling pathway. Our findings suggest that ruxolitinib may serve as a potential drug for the treatment of microglia-mediated neuroinflammation.

The activity of RelA and NF-κBp50 was assessed and confirmed using Bay 11-7082...The GNP suppressed IL-6 overexpression and secretion by deactivating NF-κBp65/NF-κBp50 transcription activity and upregulating miR-26a-5p expression in activated BC cells. These findings suggest that GNP have potential as a therapeutic intervention for BC by targeting IL-6 expression and associated pathways.

Metabolomics revealed the downregulation of pyrimidine metabolism and nucleotide metabolism, along with the upregulation of butyrate metabolism in tumor cells. This study demonstrated that EPP effectively regulated LPS leakage by modulating gut microbes, and this modulation influenced the TLR4/NF-κB pathway, ultimately disrupting tumor cell survival induced by HCC in mice.

FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2...FPFT-2216 also enhanced the anti-tumor activity of rituximab and showed anti-tumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model...In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NF-κB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma.

Conversely, siKeap1-GalNAc did not compromise chemotherapy efficacy and outperformed the conventional Nrf2 activator, bardoxolone, in mitigating CILI. This study proposes siKeap1-GalNAc as a promising therapeutic avenue for liver injury. Importantly, our study bridges a crucial gap concerning the delivery system for liver targeting but not tumor targeting and underscores the importance of selecting nucleic acid delivery systems tailored to specific diseases, not just to specific organs.

The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.

P1, N=25, Completed, Accendatech AU Pty Ltd | Active, not recruiting --> Completed

Our results suggest that LDHA and its major metabolite lactate drive NPC progression by regulating TAK1 and its downstream NF-κB signaling, which could become a therapeutic target in NPC.

To ameliorate the defects including serious side effects and drug resistance of Pt(II) drugs (e.g., cisplatin and oxaliplatin), here a novel of "dual-prodrug" by containing Pt(II) drugs and NF-κB inhibitors were synthesized and characterized. Moreover, complex 11 effectively suppressed the IKKβ phosphorylation, IκBα phosphorylation and NF-κB p65 phosphorylation and nuclear translocation, leading to blocked the NF-κB signal pathway in A549 cells. In vivo tests showed that the inhibitory rate in the complex 11 reached 69.2 %, which was much higher than that of oxaliplatin (55.6 %), 1a (39.7 %) and the combination of oxaliplatin/1a (65.1 %), without causing loss in the body weight.

Studies in vitro showed that TNF-α-induced NF-κB activation increases autotaxin expression and the clone forming ability of 4T1 breast cancer cells. This report highlights the potential role of Infliximab as an additional approach to attenuate signaling through the autotaxin-lysophosphatidate-inflammatory cycle and decrease mortality from metastatic cancer.

Interestingly, the effects of curcumin were reversed by liproxstatin-1 (an effective inhibitor of ferroptosis) and bardoxolone-methyl (an effective activator of Nrf2). Our results indicate that curcumin has therapeutic effects on osteosarcoma cells and a xenograft model by regulating the expression of the Nrf2/GPX4 signaling pathway.

P3, N=171, Terminated, InDex Pharmaceuticals | N=440 --> 171 | Trial completion date: Dec 2024 --> Dec 2023 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Dec 2023; Due to futility

Most importantly, SA attenuated cartilage degradation in a mouse OA model. Taken together, our study demonstrated that SA could alleviate cartilage degradation in OA by activating the TGF-β/Smad and inhibiting NF-κB signaling pathway.

P3, N=270, Terminated, Biogen | Trial completion date: May 2023 --> Aug 2023 | Trial primary completion date: May 2023 --> Aug 2023

We investigated novel anti-HCC treatments through either the simultaneous inhibition of glycolysis and gluconeogenesis by "phloretin" and "sodium meta-arsenite", respectively (Combination 1); or the concurrent inhibition of glycolysis and induction of gluconeogenesis by phloretin and dexamethasone, respectively, (combination 2). Biochemically, both combinations caused a significant reduction in ATP levels, ALT, and AST activity compared to the other groups. In conclusion, we propose two novel phloretin-based combinations that can be used in treating HCC through the regulation of glucose metabolism and ATP production.

The effects of a slow-releasing HS donor, GYY4137, on the expression of antiapoptotic and pro-apoptotic genes and proteins, such as B-cell lymphoma 2 (Bcl2) and Bcl-2-like protein 4 (Bax), as well as caspases, cyclooxygenase (COX)-1 and COX-2, monocytes/macrophages, and endothelial cells, in the spinal cord of male Sprague-Dawley rats with streptozotocin-induced peripheral diabetic neuropathy, were investigated using reverse transcription-PCR, western blot and immunohistochemistry...In summary, the current study demonstrated the protective properties of HS, which prevented the development of neuropathy related behavior, and suppressed apoptosis activation pathways and inflammation in the spinal cord. HS-releasing drugs could be considered as possible treatment options of diabetic peripheral neuropathy.

The role of endocytosis in the mechanisms of protection of cells by H2S and Hsp70 donors from the action of LPS was studied. It has been found that GYY4137 pretreatment of LPS-exposed cells reduces the LPS-induced induction of various pro-inflammatory genes and affects the expression of genes of various intracellular signaling pathways.

In this phase I/II trial, antroquinonol plus Gem/Nab-P showed good efficacy in survival and less adverse events than a first-line strategy of Gem/Nab-P for mPC patients. Clinical trial information: NCT03310632. >Abbreviations: mPC, metastatic pancreatic cancer; Gem/Nab-P, gemcitabine and nab-paclitaxel.#, data from U.S. FDA-approved Supplemental New Drug Application (NDA 21660/S-037) dated March 21, 2013 for paclitaxel protein-bound particles for injectable suspension (albumin-bound), 100 mg/vial.