Inhibition of DNMT3B expression in activated hepatic stellate cells overcomes chemoresistance in the tumor microenvironment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a complex disease associated with a plethora of environmental and genetic/hereditary causative risk factors, more so than other oncological indications. Additionally, patients with HCC exhibit fibrosis, cirrhosis, and liver-related disease. This complicated etiology can affect the disease course and likely contributes to its poor prognosis. In this study, we aimed to improve HCC therapy by evaluating combination treatment using anti-cancer and anti-fibrosis drugs via identification of novel anti-fibrosis drugs. We performed high-throughput screening of 10,000 compounds to identify hepatic fibrosis inhibitors through morphometry analysis of multicellular hepatic spheroid (MCHS) models and identified CHIR-99021 as a candidate anti-fibrotic drug. Treatment with CHIR-99021 induced loss of cell-cell interactions and suppression of extracellular matrix-related protein expression via reprogramming of hepatic stellate cell (HSC) activation in MCHSs. In particular, CHIR-99021 regulated DNMT3B expression only in activated HSCs. Moreover, CHIR-99021 markedly improved the efficacy of sorafenib in HCC- multicellular tumor spheroids in vitro and through induction of apoptosis by decreasing DNMT3B expression in vivo. In summary, these findings suggest that targeting HSC reprogramming by attenuation of DNMT3B expression in the tumor environment might represent a promising therapeutic strategy for liver fibrosis and HCC.

HO-1089 and HO-1197, Novel Herbal Formulas, Have Antitumor Effects via Suppression of PLK1 (Polo-like Kinase 1) Expression in Hepatocellular Carcinoma.

The treatment for hepatocellular carcinoma (HCC), a severe cancer with a very high mortality rate, begins with the surgical resection of the primary tumor. For metastasis or for tumors that cannot be resected, sorafenib, a multi-tyrosine protein kinase inhibitor, is usually the drug of choice. However, typically, neither resection nor sorafenib provides a cure. The drug discovery strategy for HCC therapy is shifting from monotherapies to combination regimens that combine an immuno-oncology agent with an angiogenesis inhibitor. Herbal formulas can be included in the combinations used for this personalized medicine approach. In this study, we evaluated the HCC anticancer efficacy of the new herbal formula, HO-1089. Treatment with HO-1089 inhibited HCC tumor growth by inducing DNA damage-mediated apoptosis and by arresting HCC cell replication during the G2/M phase. HO-1089 also attenuated the migratory capacity of HCC cells via the inhibition of the expression of EMT-related proteins. Biological pathways involved in metabolism and the mitotic cell cycle were suppressed in HO-1089-treated HCC cells. HO-1089 attenuated expression of the G2/M phase regulatory protein, PLK1 (polo-like kinase 1), in HCC cells. HCC xenograft mouse models revealed that the daily oral administration of HO-1089 retarded tumor growth without systemic toxicity in vivo. The use of HO-1197, a novel herbal formula derived from HO-1089, resulted in statistically significant improved anticancer efficacy relative to HO-1089 in HCC. These results suggest that HO-1089 is a safe and potent integrated natural medicine for HCC therapy.

Inhibition of 11ß-hydroxysteroid dehydrogenase 1 relieves fibrosis through depolarizing of hepatic stellate cell in NASH.

11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. Although 11ßHSD1 has been implicated in numerous metabolic syndromes, such as obesity and diabetes, the functional roles of 11ßHSD1 during progression of nonalcoholic steatohepatitis (NASH) and consequent fibrosis have not been fully elucidated. We found that pharmacological and genetic inhibition of 11ßHSD1 resulted in reprogramming of hepatic stellate cell (HSC) activation via inhibition of p-SMAD3, α-SMA, Snail, and Col1A1 in a fibrotic environment and in multicellular hepatic spheroids (MCHSs). We also determined that 11ßHSD1 contributes to the maintenance of NF-κB signaling through modulation of TNF, TLR7, ITGB3, and TWIST, as well as regulating PPARα signaling and extracellular matrix accumulation in activated HSCs during advanced fibrogenesis in MCHSs. Of great interest, the 11ßHSD1 inhibitor J2H-1702 significantly attenuated hepatic lipid accumulation and ameliorated liver fibrosis in diet- and toxicity-induced NASH mouse models. Together, our data indicate that J2H-1702 is a promising new clinical candidate for the treatment of NASH.

Sorbitol dehydrogenase induction of cancer cell necroptosis and macrophage polarization in the HCC microenvironment suppresses tumor progression.

Hepatocellular carcinoma (HCC) is among the most common malignant cancers worldwide, with an increasing incidence associated with an increase in deaths due to liver cancer. HCC is typically detected at an advanced stage in patients with underlying liver dysfunction, resulting in high mortality. The identification of HCC-specific targets represents a desired but unmet need for liver cancer treatment. To identify potentially novel HCC therapeutic targets, we performed a secretome analysis using HCC spheroids. Sorbitol dehydrogenase (SORD) was identified as uniquely enriched in the secretomes and lysates derived from HCC spheroids, and high SORD expression in HCC tissues was associated with favorable effects on overall survival among patients with liver cancer. We found that the introduction of excess SORD in HCC cells inhibited tumor growth and stemness by enhancing necroptosis signal and bypassing energy-yielding pathways through regulation of lactate dehydrogenase A (LDHA) expression and mitochondrial dynamics. Treatment with human recombinant SORD (hrSORD) controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment. These results demonstrate that SORD plays critical functional roles in HCC suppression through polyol pathway-independent mechanisms, suggesting that targeting SORD expression might represent a promising therapeutic strategy for liver cancer therapy.

Chromenopyrimidinone exhibit antitumor effects through inhibition of CAP1 (Adenylyl cyclase-associated protein 1) expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most malignant human cancers, with a high mortality rate worldwide. Within an HCC tumor, cancer stem cells (CSCs) are responsible for tumor maintenance and progression and may contribute to resistance to standard HCC treatments. Previously, we characterized CD133+ cells as CSCs in primary HCC and identified chromenopyrimidinone (CPO) as a novel therapeutic for the effective treatment of CD133+ HCC. However, the biological function and molecular mechanism of CD133 remain unclear. Epigenetic alterations of CSCs have impacts on tumor initiation, progression, and therapeutic response. Here, we found that pharmacological and genetic depletion of CD133 in HCC attenuated the activity of DNA methyltransferases via control of DNMT3B stabilization. Genes were ranked by degree of promoter hypo/hyper methylation and significantly differential expression to create an "epigenetically activated by CPO" ranked genes list. Through this epigenetic analysis, we found that CPO treatment altered DNA methylation-mediated oncogenic signaling in HCCs. Specifically, CPO treatment inhibited Adenylyl cyclase-associated protein 1 (CAP1) expression, thereby reducing FAK/ERK activity and EMT-related proteins in HCC. Moreover, CPO improved the efficacy of sorafenib by inhibiting CAP1 expression and FAK/ERK activation in sorafenib-resistant HCC. These novel mechanistic insights may ultimately open up avenues for strategies targeting DNA methylation in liver cancer stem cells and provides novel therapeutic function of CPO for the effective treatment of sorafenib-resistant HCC.

Device performance enhancement via a Si-rich silicon oxynitride buffer layer for the organic photodetecting device.

An advanced organic photodetector (OPD) with a butter layer of Si-rich silicon oxynitride (SiOxNy) was fabricated. The detector structure is as follows: Indium tin oxide (ITO) coated glass substrate/SiOxNy(10 nm)/naphthalene-based donor:C60(1:1)/ITO. Values of x and y in SiOxNy were carefully controlled and the detector performances such as dark current and thermal stability were investigated. When the values of x and y are 0.16 and 0.66, the detector illustrates low dark current as well as excellent thermal stability. In the OPD, silicon oxynitride layer works as electron barrier under reverse bias, leading to the decrease of dark current and increase of detectivity. Since the band gap of silicon oxynitride unlike conventional buffer layers can also be controlled by adjusting x and y values, it can be adapted into various photodiode applications.

Evaluation of wavelength-dependent hair growth effects on low-level laser therapy: an experimental animal study.

In this study, we aimed to investigate the wavelength-dependent effects of hair growth on the shaven backs of Sprague-Dawley rats using laser diodes with wavelengths of 632, 670, 785, and 830 nm. Each wavelength was selected by choosing four peak wavelengths from an action spectrum in the range 580 to 860 nm. The laser treatment was performed on alternating days over a 2-week period. The energy density was set to 1.27 J/cm(2) for the first four treatments and 1.91 J/cm(2) for the last four treatments. At the end of the experiment, both photographic and histological examinations were performed to evaluate the effect of laser wavelength on hair growth. Overall, the results indicated that low-level laser therapy (LLLT) with a 830-nm wavelength resulted in greater stimulation of hair growth than the other wavelengths examined and 785 nm also showed a significant effect on hair growth.