Browsing by Author "Liu, Shaohui"

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    Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms
    (MDPI, 2023-12-14) Wang, Jiangwei; Su, Xiaolin; Jiang, Lingxiang; Boudreau, Matthew W.; Chatkewitz, Lindsay E.; Kilgore, Jessica A.; Zahid, Kashif Rafiq; Williams, Noelle S.; Chen, Yaomin; Liu, Shaohui; Hergenrother, Paul J.; Huang, Xiumei; Biochemistry and Molecular Biology, School of Medicine
    Lung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects. However, their curative efficacy has been constrained by adverse effects and moderate lethality. To enhance the curative potential of NQO1 bioactivatable drugs, we developed a novel DNQ derivative termed isopentyl-deoxynyboquinone (IP-DNQ). Our study revealed that IP-DNQ treatment significantly increased reactive oxygen species generation, leading to double-strand break (DSB) formation, PARP1 hyperactivation, and catastrophic energy loss. Notably, we discovered that this novel drug induced both apoptosis and programmed necrosis events, which makes it entirely distinct from other NQO1 bioactivatable drugs. Furthermore, IP-DNQ monotherapy demonstrated significant antitumor efficacy and extended mice survival in A549 orthotopic xenograft models. Lastly, we identified that in mice IP-DNQ levels were significantly elevated in the plasma and tumor compared with IB-DNQ levels. This study provides novel preclinical evidence supporting IP-DNQ efficacy in NQO1+ NSCLC and breast cancer cells.
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    Belantamab mafodotin associated corneal microcyst-like epithelial changes
    (Elsevier, 2022-02-02) Chuang, Katherine; Pineda, Roberto; Liu, Shaohui; Ophthalmology, School of Medicine
    Purpose: To report a case of bilateral corneal microcyst-like epithelial changes associated with belantamab mafodotin (belamaf) therapy. Observations: A 70-year-old man with refractory multiple myeloma was placed on belamaf, a recently FDA-approved treatment for relapsed or refractory multiple myeloma. He developed decreased visual acuity and bilateral corneal microcyst-like peripheral epithelial changes. Belamaf was withheld.Anterior segment OCT showed intra-epithelial opacities at various depths. After resolution of corneal changes and recovery of vision, belamaf was restarted. The patient underwent two additional treatments, each time with recurrence of diffuse microcyst-like corneal epithelial changes. It took a total of 8, 11.5 and 17 weeks after each respective infusion for the microcyst-like epithelial changes to resolve. This suggested a longer recovery time after each subsequent infusion. Conclusions and importance: The care for patients on belamaf requires the collaboration of eye care providers and hematologists-oncologists to assess for ocular adverse effects and adjust treatment as necessary. Further study is needed to illustrate the mechanism of corneal microcyst-like epithelial changes and its effects on limbal stem cells.
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    The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork
    (Elsevier, 2021) Sugali, Chenna Kesavulu; Rayana, Naga Pradeep; Dai, Jiannong; Peng, Michael; Harris, Sherri L.; Webber, Hannah C.; Liu, Shaohui; Dixon, Stephan G.; Parekh, Priyanka H.; Martin, Elizabeth A.; Cantor, Louis B.; Fellman, Ronald L.; Godfrey, David G.; Butler, Michelle R.; Emanuel, Matthew E.; Grover, Davinder S.; Smith, Oluwatosin U.; Clark, Abbot F.; Raghunathan, Vijay Krishna; Mao, Weiming; Ophthalmology, School of Medicine
    Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.
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    Comparison of porcine corneal decellularization methods and importance of preserving corneal limbus through decellularization
    (PLOS, 2021-03-05) Isidan, Abdulkadir; Liu, Shaohui; Chen, Angela M.; Zhang, Wenjun; Li, Ping; Smith, Lester J.; Hara, Hidetaka; Cooper, David K. C.; Ekser, Burcin; Surgery, School of Medicine
    Background: The aim of this study is to compare the three previously applied, conventional porcine corneal decellularization methods and to demonstrate the importance of preserving the corneal limbus through decellularization. Methods: Fresh, wild-type (with or without) limbus porcine corneas were decellularized using three different methods, including (i) sodium dodecyl sulfate (SDS), (ii) hypertonic saline (HS), and (iii) N2 gas (NG). Post-treatment evaluation was carried out using histological, residual nuclear material, and ultrastructural analyses. Glycerol was used to help reduce the adverse effects of decellularization. The corneas were preserved for two weeks in cornea storage medium. Results: All three decellularization methods reduced the number of keratocytes at different rates in the stromal tissue. However, all methods, except SDS, resulted in the retention of large numbers of cells and cell fragments. The SDS method (0.1% SDS, 48h) resulted in almost 100% decellularization in corneas without limbus. Low decellularization capacity of the NG method (<50%) could make it unfavorable. Although HS method had a more balanced damage-decellularization ratio, its decellularization capacity was lower than SDS method. Preservation of the corneoscleral limbus could partially prevent structural damage and edema, but it would reduce the decellularization capacity. Conclusion: Our results suggest that SDS is a very powerful decellularization method, but it damages the cornea irreversibly. Preserving the corneoscleral limbus reduces the efficiency of decellularization, but also reduces the damage.
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    Conjunctival Fungal Ball Mimicking Melanoma
    (Elsevier, 2020-04) Chuang, Katherine; Vortmeyer, Alexander; Liu, Shaohui; Ophthalmology, School of Medicine
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    Decellularization methods for developing porcine corneal xenografts and future perspectives
    (Wiley, 2019-11) Isidan, Abdulkadir; Liu, Shaohui; Li, Ping; Lashmet, Matthew; Smith, Lester J.; Hara, Hidetaka; Cooper, David K. C.; Ekser, Burcin; Ophthalmology, School of Medicine
    Corneal transplantation is the only option to cure corneal opacities. However, there is an imbalance between supply and demand of corneal tissues in the world. To solve the problem of corneal shortage, corneal xenotransplantation studies have been implemented in the past years using porcine corneas. The corneal xenografts could come from (a) wild-type pigs, (b) genetically engineered pigs, (c) decellularized porcine corneas, and (d) decellularized porcine corneas that are recellularized with human corneal cells, eventually with patients' own cells, as in all type of xenografts. All approaches except, the former would reduce or mitigate recipient immune responses. Although several techniques in decellularization have been reported, there is still no standardized protocol for the complete decellularization of corneal tissue. Herein, we reviewed different decellularization methods for porcine corneas based on the mechanism of action, decellularization efficacy, biocompatibility, and the undesirable effects on corneal ultrastructure. We compared 9 decellularization methods including: (a) sodium dodecyl sulfate, (b) triton x-100, (c) hypertonic saline, (d) human serum with electrophoresis, (e) high hydrostatic pressure, (f) freeze-thaw, (h) nitrogen gas, (h) phospholipase A2 , and (i) glycerol with chemical crosslinking methods. It appears that combined methods could be more useful to perform efficient corneal decellularization.
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    Spontaneously Regressed Corneal Intrastromal Cyst
    (Elsevier, 2020-10) Fox, Allison; Pineda, Roberto; Liu, Shaohui; Ophthalmology, School of Medicine
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    Using CRISPR Interference as a Therapeutic Approach to Treat TGFβ2-Induced Ocular Hypertension and Glaucoma
    (Association for Research in Vision and Ophthalmology, 2021-09-02) Rayana, Naga Pradeep; Sugali, Chenna Kesavulu; Dai, Jiannong; Peng, Michael; Liu, Shaohui; Zhang, Yucheng; Wan, Jun; Mao, Weiming; Ophthalmology, School of Medicine
    Purpose: Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide with elevated intraocular pressure (IOP) as the most important risk factor. POAG IOP elevation is due to pathological changes in the trabecular meshwork (TM). Elevated TGFβ2 contributes to these changes and increases IOP. We have shown that histone hyperacetylation is associated with TGFβ2 elevation in the TM. In this study, we determined if clustered regularly interspaced short palindromic repeats (CRISPR) interference could specifically deacetylate histones and decrease TGFβ2 in the TM. Methods: We tested the efficiency of different promoters in driving KRAB-dCAS9 expression in human TM cells. We also screened and determined the optimal sgRNA sequence in the inhibition of TGFβ2. Chromatin immunoprecipitation-qPCR was used to determine the binding of KRAB-dCAS9. An adenovirus-mediated TGFβ2-induced ocular hypertension (OHT) mouse model was used to determine the effect of the CRISPR interference system in vivo. Results: We found that the CRISPR interference system inhibited TGFβ2 expression in human TM cells, and properly designed sgRNA targeted the promoter of the TGFβ2 gene. Using sgRNA targeting the CMV promoter of the Ad5-CMV-TGFβ2 viral vector, we found that lentivirus-mediated KRAB-dCAS9 and sgRNA expression was able to inhibit Ad5-CMV-TGFβ2-induced OHT in C57BL/6J female and male mice eyes. This inhibition of OHT was associated with decreased levels of TGFβ2 and extracellular matrix proteins in the mouse eye. Conclusions: Our results indicate that CRISPR interference is a useful tool for gene inhibition and may be a therapeutic approach to treat TGFβ2-induced OHT.