MG53 Mitigates Nitrogen Mustard-Induced Skin Injury

Li, Hai-chang; Li, Zhong-Guang; Li, Xiuchun; Cai, Chuanxi; Zhao, Serena Li; Merritt, Robert E.; Zhou, Xinyu; Tan, Tao; Bergdall, Valerie; Ma, Jianjie

doi:10.3390/cells12141915

Cited by 3 publications

(2 citation statements)

References 62 publications

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“…Topical formulations used to treat SM skin burns include solvent mixture, cream, ointment, gel, and hydrogel vehicles [ 20 , 22 , 23 , 24 , 25 ]. For NM skin burn treatments, vehicles are comprised of organic and polymeric solvents, ointments, creams, and hydrogels [ 23 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Chang et al reduced SM-induced edema by administering NDH-4338 in a dimethyl isosorbide/ethyl oleate vehicle [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

Roldan,

Li,

Guillon

et al. 2024

Pharmaceutics

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NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions.

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Section: Introductionmentioning

confidence: 99%

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

Roldan,

Li,

Guillon

et al. 2024

Pharmaceutics

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“…Earlier, we and others have identified various molecular targets associated with manifestations of blistering caused by exposure to arsenicals (King et al, 1994;Li et al, 2016b;Srivastava et al, 2021;Surolia et al, 2021) and mustards (Achanta et al, 2018;Rose et al, 2018;Chen et al, 2021b;Dong et al, 2021;Li et al, 2023). Accordingly, multiple mechanismbased antidotes or MCMs have been tested in experimental animal models of these chemicals.…”

Section: Introductionmentioning

confidence: 99%

HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents

Srivastava,

Muzaffar,

Khan

et al. 2023

J Pharmacol Exp Ther

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Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence, developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES) respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells and appearance of apoptotic epidermal and dermal cells. RNAseq analysis identified ~346 inflammatory genes that were commonly altered by both PAO and CEES along with identification of cytokine signaling activation as the top canonical pathway. Activation of several of these inflammatory genes and pathways are associated with phosphorylationdependent activation of heat shock protein 90α (p-HSP90α). Topical treatment with known HSP90 inhibitors, SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated these chemical-induced skin damage (reduction in overall skin injury and clinical scores). In addition, highly upregulated inflammatory genes Saa3,

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MG53/TRIM72: multi-organ repair protein and beyond

Wang,

An,

et al. 2024

Front. Physiol.

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MG53, a member of the tripartite motif protein family, possesses multiple functionalities due to its classic membrane repair function, anti-inflammatory ability, and E3 ubiquitin ligase properties. Initially recognized for its crucial role in membrane repair, the therapeutic potential of MG53 has been extensively explored in various diseases including muscle injury, myocardial damage, acute lung injury, and acute kidney injury. However, further research has revealed that the E3 ubiquitin ligase characteristics of MG53 also contribute to the pathogenesis of certain conditions such as diabetic cardiomyopathy, insulin resistance, and metabolic syndrome. Moreover, recent studies have highlighted the anti-tumor effects of MG53 in different types of cancer, such as small cell lung cancer, liver cancer, and colorectal cancer; these effects are closely associated with their E3 ubiquitin ligase activities. In summary, MG53 is a multifunctional protein that participates in important physiological and pathological processes of multiple organs and is a promising therapeutic target for various human diseases. MG53 plays a multi-organ protective role due to its membrane repair function and its exertion of anti-tumor effects due to its E3 ubiquitin ligase properties. In addition, the controversial aspect of MG53’s E3 ubiquitin ligase properties potentially causing insulin resistance and metabolic syndrome necessitates further cross-validation for clarity.

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MG53 Mitigates Nitrogen Mustard-Induced Skin Injury

Cited by 3 publications

References 62 publications

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

Optimizing Nanosuspension Drug Release and Wound Healing Using a Design of Experiments Approach: Improving the Drug Delivery Potential of NDH-4338 for Treating Chemical Burns

HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents

MG53/TRIM72: multi-organ repair protein and beyond

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