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Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress. In this study, we utilised structure-based virtual screening (SBVS) from NCI library to discover novel DYRK1A inhibitors. The top-ranked compounds were then validated through enzymatic assays to assess their efficacy towards DYRK1A. Among them, NSC361563 emerged as a potent and selective DYRK1A inhibitor. It was shown to decrease tau phosphorylation at multiple sites, thereby enhancing tubulin stability. Moreover, NSC361563 diminished the formation of amyloid β and offered neuroprotective benefits against amyloid β-induced toxicity. Our research highlights the critical role of selective DYRK1A inhibitors in treating neurodegenerative diseases and presents a promising starting point for the development of targeted therapies.

Aging is characterized by molecular damage from free radicals, leading to neural dysfunction and memory impairment. This study investigated using bioceramic material and colored light to mitigate neurodegenerative symptoms in aging rats. We assessed the effects of different color light spectrums on D-galactose-induced aging rats using the Morris water maze, novel object recognition, and open field tests. Findings revealed that bioceramic material with various light wavelengths improved activity, recognition, and memory in aging rats. Significant enhancements were observed in the open field and novel object recognition tests, with a trend toward improvement in the Morris water maze. These effects are attributed to the antioxidant properties and microcirculation enhancement associated with bioceramic materials. Color stimulation may impact enzymes, human physiology, psychological activity, and the autonomic nervous system. This study highlights the significance of exploring novel interventions for neurodegenerative symptoms and memory deficits in aging rats. Results indicate that bioceramic material with different colored light spectrums positively influences cognitive function. These findings contribute to our understanding of the therapeutic potential of bioceramic materials and emphasize the need for further research in this area.

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC 50 ) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy., (© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Advances in modern medicine have extended human life expectancy, leading to a world with a gradually aging society. Aging refers to a natural decline in the physiological functions of a species over time, such as reduced pain sensitivity and reaction speed. Healthy-level physiological pain serves as a warning signal to the body, helping to avoid noxious stimuli. Physiological pain sensitivity gradually decreases in the elderly, increasing the risk of injury. Therefore, geriatric health care receives growing attention, potentially improving the health status and life quality of the elderly, further reducing medical burden. Health food is a geriatric healthcare choice for the elderly with Ganoderma tsuage (GT), a Reishi type, as the main product in the market. GT contains polysaccharides, triterpenoids, adenosine, immunoregulatory proteins, and other components, including anticancer, blood sugar regulating, antioxidation, antibacterial, antivirus, and liver and stomach damage protective agents. However, its pain perception-related effects remain elusive. This study thus aimed at addressing whether GT could prevent pain sensitivity reduction in the elderly. We used a galactose-induced animal model for aging to evaluate whether GT could maintain pain sensitivity in aging mice undergoing formalin pain test, hot water test, and tail flexes. Our results demonstrated that GT significantly improved the sensitivity and reaction speed to pain in the hot water, hot plate, and formalin tests compared with the control. Therefore, our animal study positions GT as a promising compound for pain sensitivity maintenance during aging., (© 2024. The Author(s).)

Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC 50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

The K 2 S 2 O 8 -mediated generation of p -iminoquinone contributed to the regioselective substitution of isoquinolin-5,8-dione. This hydroxyl group-guided substitution was also applied to selected heterocycles and addressed the regioselectivity issue of quinones. This study has provided an expeditious pathway from isoquinolin-5-ol (5) to ellipticine (1) and isoellipticine (2), which benefits the comprehensive comparison of their activity. Compounds 1 and 2 displayed marked MYLK4 inhibitory activity with IC 50 values of 7.1 and 6.1 nM, respectively. In the cellular activity of AML cells (MV-4-11 and MOLM-13), compound 1 showed better AML activity than compound 2., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.

Dendritic spines are small, ratchet-like protrusions on neuronal dendrites that form synapses for receiving neuronal messages. Dendritic spine morphology is associated with synapse function. If neurons degrade or are damaged, the spine morphology of neurons changes. Given that most commercially available spine analysis software is expensive and complex, this study investigated a semi-automated spine analysis software, CTSpine, and used previously published data to verify the accuracy of the analysis results of this software. We also applied CTSpine to understand whether aging causes alterations in the hippocampal spine morphology and whether physical exercise can impede dendritic spine changes in 20 male Sprague Dawley rats. The spines of pyramidal cells in the hippocampal Cornu Ammonis 1 (CA1) region in the aging group were more enriched in filopodium type pattern than those in the control group, whereas the spines of the exercised aging group showed a similar pattern to that of the control. No significant changes were observed in neuronal dendritic spines in other hippocampal regions. However, long-term hippocampal memory was considerably decreased in the aging group, which was reversed to some extent in the exercised aging group. CTSpine, a self-developed semi-automatic spine analysis software, showed results similar to those noted in published data and can be effectively applied to the study of dendritic patterns, including neurodevelopment and disease., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications., Purpose: In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells., Methods: The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively., Results: In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC 50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G 0 /G 1 phase and followed by the cells undergoing apoptosis., Conclusion: O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

A traumatic brain injury (TBI) causes abnormal proliferation of neuroglial cells, and over-release of glutamate induces oxidative stress and inflammation and leads to neuronal death, memory deficits, and even death if the condition is severe. There is currently no effective treatment for TBI. Recent interests have focused on the benefits of supplements or natural products like Ganoderma. Studies have indicated that immunomodulatory protein from Ganoderma microsporum (GMI) inhibits oxidative stress in lung cancer cells A549 and induces cancer cell death by causing intracellular autophagy. However, no evidence has shown the application of GMI on TBI. Thus, this study addressed whether GMI could be used to prevent or treat TBI through its anti-inflammation and antioxidative effects. We used glutamate-induced excitotoxicity as in vitro model and penetrating brain injury as in vivo model of TBI. We found that GMI inhibits the generation of intracellular reactive oxygen species and reduces neuronal death in cortical neurons against glutamate excitotoxicity. In neurite injury assay, GMI promotes neurite regeneration, the length of the regenerated neurite was even longer than that of the control group. The animal data show that GMI alleviates TBI-induced spatial memory deficits, expedites the restoration of the injured areas, induces the secretion of brain-derived neurotrophic factors, increases the superoxide dismutase 1 (SOD-1) and lowers the astroglial proliferation. It is the first paper to apply GMI to brain-injured diseases and confirms that GMI reduces oxidative stress caused by TBI and improves neurocognitive function. Moreover, the effects show that prevention is better than treatment. Thus, this study provides a potential treatment in naturopathy against TBI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Lingzhi has long been regarded as having life-prolonging effects. Research in recent years has also reported that Lingzhi possesses anti-tumor, anti-inflammatory, immunomodulatory, hepatoprotective, and anti-lipogenic effects. The D-galactose (D-gal, 100 mg/kg/day)-induced aging Long-Evans rats were simultaneously orally administered a DMSO extract of Ganoderma tsugae (GTDE, 200 μg/kg/day) for 25 weeks to investigate the effects of GTDE on oxidative stress and memory deficits in the D-galactose-induced aging rats. We found that GTDE significantly improved the locomotion and spatial memory and learning in the aging rats. GTDE alleviated the aging-induced reduction of dendritic branching in neurons of the hippocampus and cerebral cortex. Immunoblotting revealed a significant increase in the protein expression levels of the superoxide dismutase-1 (SOD-1) and catalase, and the brain-derived neurotrophic factor (BDNF) in rats that received GTDE. D-gal-induced increase in the lipid peroxidation product 4-hydroxynonenal (4-HNE) was significantly attenuated after the administration of GTDE, and pyrin domain-containing 3 protein (NLRP3) revealed a significant decrease in NLRP3 expression after GTDE administration. Lastly, GTDE significantly reduced the advanced glycosylation end products (AGEs). In conclusion, GTDE increases antioxidant capacity and BDNF expression of the brain, protects the dendritic structure of neurons, and reduces aging-induced neuronal damage, thereby attenuating cognitive impairment caused by aging., Competing Interests: The authors have declared that no competing interests exist.

The dysregulation of DYRK1A is implicated in many diseases such as cancer, diabetes, and neurodegenerative diseases. Alzheimer's disease is one of the most common neurodegenerative disease and has elevated interest in DYRK1A research. Overexpression of DYRK1A has been linked to the formation of tau aggregates. Currently, an effective therapeutic treatment that targets DYRK1A is lacking. A specific small-molecule inhibitor would further our understanding of the physiological role of DYRK1A in neurodegenerative diseases and could be presented as a possible therapeutic option. In this study, we identified pharmacological interactions within the DYRK1A active site and performed a structure-based virtual screening approach to identify a selective small-molecule inhibitor. Several compounds were selected in silico for enzymatic and cellular assays, yielding a novel inhibitor. A structure-activity relationship analysis was performed to identify areas of interactions for the compounds selected in this study. When tested in vitro, reduction of DYRK1A dependent phosphorylation of tau was observed for active compounds. The active compounds also improved tau turbidity, suggesting that these compounds could alleviate aberrant tau aggregation. Testing the active compound against a panel of kinases across the kinome revealed greater selectivity towards DYRK1A. Our study demonstrates a serviceable protocol that identified a novel and selective DYRK1A inhibitor with potential for further study in tau-related pathologies., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic inflammation is an underlying cause in a number of diseases. Cyclin-dependent kinase 8 (CDK8) has been implicated as an inflammatory mediator, indicating its potential as an anti-inflammatory target. Herein, we performed structure-based virtual screening (SBVS) to identify novel CDK8 inhibitors. The pharmacological interactions for CDK8 were identified and incorporated into a SBVS protocol. Selected compounds were tested in enzymatic assays, and one compound was confirmed to be a CDK8 inhibitor with a 50% inhibitory concentration (IC 50 ) value of 1684.4 nM. Comparing structural analogs identified a compound, F059-1017, with greater potency (IC 50 558.1 nM). When tested in cell lines, the compounds displayed low cytotoxicity. Cellular assays revealed that the identified CDK8 inhibitors can reduce phosphorylation and expression of signaling mediators associated with inflammation. In addition, results of kinase profiling showed that compound F059-1017 is selective towards CDK8. These findings suggest that the new inhibitors have great potential as lead compounds for developing novel anti-inflammatory therapeutics., (Copyright © 2021. Published by Elsevier Masson SAS.)

The STE20 kinase family is a complex signalling cascade that regulates cytoskeletal organisation and modulates the stress response. This signalling cascade includes various kinase mediators, such as TAOK1 and MAP4K5. The dysregulation of the STE20 kinase pathway is linked with cancer malignancy. A small-molecule inhibitor targeting the STE20 kinase pathway has therapeutic potential. In this study, a structure-based virtual screening (SBVS) approach was used to identify potential dual TAOK1 and MAP4K5 inhibitors. Enzymatic assays confirmed three potential dual inhibitors (>50% inhibition) from our virtual screening, and analysis of the TAOK1 and MAP4K5 binding sites indicated common interactions for dual inhibition. Compound 1 revealed potent inhibition of colorectal and lung cancer cell lines. Furthermore, compound 1 arrested cancer cells in the G0/G1 phase, which suggests the induction of apoptosis. Altogether, we show that the STE20 signalling mediators TAOK1 and MAP4K5 are promising targets for drug research.

A series of ring-opened dihydroxybenzamides have been designed and synthesized as heat shock protein 90 inhibitors. One of derivatives, compound 6b ((N-ethyl-2,4-dihydroxy-5-isopropyl-N-(pyridin-3-yl)benzamide)) demonstrated remarkable antiproliferative activity against in human KRAS mutant A549 and EGFR T790 M mutant H1975 lung cancer cell lines with GI 50 values of 0.07 and 0.05 μM, respectively. It is also active against in other cancer cell lines, such as colorectal HCT116 (GI 50  = 0.09 μM), liver Hep3B (GI 50  = 0.20 μM) and breast MDA-MB-231 (GI 50  = 0.09 μM), and shows no evidence of toxicity in normal cell line. Compound 6b has an IC 50 of 110.18 nM in HSP90α inhibitory activity, slightly better than reference compound 1 (17-AAG, IC 50  = 141.62 nM) and achieves the degradation of multiple HSP90 client proteins in a dose- and time-dependent manner and downstream signaling of Akt in a concentration- and time-dependent manner in the human A549 lung cancer cell line. In the Boyden chamber assay, compound 6b can efficiently inhibit the migration of A549 cells when compared to the reference compound 1. It also induce significant activity through the apoptotic pathway. Treatment with 6b showed no vision toxicity (IC 50  > 10 μM) on 661w photoreceptor cells as compared to AUY922 (3a) with a 0.04 μM values of IC 50 and has no effect in hERG test. In a bidirectional Caco-2 permeability assay, compound 6b was classified as a highly permeable compound which is not a substrate of efflux transporters. In a pharmacokinetic study in rats, 6b showed an F = 17.8% of oral bioavailability. The effect of metabolic stability of compound 6b in human hepatocytes showed a T 1/2 of 67.59 min. Compound 6b (50 mg/kg, po, daily) exhibits antitumor activity with a 72% TGD (tumor growth delay) in human A549 lung xenograft. The combination of 6b and afatinib, orally administered, showed tumor growth suppression with 67.5% of TGI in lung H1975 xenograft model. Thus compound 6b is a lead compound for further development of potential agents to treat lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Masson SAS.)

Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug-drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G 2 arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is used in a variety of consumer products such as electronic equipment, fire extinguishers, furniture, plastics, textiles, and kitchen hoods. Most studies show that the TBBPA production process and TBBPA in industrial and urban sewage waste result in extensive human exposure and environmental contamination. TBBPA can accumulate in organisms, particularly aquatic life, and is classified as a group 2A carcinogen (likely carcinogenic to humans) by the International Agency for Research on Cancer. This compound produces low acute toxicity, but chronic exposure may produce serious consequences. In this review, we focus on TBBPA toxicity by discussing results of various studies that were published in the last two decades. Studies show that TBBPA acts as an endocrine disruptor, causing neurobehavioral and immunotoxic effects, oxidative stress, and apoptosis. Although several experiments were performed in vitro and in vivo, human data are lacking, and thus, chronic toxic effects of TBBPA on humans are not well known, particularly in sensitive populations including pregnant women, newborns, children, and the elderly. Epidemiological studies that comprehensively assess TBBPA levels in biological fluids of different populations and in different pathological conditions are needed. Research on the impact of TBBPA, particularly regarding endocrine disorders and cancer, must also be performed.

PM2.5 causes abnormal immune response and asthma in animals. In this study, a Balb/c mouse animal model was exposed to PM2.5 to induce asthma. Lactobacillus paracasei HB89 was fed at the same time, in order to observe whether L. paracasei HB89 mitigates respiratory tract allergies stimulated by PM2.5. The results showed that PM2.5 stimulated a significant increase in white blood cells and immunoglobulin (IgE) in OVA-induced allergic Balb/c mice, and IgE in the blood further triggered the release of histamine in the lung immune cells. This not only increased overall immune cell counts, but the lymphocyte counts also increased significantly, resulting in significant inhibitions of cytokines INF-r and TGF-β, and induction of IL-4, IL-5, IL-13 and IL-17a. After feeding with HB89, apart from the absence of observable changes in body weight, the total white blood cell count in the animal blood and IgE response were also be reduced; the proliferation of immune cells in the lungs caused by PM2.5 was slowed down; and histamine and cytokines INF-r and TGF-β were secreted in large quantities, but IL- 4, IL-5, IL-13, IL-17a were inhibited, which effectively reduced the possibility of asthma induction., Competing Interests: The authors have read the journal’s policy and have the following competing interests: Yuan Li Tong Co., Ltd. provided support for this study in the form of a grant awarded to MWC. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC 50 value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.

[This retracts the article DOI: 10.18632/oncotarget.6427.]., (Copyright: © 2020 Chao et al.)

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC 50  = 4.3 nM) and HSP90a inhibition (IC 50  = 46.8 nM) along with substantial cell growth inhibitory effects with GI 50  = 0.76 μM (lung A549) and GI 50  = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI 50  = 0.37 μM) and lung H1975 cell lines (GI 50  = 0.13 μM) mediated through selective HDAC6 inhibition (IC 50  = 33.3 nM) and HSP90 inhibition (IC 50  = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Masson SAS.)

Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC 50 values in nanomolar range with Compound 20 (HDAC IC 50  = 194 nM; HSP90α IC 50  = 153 nM) and compound 26 (HDAC IC 50  = 360 nM; HSP90α IC 50  = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future., (Copyright © 2019. Published by Elsevier Masson SAS.)

The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined., (Copyright © 2019. Published by Elsevier Inc.)

Background: Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028., Methods: The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo., Results: The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone., Conclusions: The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.

Fine particulate matter 2.5 (PM 2.5 ) induces free radicals and oxidative stress in animals, leading to a range of illnesses. In this study, Ganoderma Microsporum immunomodulatory (GMI) proteins were administered to alleviate PM 2.5 -induced inflammatory responses in mother rats, and PM 2.5 -induced inflammatory responses and neurological damage in their offspring. The results suggested that GMI administration decreased the risk of neurological disorders in mother rats and their offspring by reducing the white blood cell count, lessening inflammatory responses and PM 2.5 -induced memory impairment, and preventing dendritic branches in the hippocampi from declining and microRNAs from PM 2.5 -induced modulation.

3,5-Dimethylaniline (3,5-DMA), a monocyclic aromatic amine, is widely present in a spectrum of sources including tobacco, dyes, combustion products, and suspended particulates. 3,5-DMA and its metabolites form superoxides, resulting in apoptosis or oncogenesis. Data of a direct effect of 3,5-DMA on the nervous system, especially the developing brain, are lacking. Therefore, we investigated the effects of 3,5-DMA and its metabolites on fetal neurite growth and brain development using in vitro cell cultures of primary cortical neurons to observe whether these compounds caused neuronal cytotoxicity and affected neurite structural development. With increasing concentrations of 3,5-DMA (10, 50, 100, 500, 1000 μM) and its major metabolite 5-dimethylaminophenol (3,5-DMAP) (10, 50, 100, 500, 1000 μM), reactive oxygen species (ROS), cytotoxicity, and DNA damage increased significantly in the cells and dendritic arborization decreased. The addition of 5 mM N-acetylcysteine, an ROS scavenger, reduced ROS in the cells and alleviated the neuronal damage. In vivo studies in Sprague Dawley pregnant rats suggested that exposure to 3,5-DMA (10, 30, 60, 100 mg/kg/day) subcutaneously from GD15 to GD17 led to fetal cerebral cortex thinning. BrdU labeling showed that 3,5-DMA reduced the number and generation of cortical cells. To detect the laminar position of newly generated neurons, cortex layer markers such as Satb2, Ctip2, and Tbr1 were used. 3,5-DMA perturbed the cortical layer distribution in developing fetal rats. In summary, this is the first study to provide evidence for 3,5-DMA and its metabolites causing anomalies of the fetal central nervous system development through ROS production., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Exposure to alkyl anilines may lead to bladder cancer, which is the second most frequent cancer of the urogenital tract. 3,5-dimethylaniline is highly used in industry. Studies on its primary metabolite 3,5-dimethylaminophenol (3,5-DMAP) showed that this compound causes oxidative stress, changes antioxidant enzyme activities, and leads to death of different mammalian cells. However, there is no in vitro study to show the direct effects of 3,5-DMAP on human bladder and urothelial cells. Selenocompounds are suggested to decrease oxidative stress caused by some chemicals, and selenium supplementation was shown to reduce the risk of bladder cancer. The main aim of this study was to investigate whether selenocompounds organic selenomethionine (SM, 10 µmol/L) or inorganic sodium selenite (SS, 30 nmol/L) could reduce oxidative stress, DNA damage, and apoptosis in UROtsa cells exposed to 3,5-DMAP. 3,5-DMAP caused a dose-dependent increase in intracellular generation of reactive oxygen species, and its dose of 50 µmol/L caused lipid peroxidation, protein oxidation, and changes in antioxidant enzyme activities in different cellular fractions. The comet assay also showed single-strand DNA breaks induced by the 3,5-DMAP dose of 50 µmol/L, but no changes in double-strand DNA breaks. Apoptosis was also triggered. Both selenocompounds provided partial protection against the cellular toxicity of 3,5-DMAP. Low selenium status along with exposure to alkyl anilines can be a major factor in the development of bladder cancer. More mechanistic studies are needed to specify the role of selenium in bladder cancer.

Background: There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells., Results: MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model., Conclusions: Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia.

The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

Background: Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium-derived thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma., Methods: Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR-mediated IL-33, Il-25, and TSLP synthesis and release., Results: Primary bronchial epithelial cells exposed to DEP showed upregulation of IL-33, IL-25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL-33, IL-25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL-33, IL-25, and TSLP. These patients derived clinical benefit from anti-IgE treatment., Conclusion: Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL-33, IL-25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Exposure to 3,5-dimethylaminophenol (3,5-DMAP), the metabolite of the 3-5-dimethylaniline, was shown to cause high levels of oxidative stress in different cells. The aim of the present work was to observe whether this metabolite can lead to cytotoxicity, oxidative stress, DNA damage and cell cycle changes in non-small cell lung cancer A549 cells. 3,5-DMAP caused a dose-dependent increase in cytotoxicity, generation of superoxide (O2-.), inductions in the enzyme activities orchestrating cellular antioxidant balance, increases in lipid peroxidation as well as DNA damage. However, 3,5-DMAP showed significantly lower cytotoxicity towards human lung fibroblast (HLF) cells. 3,5-DMAP also led to molecular events, like inducing apoptotic markers (ie. p53, Bad, Bax and cytochrome c); decreasing anti-apoptotic proteins (Bcl-2) and alterations in cell cycle. Our findings indicate that the cytotoxicity caused by this particular alkylaniline metabolite led to initiation of caspase 3-mediated apoptosis. Furthermore, 3,5-DMAP attenuated carcinogenic properties like migration capacity of A549 cells and eventually inhibited growth of A549 cells in an in vivo mouse model. Tumor sections showed that 3,5-DMAP down-regulated c-Myc expression but up-regulated p53 and cytochrome c, all of which might result in tumor growth arrest. Co-treatment with N-acetylcysteine provided reductions in cytotoxicity and positively modulated genetic events induced by 3,5-DMAP in A549 cells. In conclusion, our findings demonstrate 3,5-DMAP may be a potential anti-cancer drug in cancer, due to its self redox cycling properties., Competing Interests: The authors have declared that no competing interests exist.

IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration-dependently increased IL-17A synthesis and release by 122.3 ± 15.72% and 235.5 ± 18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IκBα degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-κB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-κB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF-κB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Epidemiological studies suggest that an increase of diesel exhaust particles (DEP) in ambient air corresponds to an increase in hospital-recorded myocardial infarctions within 48 h after exposure. Among the many theories to explain this data are endothelial dysfunction and translocation of DEP into vasculature. The mechanisms for such DEP-induced vascular permeability remain unknown. One of the major mechanisms underlying the effects of DEP is suggested to be oxidative stress. Experiments have shown that DEP induce the generation of reactive oxygen species (ROS), such as superoxide anion and H 2 O 2 in the HUVEC tube cells. Transcription factor Nrf2 is translocated to the cell nucleus, where it activates transcription of the antioxidative enzyme HO-1 and sequentially induces the release of vascular permeability factor VEGF-A. Furthermore, a recent study shows that DEP-induced intracellular ROS may cause the release of pro-inflammatory TNF-α and IL-6, which may induce endothelial permeability as well by promoting VEGF-A secretion independently of HO-1 activation. These results demonstrated that the adherens junction molecule, VE-cadherin, becomes redistributed from the membrane at cell-cell borders to the cytoplasm in response to DEP, separating the plasma membranes of adjacent cells. DEP were occasionally found in endothelial cell cytoplasm and in tube lumen. In addition, the induced ROS is cytotoxic to the endothelial tube-like HUVEC. Acute DEP exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and induces endothelial apoptosis. Nevertheless, high-dose DEP augments tube cell apoptosis up to 70 % but disrupts the p53 negative regulator Mdm2. In summary, exposure to DEP affects parameters influencing vasculature permeability and viability, i.e., oxidative stress and its upregulated antioxidative and pro-inflammatory responses, which sequentially induce vascular permeability factor, VEGF-A release and disrupt cell-cell junction integrity. While exposure to a low dose of DEP actin triggers cytoskeleton depolarization, reduces PI3K/Akt activity, and induces a p53/Mdm2 feedback loop, a high dose causes apoptosis by depleting Mdm2. Addition of ROS scavenger N-acetyl cysteine suppresses DEP-induced oxidative stress efficiently and reduces subsequent damages by increasing endogenous glutathione.

Despite great advances in the treatment of acute leukemia, a renaissance of current chemotherapy needs to be improved. The present study elucidates the underlying mechanism of a new synthetic quinoline derivative, MPT0B392 (B392) against acute leukemia and its potential anticancer effect in drug resistant cells. B392 caused mitotic arrest and ultimately led to apoptosis. It was further demonstrated to be a novel microtubule-depolymerizing agent. The effects of oral administration of B392 showed relative potent anti-leukemia activity in an in vivo xenograft model. Further investigation revealed that B392 triggered induction of the mitotic arrest, followed by mitochondrial membrane potential loss and caspases cleavage by activation of c-Jun N-terminal kinase (JNK). In addition, B392 enhanced the cytotoxicity of sirolimus in sirolimus-resistant acute leukemic cells through inhibition of Akt/mTOR pathway and Mcl-1 protein expression, and also was active in the p-glycoprotein (p-gp)-overexpressing National Cancer Institute/Adriamycin-Resistant cells with little susceptibility to p-gp. Taken together, B392 has potential as an oral mitotic drug and adjunct treatment for drug resistant cancer cells.

Recent studies have revealed that cardiac glycosides, such as digitalis and digoxin, have anticancer activity and may serve as lead compounds for the development of cancer treatments. The poor prognosis of hepatocellular carcinoma (HCC) patients reflects the development of resistance to current chemotherapeutic agents, highlighting the need for discovering new small-molecule therapeutics. Here, we found that lanatoside C, an anti-arrhythmic agent extracted from Digitalis lanata, inhibited the growth of HCC cells and dramatically decreased tumor volume as well as delayed tumor growth without obvious body weight loss. Moreover, lanatoside C triggered mitochondrial membrane potential (MMP) loss, activation of caspases and translocation of apoptosis-inducing factor (AIF) into the nucleus, which suggests that lanatoside C induced apoptosis through both caspase-dependent and -independent pathways. Furthermore, we discovered that lanatoside C activated protein kinase delta (PKCδ) via Thr505 phosphorylation and subsequent membrane translocation. Inhibition of PKCδ reversed lanatoside C-induced MMP loss and apoptosis, confirming that lanatoside C caused apoptosis through PKCδ activation. We also found that the AKT/mTOR pathway was negatively regulated by lanatoside C through PKCδ activation. In conclusion, we provide the first demonstration that the anticancer effects of lanatoside C are mainly attributable to PKCδ activation.

PM 2.5 travels along the respiratory tract and enters systemic blood circulation. Studies have shown that PM 2.5 increases the incidence of various diseases not only in adults but also in newborn infants. It causes chronic inflammation in pregnant women and retards fetal development. In this study, pregnant rats were exposed to PM 2.5 for extended periods of time and it was found that PM 2.5 exposure increased immune cells in mother rats. In addition, cytokines and free radicals rapidly accumulated in the amniotic fluid and indirectly affected the fetuses. The authors collected cerebral cortex and hippocampus samples at E18 and analyzed changes of miRNA levels. Expression levels of cortical miR-6315, miR-3588, and miR-466b-5p were upregulated, and positively correlated with the genes Pkn2 (astrocyte migration), Gorab (neuritogenesis), and Mobp (allergic encephalomyelitis). In contrast, PM 2.5 decreased expression of miR-338-5p and let-7e-5p, both related to mental development. Further, PM 2.5 exposure increased miR-3560 and let-7b-5p in the hippocampus, two proteins that regulate genes Oxct1 and Lin28b that control ketogenesis and glycosylation, and neural cell differentiation, respectively. miR-99b-5p, miR-92b-5p, and miR-99a-5p were decreased, leading to reduced expression of Kbtbd8 and Adam11 which reduced cell mitosis, migration, and differentiation, and inhibited learning abilities and motor coordination of the fetus. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1412-1425, 2017., (© 2016 Wiley Periodicals, Inc.)

Epidemiological studies suggest that an increase of PM2.5 diesel exhaust particles (DEP) in ambient air corresponds to increased myocardial infarctions and atherosclerosis. When exposed to DEP, endothelial cells exhibit increases in oxidative stress and apoptosis, but the role of autophagy in this DEP-induced cell death remains unclear. Here, we suggest that acute DEP exposure produces intracellular reactive oxygen species (ROS) leading to induction of DEP internalization, endothelial dysfunction, and pro-inflammation in an in vitro human umbilical vein endothelial cells (HUVEC) model. This study found that increases in intracellular oxidative stress and cellular internalization of DEP occurred within 2 h of exposure to DEP. After 2 h of DEP exposure, Mdm2 expression was increased, which triggered cellular autophagy after 4 h of DEP exposure and suppressed cellular senescence. Unfortunately, phagocytized DEP could not be eliminated by cellular autophagy, which led to a continuous buildup of ROS, an increased release of cytokines, and an increased expression of anchoring molecules. After 12 h of DEP exposure, HUVEC reduced Mdm2 expression leading to increased p53 expression, which triggered apoptosis and ultimately resulted in endothelial dysfunction. On the other hand, when cells lacked the ability to induce autophagy, DEP was unable to induce cell senescence and most of the cells survived with only a small percentage of the cells undergoing necrosis. The results presented in this study clearly demonstrate the role cellular autophagy plays in DEP-induced atherosclerosis., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Di-(2-ethylhexyl) phthalate (DEHP), the common plasticizer used in the production of polyvinyl chloride, can be converted to the more potent metabolite mono-ethylhexyl phthalate (MEHP). Epidemiological studies have shown an association with elevated induction of rat hepatic cancer and reproductive toxicity in response to MEHP exposure. However, the mechanism of genotoxicity and carcinogenicity induced by MEHP treatment remains unclear. As a means to elucidate the mechanisms of action, lethality and mutagenicity in the adenine phosphoribosyltransferase (aprt+/-) gene induced in several CHO cell types by MEHP were assessed. Dose-response relationships were determined in the parental AA8 cell line, its nucleotide repair-deficient UV5 and base repair-deficient EM9 subclones, and also in AS52 cells harboring the bacterial guanine-hypoxanthine phosphoribosyltransferase (gpt) gene and its derived AS52-XPD-knockdown and AS52-PARP-1-knockdown cells. Treatment of AS52 with MEHP led to intracellular production of reactive oxygen species (ROS) and DNA strand breaks in a dose-dependent manner. Separately, mutations in the gpt gene of AS52 cells were characterized and found to be dominated by G:C to A:T and A:T to G:C transitions. Independent AS52-mutant cell (ASMC) clones were collected for the sequential in vivo xenograft tumorigenic studies, 4 of total 20 clones had aggressive tumor growth. Moreover, microarray analysis indicated miR-let-7a and miR-125b downregulated in ASMC, which might raise oncogenic MYC and RAS level and activate ErbB pathway. Comparative evaluation of the results indicates that the principal mechanism of this mutagenic action is probably to be through generation of ROS, causing base excision damage resulting in carcinogenicity., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cancers are the major cause of death worldwide. Chemotherapy using cytotoxic drugs and targeted therapy is required when surgery is difficult, ineffective, or impossible. We previously synthesized the novel synthetic 1-benzylindole derivative 21-900 and found that it inhibits histone deacetylase (HDAC) activities and tubulin assembly. Here we tested its effects on the human leukaemia cell lines HL-60 and MOLT-4 in vitro and in vivo. We found that its potent cytotoxic effects were mediated through cell cycle arrest at the G2/M phase, which increased the population of sub-G1 cells, leading to apoptosis. Further, tubulin was depolymerized by 21-900 in a manner similar to that of vincristine, leading to disruption of microtubule dynamics and increased levels of the mitotic marker MPM-2. Further, 21-900 increased the expression of cleavage form of poly (ADP-ribose) polymerase (PARP), caspase 3, 7 (cleavage form), and pro-apoptotic protein BAK and decreased the expression of pro-survival BCL-2-family proteins BCL-2, MCL-1, and BID pro-form, leading to the induction of apoptosis. The growth of tumours in nude mice formed by xenografts of HL-60 and MOLT-4 cells was significantly inhibited by 21-900 without causing the mice to lose body weight. These findings indicate that 21-900 may serve as a potent anti-leukaemia drug., Competing Interests: The authors declare no competing financial interests.

The association between inflammation and cancer has long been recognized. Several studies have found that different types of tumors develop at sites of chronic inflammation. It is stated that over 15%-20% of malignancies worldwide can be related to infections caused by viruses, bacteria, and schistosomes. Inflammatory conditions are characterized by overexpression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide/reactive nitrogen species (ROSs/RNSs) in epithelial cells. Reactive oxygen species (ROSs) may also lead to cellular alterations and eventually to inflammation. A variety of chronic infectious diseases can generate steady-state levels of ROSs/RNSs within infected cells and possibly lead to different types of DNA lesions. Accumulation of DNA lesions may finally lead to mutations that may activate oncogenes or inactivate tumor suppressor genes. Helicobacter pylori has been shown to generate ROSs/RNSs, induce DNA damage, and lead to chronic inflammation in gastric epithelial cells. A limited number of studies have addressed the effects of Helicobacter pylori on DNA damage, particularly its impact on single-strand and double-strand DNA breaks. This bacterium is classified as a Group I carcinogen by the International Agency for Research on Cancer on the basis of numerous animal and epidemiological studies. Chronic Helicobacter pylori infection can lead to increased risk of gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. This review addresses the DNA-damaging and double-strand break-inducing effects of different microorganisms and their toxins, specifically focusing on Helicobacter pylori.

The development of hepatocellular carcinoma (HCC) is a multistep process. In HCC, progressive and morphologically distinct preneoplastic lesions/alterations associated with chronic liver injury, inflammation, hepatocellular degeneration/regeneration, necrosis, and small-cell dysplasia can be observed. The incidence of HCC exhibits regional and ethnic differences. Several cytotoxic and DNA-damaging chemicals are suggested to be the underlying causes of HCC-for example, acrylamide, perfluorooctanoic acid (PFOA), polychlorinated biphenyls (PCBs), benzo(a)pyrene (BaP), perfluorinated chemicals (PFCs), vinyl chloride monomer (VCM), and dietary contaminants (aflatoxins, ochratoxins). Also suggested are substances of abuse (alcohol) and biological agents, such as hepatitis B and C and human immunodeficiency virus 1 (HIV-1). These can act through genetic and/or epigenetic mechanisms. This review will shortly address the genetic and epigenetic mechanisms of HCC and focus on cytotoxic and DNA-damaging chemicals and biological agents, exposure to which are suggested to lead to HCC initiation, promotion, and/or progression.

The epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitors (TKIs) have shown remarkable benefits in non-small cell lung cancer (NSCLC) patients with drug-sensitive mutations in the EGFR gene. Responsive patients are usually continuously prescribed with TKIs until disease progression. Glucocorticoids (GCs) are potent homeostasis maintaining drugs and are frequently used in cancer patients to alleviate discomforts caused by anti-cancer therapies. Several previous studies reported that concomitant use of GCs may compromise the efficacy of chemo-therapeutics in patients with solid tumors. Little is known in the concomitant use of target therapy with GCs in treating NSCLC. In this study, we hypothesized that concomitant use of GCs in EGFR-TKI therapy may be detrimental and addressed this issue using cell cultures and xenograft studies followed by a retrospective population study based on data from the Taiwan national health insurance system. In cell cultures and xenograft studies, GCs were shown to unequally compromise the anti-cancer efficacy of TKIs in both PC9 and NCI-H1975 NSCLC cells models. In the retrospective population study, patients with similar disease status that were co-medicated with GCs had a significantly higher risk of disease progression.

Oxidative stress and inflammatory insults are the major instigating events of bacterial intrauterine infection that lead to fetal brain injury. The purpose of this study is to investigate the remedial effects of N-acetyl-cysteine (NAC) for inflammation-caused deficits in brain development. We found that lipopolysaccharide (LPS) induced reactive oxygen species (ROS) production by RAW264.7 cells. Macrophage-conditioned medium caused noticeable cortical cell damage, specifically in cortical neurons. LPS at 25 μg/kg caused more than 75% fetal loss in rats. An increase in fetal cortical thickness was noted in the LPS-treated group. In the enlarged fetal cortex, laminar positioning of the early born cortical cells expressing Tbr1 and Ctip2 was disrupted, with a scattered distribution. The effect was similar, but minor, in later born Satb2-expressing cortical cells. NAC protected against LPS-induced neuron toxicity in vitro and counteracted pregnancy loss and alterations in thickness and lamination of the neocortex in vivo. Fetal loss and abnormal fetal brain development were due to LPS-induced ROS production. NAC is an effective protective agent against LPS-induced damage. This finding highlights the key therapeutic impact of NAC in LPS-caused abnormal neuronal laminar distribution during brain development.

Developing new anticancer agents against ovarian cancer is an urgent medical need. MPT0G066, a novel synthetic arylsulfonamide compound, was shown to inhibit cell growth and decrease viability in human ovarian cancer cells. MPT0G066 induced arrest of the cell cycle at the multipolyploidy (MP) phase in SKOV3 and at the G2/M phase in A2780 cells, while increasing the proportion of cells in the subG1. Additionally, MPT0G066 induced c-Jun-NH2 terminal kinase (JNK) activation, influenced cell cycle regulatory and Bcl-2 family proteins, which triggered intrinsic apoptotic pathways through cleavage of caspase-3, -7, -9, and poly-(ADP-ribose) polymerase (PARP). Flow cytometry analysis of p-glycoprotein (p-gp) function showed that MPT0G066 was not a substrate of p-gp. Additionally, it was shown that MPT0G066 could decrease cell viability in multiple-drug-resistant human ovarian cancer cells. Furthermore, the combination of MPT0G066 and cisplatin presented a synergistic cytotoxic effect against ovarian cancer cell lines in vitro. MPT0G066 also significantly suppressed the growth of ovarian carcinoma and potentiated the antineoplastic effects of cisplatin in vivo. In conclusion, these findings indicate that MPT0G066 can be a potential anticancer agent against ovarian cancer that worthy of further development.

Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment.

Traditional lung cancer treatments involve chemical or radiation therapies after surgical tumor removal; however, these procedures often kill normal cells as well. Recent studies indicate that chemotherapies, when combined with Traditional Chinese Medicines, may offer a new way to treat cancer. In vitro tests measuring the induction of autophagy and/or apoptosis were used to examine the cytotoxicity of SBPE, commonly used for lung inflammation on A549 cell line. The results indicated that intercellular levels of p62 and Atg12 were increased, LC3-I was cleaved into LC3-II, and autophagy was induced with SBPE only. After 24 hours, the apoptotic mechanism was induced. If the Cisplatin was added after cells reached the autophagy state, we observed synergistic effects of the two could achieve sufficient death of lung cancer cells. Therefore, the Cisplatin dosage used to induce apoptosis could be reduced by half, and the amount of time needed to achieve the inhibitory concentration of 50% was also half that of the original. In addition to inducing autophagy within a shortened period of time, the SBPE and chemotherapy drug combination therapy was able to achieve the objective of rapid low-dosage cancer cell elimination. Besides, SBPE was applied with Gemcitabine or Paclitaxel, and found that the combination treatment indeed achieve improved lung cancer cell killing effects. However, SBPE may also be less toxic to normal cells.