Last update 01 Nov 2024

DNM1 x DNM2

Last update 01 Nov 2024

Basic Info

Related Targets

DNM1DNM2

Drugs associated with DNM1 x DNM2

Dynasore

Target

DNM1 x DNM2

Mechanism

DNM1 inhibitors [+1]

Active Org.

Harvard Medical School

Originator Org.

Harvard Medical School

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with DNM1 x DNM2

100 Translational Medicine associated with DNM1 x DNM2

0 Patents (Medical) associated with DNM1 x DNM2

Literatures (Medical) associated with DNM1 x DNM2

01 Sep 2024·Archives of Insect Biochemistry and Physiology

Selenium Treatment Ameliorates the Adverse Effects Caused by Dynamin Gene Knockdown in Bombyx mori

Article

Author: Wei, Zhao‐Jun ; Hong, Ting‐Ting ; Thakur, Kiran ; Hu, Shuo ; Hu, Fei ; Ge, Wen‐Jie ; Tang, Shun‐Ming

ABSTRACTOur previous research reported the influence of 50 μM selenium (Se) on the cytosolization (endocytosis) pathway, which in turn stimulates the growth and development of Bombyx mori. Lately, dynamin is recognized as one of the key proteins in endocytosis. To explore the underlying mechanisms of Se impact, the dynamin gene was knocked down by injecting siRNAs (Dynamin‐1, Dynamin‐2, and Dynamin‐3). This was followed by an analysis of the target gene and levels of silk protein genes, as well as growth and developmental indices, Se‐enrichment capacity, degree of oxidative damage, and antioxidant capacity of B. mori. Our findings showed a considerable decrease in the relative expression of the dynamin gene in all tissues 24 h after the interference and a dramatic decrease in the silkworm body after 48 h. RNAi dynamin gene decreased the silkworm body weight, cocoon shell weight, and the ratio of cocoon. In the meantime, malondialdehyde level increased and glutathione level and superoxide dismutase/catalase activities decreased. 50 μM Se markedly ameliorated these growth and physiological deficits as well as decreases in dynamin gene expression. On the other hand, there were no significant effects on fertility (including produced eggs and laid eggs) between the interference and Se treatments. Additionally, the Se content in the B. mori increased after the dynamin gene interference. The dynamin gene was highly expressed in the silk gland and declined significantly after interference. Among the three siRNAs (Dynamin‐1, Dynamin‐2, and Dynamin‐3), the dynamin‐2 displayed the highest interference effects to target gene expression. Our results demonstrated that 50 μM Se was effective to prevent any adverse effects caused by dynamin knockdown in silkworms. This provides practical implications for B. mori breeding industry.

01 Feb 2024·Journal of Pharmacology and Experimental Therapeutics

Differential Efficacy of Small Molecules Dynasore and Mdivi-1 for the Treatment of Dry Eye Epitheliopathy or as a Countermeasure for Nitrogen Mustard Exposure of the Ocular Surface

Article

Author: Martinez-Carrasco, Rafael ; Pan, Jinhong ; Fini, M Elizabeth ; Pany, Satyabrata

The ocular surface comprises the wet mucosal epithelia of the cornea and conjunctiva, the associated glands, and the overlying tear film. Epitheliopathy is the common pathologic outcome when the ocular surface is subjected to oxidative stress. Whether different stresses act via the same or different mechanisms is not known. Dynasore and dyngo-4a, small molecules developed to inhibit the GTPase activity of classic dynamins DNM1, DNM2, and DNM3, but not mdivi-1, a specific inhibitor of DNM1L, protect corneal epithelial cells exposed to the oxidant tert-butyl hydroperoxide (tBHP). Here we report that, while dyngo-4a is the more potent inhibitor of endocytosis, dynasore is the better cytoprotectant. Dynasore also protects corneal epithelial cells against exposure to high salt in an in vitro model of dysfunctional tears in dry eye. We now validate this finding in vivo, demonstrating that dynasore protects against epitheliopathy in a mouse model of dry eye. Knockdown of classic dynamin DNM2 was also cytoprotective against tBHP exposure, suggesting that dynasore's effect is at least partially on target. Like tBHP and high salt, exposure of corneal epithelial cells to nitrogen mustard upregulated the unfolded protein response and inflammatory markers, but dynasore did not protect against nitrogen mustard exposure. In contrast, mdivi-1 was cytoprotective. Interestingly, mdivi-1 did not inhibit the nitrogen mustard-induced expression of inflammatory cytokines. We conclude that exposure to tBHP or nitrogen mustard, two different oxidative stress agents, cause corneal epitheliopathy via different pathologic pathways. SIGNIFICANCE STATEMENT: Results presented in this paper, for the first time, implicate the dynamin DNM2 in ocular surface epitheliopathy. The findings suggest that dynasore could serve as a new topical treatment for dry eye epitheliopathy and that mdivi-1 could serve as a medical countermeasure for epitheliopathy due to nitrogen mustard exposure, with potentially increased efficacy when combined with anti-inflammatory agents and/or UPR modulators.

01 Nov 2023·Journal of Diabetes and its Complications

Targeting of insulin receptor endocytosis as a treatment to insulin resistance

Article

Author: Tsigelny, Igor F ; Kouznetsova, Valentina L ; Tim, Bryce ; Kesari, Santosh

BACKGROUNDInsulin resistance is the decreased effectiveness of insulin receptor function during signaling of glucose uptake. Insulin receptors are regulated by endocytosis, a process that removes receptors from the cell surface to be marked for degradation or for re-use.OBJECTIVESOur goal was to discover insulin-resistance-related genes that play key roles in endocytosis which could serve as potential biological targets to enhance insulin sensitivity.METHODSThe gene mutations related to insulin resistance were elucidated from ClinVar. These were used as the seed set. Using the GeneFriends program, the genes associated with this set were elucidated and used as an enriched set for the next step. The enriched gene set network was visualized by Cytoscape. After that, using the VisANT program, the most significant cluster of genes was identified. With the help of the DAVID program, the most important KEGG pathway corresponding to the gene cluster and insulin resistance was found. Eleven genes part of the KEGG endocytosis pathway were identified. Finally, using the ChEA3 program, seven transcription factors managing these genes were defined.RESULTSThirty-two genes of pathogenic significance in insulin resistance were elucidated, and then co-expression data for these genes were utilized. These genes were organized into clusters, one of which was singled out for its high node count of 58 genes and low p-value (p = 4.117 × 10^-7). DAVID Pathways, a functional annotation tool, helped identify a set of 11 genes from a single cluster associated with the endocytosis pathway related to insulin resistance. These genes (AMPH, BIN1, CBL, DNM1, DNM2, DNM3, ITCH, SH3GL1, SH3GL2, SH3GL3, and SH3KBP1) are all involved in either clathrin-mediated endocytosis of the insulin receptor (IR) or clathrin-independent endocytosis of insulin-resistance-related G protein-coupled receptors (GPCR). They represent prime therapeutic targets to improve insulin sensitivity through modulation of transmembrane cell signaling. Using the ChEA3 database, we also found seven transcription factors (REST, MYPOP, CAMTA2, MYT1L, ZBTB18, NKX6-2, and CXXC5) that control the expression of these 11 genes. Inhibiting these key transcription factors would be another strategy to downregulate endocytosis.CONCLUSIONWe believe that delaying removal of insulin receptors from the cell surface would prolong signaling of glucose uptake and counteract the symptoms of insulin resistance.

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