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- | Journal: Berberine regulates glucose and lipid metabolism via clock-controlled genes to ameliorate insulin resistance of hepatocytes (Pubmed Central) - Jan 14, 2025
and mTOR levels by inhibiting the BMAL1 and CLOCK interaction. In summary, berberine regulated glucose and lipid metabolism via clock-controlled genes with BMAL1 at the core to ameliorate IR of hepatocytes.
- | Journal: The Circadian Clock Gene Bmal1 Regulates Microglial Pyroptosis After Spinal Cord Injury via NF-?B/MMP9. (Pubmed Central) - Dec 9, 2024
In summary, berberine regulated glucose and lipid metabolism via clock-controlled genes with BMAL1 at the core to ameliorate IR of hepatocytes. Our study initially identified that Bmal1 regulates the NF-?B /MMP9 pathway to reduce microglial pyroptosis and thereby reduce secondary spinal cord injury, providing a new promising therapeutic target for SCI.
- || P1 data, Preclinical, Journal: Advancing Clinical Response Against Glioblastoma: Evaluating SHP1705 CRY2 Activator Efficacy in Preclinical Models and Safety in Phase I Trials. (Pubmed Central) - Sep 30, 2024
SHP1705, a CRY2 activator that has shown success in Phase 1 safety trials, has significantly improved preclinical efficacy. Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells.
- | Preclinical, Journal: High salt diet inhibits the expression of Bmal1 and promotes atrial fibrosis and vulnerability to atrial fibrillation in Dahl salt sensitive rats. (Pubmed Central) - May 18, 2024
Novel REV-ERB agonist SR29065 displays synergistic effects against diverse GBM cells. We demonstrated that a high-salt diet leads to circadian changes in hypertension due to reduction Bmal1 expression, which plays a crucial role in atrial fibrosis and increased susceptibility to AF in SSHT rats.
- | Venclexta (venetoclax) / Roche, AbbVie
Journal: Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway. (Pubmed Central) - May 5, 2024
Our research results suggest that BMAL1 plays a crucial regulatory role in AML cell proliferation, drug resistance, and ferroptosis. BMAL1 could be a potential important therapeutic target for AML.
- The role and mechanism of circadian clock gene BMAL1 in the proliferation and metastasis of nasopharyngeal carcinoma by inhibition TGF-?1/Smads pathway. (Hall A; Poster Bd #: 330) - Apr 24, 2024 - Abstract #ASCO2024ASCO_3478;
BMAL1 can inhibit the proliferation, epithelial-mesenchymal transformation and invasion and metastasis ability of NPC cells, and its mechanism is related to the inhibition of TGF-?1/Smads signaling pathway activity. It is speculated that it may become a new prognostic marker and therapeutic target for nasopharyngeal carcinoma.
- Avastin (bevacizumab) / Roche
A compound targeting the circadian clock protein CRY2 enhances therapeutic efficacy of bevacizumab in a colorectal cancer (CRC) xenograft model (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_9283;
Our study shows that CRY stabilizers in combination with bevacizumab significantly enhances anti-tumor efficacy in CRC mouse models. Although mechanism of action of SHP compounds on angiogenesis pathway still needs further investigation, these findings may support development of novel treatment strategies modulating circadian clock to overcome bevacizumab resistance in CRC patients.
- | Journal: Circadian misalignment impairs oligodendrocyte myelination via Bmal1 overexpression leading to anxiety and depression-like behaviors. (Pubmed Central) - Jan 23, 2024
Although mechanism of action of SHP compounds on angiogenesis pathway still needs further investigation, these findings may support development of novel treatment strategies modulating circadian clock to overcome bevacizumab resistance in CRC patients. Furthermore, we demonstrated in the OL precursor cell
- | PD98059 / Wayne State University
Journal: BMAL1 inhibits renal fibrosis and renal interstitial inflammation by targeting the ERK1/2/ELK-1/Egr-1 axis. (Pubmed Central) - Nov 21, 2023
Furthermore, we demonstrated in the OL precursor cell Our findings suggest that BAML1 can target the ERK1/2/ELK-1/Egr-1 axis to suppress fibrotic progression and inflammatory events in obstructed kidneys, thereby inhibiting the development of CKD.
- temozolomide / Generic mfg.
Targeting the circadian clock with small molecule compounds results in anti-tumor effects specifically in glioblastoma stem cells (Room 109-110) - Nov 11, 2023 - Abstract #SNO2023SNO_1502;
Treatment success remains challenging despite aggressive, multimodal current standard-of-care consisting of maximal surgical resection followed by concurrent temozolomide (TMZ) chemotherapy and radiation...Application of the CRY stabilizer SHP1705 in GBM PDX patient derived xenograft (PDX) models resulted in decreased tumor growth rate and increased survival time compared to vehicle control. These results highlight the therapeutic potential of circadian clock compounds as single agents, in combinations and as adjuvants to existing therapies by specifically targeting the GSC population in GBM.
- Circadian clock genes Bmal1 and Per2 in the nucleus accumbens are negative regulators of alcohol drinking in male and female mice (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_9323;
In females, the inhibitory effect of Bmal1 is strictly localized to the NAc, because striatal-wide deletion of Bmal1 caused a suppression of alcohol consumption. This sex-dependent stimulatory effect of Bmal1 on alcohol drinking is probably mediated through other striatal subregions such as the dorsal striatum.
- | Journal: Effect of miR-34a on the expression of clock and clock-controlled genes in DLD1 and Lovo human cancer cells with different backgrounds with respect to p53 functionality and 17?-estradiol-mediated regulation. (Pubmed Central) - Oct 13, 2023
With respect to the possible use of miR-34a in cancer treatment, clock genes can be considered as off-target genes, as changes in their expression induced by miR-34a treatment do not contribute to the oncostatic functions of miR-34a. Possible ambiguous oncogenic characteristics should be taken into consideration in future clinical studies focused on miR-34a.
- Differential Metabolic Profiles, Activation and Circadian Dynamics in Rheumatoid Arthritis and Psoriatic Arthritis Circulatory Monocytes (Poster Hall; in person) - Sep 23, 2023 - Abstract #ACRConvergence2023ACR_Convergence_2193;
Metabolic/immune markers are differentially expressed between RA and PsA monocytes, expression of which are inversed in classical vs intermediate monocytes. Altered regulation of genes involved in circadian rhythm suggest differences in the cellular clock, and effect that was more pronounced in RA compared to PsA monocytes.
- | Journal: Dynamic regulation of the serine loop by distant mutations reveals allostery in cryptochrome1. (Pubmed Central) - Sep 14, 2023
Our findings highlighted the crucial roles of S44 and S45 in the dynamic behavior of the serine loop, specifically through their interactions with E382 in CRY1. Considering the clinical implications of altered CRY1 function, our study opens up new possibilities for the development of drugs that target the allosteric regulation of CRY1.Communicated by Ramaswamy H. Sarma.
- | Preclinical, Journal: Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons. (Pubmed Central) - Aug 24, 2023
Furthermore, we uncover an epigenetic rhythm of diurnal oscillation of Tet3 and 5hmC levels in DRG neurons, corresponding to time-of-day effect on axon growth potential. Collectively, our studies demonstrate that targeting Bmal1 enhances axon regeneration.
- | RSL3 / Stanford University
Journal: Circadian clock protein Bmal1 accelerates acute myeloid leukemia by inhibiting ferroptosis through the EBF3/ALOX15 axis. (Pubmed Central) - Aug 3, 2023
We established a subcutaneous AML xenograft tumor model and reported that knockdown of Bmal1 and overexpression of EBF3 restrained AML growth by promoting ALOX15-mediated ferroptosis in vivo. Collectively, Bmal1 inhibits RSL3-induced ferroptosis by promoting EZH2-mediated EBF3 methylation and suppressing the expression of EBF3 and ALOX15, thus accelerating AML.
- | Journal: Developmental growth plate cartilage formation suppressed by artificial light at night via inhibiting BMAL1-driven collagen hydroxylation. (Pubmed Central) - Jun 8, 2023
Restoration of BMAL1/P4HA1 signaling can effectively rescue the dysregulation of cartilage formation within the developmental growth plate induced by artificial LAN exposure. In summary, our investigations suggested that LAN is a significant risk factor in bone growth and development, and a proposed novel strategy targeting enhancement of BMAL1-mediated collagen hydroxylation could be a potential therapeutic approach to facilitate bone growth.
- temozolomide / Generic mfg.
Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells (Section 18; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_2563;
One of the major challenges in treating GBM is the presence of GBM stem cells (GSCs) that are resistant to temozolomide (TMZ) chemotherapy and radiation, which is part of the current standard of care for GBM following maximal surgical resection...The clock compound SHP1705 increased over survival and delayed tumor growth in GBM PDX models. These results highlight the therapeutic potential small molecule circadian clock compounds have against GBM as both a single agent and adjuvant to existing therapies by specifically targeting the GSC population.
- | Journal: BMAL1/p53 mediating bronchial epithelial cell autophagy contributes to PM2.5-aggravated asthma. (Pubmed Central) - Feb 27, 2023
This study highlights the functional importance of BMAL1-dependent p53 regulation during asthma, and provides a novel mechanistic insight into the therapeutic mechanisms of BMAL1. Video Abstract.
- Cell synchronization induced by hypo-osmotic stress (Hall F-H (Indiana Convention Center)) - Feb 14, 2023 - Abstract #ACSSp2023ACS_SP_4672;
We found that BMAL1 intensity decreases inside nuclei of cells subjected to hypo-osmotic stress for 12 hours, inducing cell cycle arrest, and inhibiting BMAL1 function and transcription of circadian rhythm genes. This important finding provides insight into the role of BMAL1 during the circadian rhythm and shows a wide variety of applications, including cancer therapeutics.
- Mucosal clock and inflammation regulatory genes are disrupted in treatment naïve pediatric patients with ulcerative colitis (Poster exhibition) - Feb 1, 2023 - Abstract #ECCOIBD2023ECCO_IBD_680;
The demonstration of discordant correlations of some positive vs. negative feedback loop genes in UC highlights the clock disruption in active inflammation. Since these clock regulators also ameliorate inflammation, their reduced expression may explain not only clock dysregulation but also increased tissue inflammation.
- | Journal: Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle. (Pubmed Central) - Jan 4, 2023
Collectively, our results suggest that the circadian clock regulators BMAL1 and CLOCK promote HCC cell proliferation by controlling Wee1 and p21 levels, thereby preventing apoptosis and cell cycle arrest. Our findings shed light on cellular impact of the clock proteins for maintaining HCC oncogenesis and provide proof-of-principle for developing cancer therapy based on modulation of the circadian clock.
- | Journal: Circadian clock control of MRTF/SRF pathway suppresses beige adipocyte thermogenic recruitment. (Pubmed Central) - Dec 30, 2022
Selective ablation of Bmal1 induces beigeing with improved glucose homeostasis, whereas its targeted overexpression attenuates thermogenic induction resulting in obesity. Collectively, our findings identify the clock-MRTF/SRF regulatory axis as an inhibitory mechanism of beige fat thermogenic recruitment with significant contribution to systemic metabolic homeostasis.
- | Journal: BMAL1/FOXA2-induced rhythmic fluctuations in IL-6 contribute to nocturnal asthma attacks. (Pubmed Central) - Dec 13, 2022
Furthermore, knockdown of the BMAL1 and FOXA2 in 16HBE cells reduced the expression and rhythmic fluctuations of IL-6. Our findings suggest that there are increased IL-6 levels in nocturnal asthma resulting from inhibition of the BMAL1/FOXA2 signalling pathway in airway epithelial cells.
- | Journal: 7,8-Dihydroxyflavone alleviates cardiac fibrosis by restoring circadian signals via downregulating Bmal1/Akt pathway. (Pubmed Central) - Nov 26, 2022
Further, inhibition of Bmal1 by SR9009 effectively attenuated CFs proliferation and collagen production of CFs. In summary, these findings indicate that 7,8-DHF attenuates cardiac fibrosis and regulates circadian rhythmic signals, at least partly, by inhibiting Bmal1/Akt pathway, which may provide new insights into therapeutic cardiac remodeling.
- | Journal: Circadian clock gene Clock-Bmal1 regulates cellular senescence in Chronic obstructive pulmonary disease. (Pubmed Central) - Nov 25, 2022
We found that knockdown of Clock or Bmal1 lead to upregulation of cell senescence in Beas-2B cells, while overexpression of Clock or Bmal1 inhibited cell senescence in Beas-2B cells, which is through the MAPK pathways. Therefore, our findings indicated that Bmal1 or Clock deficiency may be a significant factor to increase cellular senescence of the lung to develop COPD.
- | Journal: Circadian clock gene BMAL1 inhibits the proliferation and tumor-formation ability of nasopharyngeal carcinoma cells and increases the sensitivity of radiotherapy. (Pubmed Central) - Sep 3, 2022
Overexpression of BMAL1 promoted the expression of p53 and p21, while the knockdown of BMAL1 inhibited the expression of p53 and p21. We speculate that BMAL1 has the potential to be a prognostic biomarker and therapeutic target for NPC.
- | Journal: BMAL1 modulates ROS generation and insulin secretion in pancreatic β-cells: An effect possibly mediated via NOX2. (Pubmed Central) - Aug 31, 2022
The isolated islets from β-cell Bmal1 mice have shown a similar cellular response, where an increased NOX2-derived ROS content and a reduced basal- and glucose-stimulated insulin secretion were observed. Therefore, together with NOX inhibition (Apocynin), polyethene-glycol linked to superoxide dismutase (PEG-SOD), phorbol myristate acetate (PMA), and diethyldithiocarbamate (DDC) data, our findings suggest a possible BMAL1-mediated NOX2-derived ROS generation in pancreatic β cells, leading to the modulation of both basal- and glucose-stimulated insulin secretion.