In†Vitro and in†Silico Studies of Lichen Compounds Atranorin and Salazinic Acid as Potential Antioxidant, Antibacterial and Anticancer Agents.

Lichens are symbiotic organisms made up of alga/cyanobacterium and fungus. We investigated antioxidant, antibacterial and anticancer properties of two lichen compounds, atranorin and salazinic acid, and five lichen species: Heterodermia boryi, Heterodermia diademata, Heterodermia hypocaesia, Parmotrema reticulatum, and Stereocaulon foliolosum. Free radical scavenging, Ferric reducing potential, Nitric oxide scavenging, and Trolox equivalent capacity were used to measure antioxidant activity. Strong radical scavenging action was demonstrated by atranorin and salazinic acid, with IC50 values of 39.31 µM and 12.14 µM, respectively. The Minimum Inhibitory Concentration (MIC) assay based on resazurin, was used to measure antibacterial activity. Parmotrema reticulatum demonstrated significant antibacterial activity against Raoultella planticola with MIC of 7.8 µg/mL. Cytotoxicity assay on breast cancer cell line was used to assess anticancer activity. To further understand the binding locations on the target proteins Er (Estrogen Receptor alpha), EGFR (Epidermal Growth Factor Receptor), mTOR (Mammalian Target of Rapamycin), and PgR (Progesterone Receptor), molecular docking experiments were conducted. Docking study showed that the binding energies of atranorin and salazinic acid with mTOR were -5.31 kcal/mol and -3.43 kcal/mol, respectively. The results suggest that atranorin has the potential to be a multitargeted molecule with natural antioxidant, antibacterial, and anticancer properties.

Identification of new hit to lead magmas inhibitors as potential therapeutics for glioblastoma.

In continuation of our previous efforts for the development of potent small molecules against brain cancer, herein we synthesized seventeen new compounds and tested their anti-gliomapotential against established glioblastoma cell lines, namely, D54MG, U251, and LN-229 as well as patient derived cell lines (DB70 and DB93). Among them, the carboxamide derivatives, BT-851 and BT-892 were found to be the most active leads in comparison to our established hit compound BT#9.The SAR studies of our hit BT#9 compound resulted in the development of two new lead compounds by hit to lead strategy. The detailed biological studies are currently underway. The active compounds could possibly act as template for the future development of newer anti-glioma agents.

Anti-inflammatory Action of BT75, a Novel RARα Agonist, in Cultured Microglia and in an Experimental Mouse Model of Alzheimer's Disease.

BT75, a boron-containing retinoid, is a novel retinoic acid receptor (RAR)α agonist synthesized by our group. Previous studies indicated that activation of retinoic acid (RA) signaling may attenuate progression of Alzheimer's disease (AD). Presently, we aimed to examine the anti-inflammatory effect of BT75 and explore the possible mechanism using cultured cells and an AD mouse model. Pretreatment with BT75 (1-25 µM) suppressed the release of nitric oxide (NO) and IL-1ß in the culture medium of mouse microglial SIM-A9 cells activated by LPS. BMS195614, an RARα antagonist, partially blocked the inhibition of NO production by BT75. Moreover, BT75 attenuated phospho-Akt and phospho-NF-κB p65 expression augmented by LPS. In addition, BT75 elevated arginase 1, IL-10, and CD206, and inhibited inducible nitric oxide synthase (iNOS) and IL-6 formation in LPS-treated SIM-A9 cells, suggesting the promotion of M1-M2 microglial phenotypic polarization. C57BL/6 mice were injected intracerebroventricularly (icv) with streptozotocin (STZ) (3 mg/kg) to provide an AD-like mouse model. BT75 (5 mg/kg) or the vehicle was intraperitoneally (ip) injected to icv-STZ mice once a day for 3 weeks. Immunohistochemical analyses indicated that GFAP-positive cells and rod or amoeboid-like Iba1-positive cells, which increased in the hippocampal fimbria of icv-STZ mice, were reduced by BT75 treatment. Western blot results showed that BT75 decreased levels of neuronal nitric oxide synthase (nNOS), GFAP, and phosphorylated Tau, and increased levels of synaptophysin in the hippocampus of icv-STZ mice. BT75 may attenuate neuroinflammation by affecting the Akt/NF-κB pathway and microglial M1-M2 polarization in LPS-stimulated SIM-A9 cells. BT75 also reduced AD-like pathology including glial activation in the icv-STZ mice. Thus, BT75 may be a promising anti-inflammatory and neuroprotective agent worthy of further AD studies.

Magmas Inhibition in Prostate Cancer: A Novel Target for Treatment-Resistant Disease.

The purpose of our study was to evaluate Magmas as a potential target in prostate cancer. In addition, we evaluated our synthetic Magmas inhibitor (BT#9) effects on prostate cancer and examined the molecular mechanism of BT#9. A cell viability assay showed that treatment with BT#9 caused a significant decrease in the viability of DU145 and PC3 prostate cancer cells with little effect on the viability of WPMY-1 normal prostate cells. Western blot proved that BT#9 downregulated the Magmas protein and caspase-3 activation. Flow cytometry studies demonstrated increased apoptosis and disturbed mitochondrial membrane potential. However, the main mode of cell death was caspase-independent necrosis, which was correlated with the accumulation of mitochondrial and intra-cellular Reactive Oxygen Species (ROS). Taken together, our data suggest Magmas is a potential molecular target for the treatment of prostate cancer and that Magmas inhibition results in ROS-dependent and caspase-independent necrotic cell death.

Boron Chemicals in Drug Discovery and Development: Synthesis and Medicinal Perspective.

A standard goal of medicinal chemists has been to discover efficient and potent drug candidates with specific enzyme-inhibitor abilities. In this regard, boron-based bioactive compounds have provided amphiphilic properties to facilitate interaction with protein targets. Indeed, the spectrum of boron-based entities as drug candidates against many diseases has grown tremendously since the first clinically tested boron-based drug, Velcade. In this review, we collectively represent the current boron-containing drug candidates, boron-containing retinoids, benzoxaboroles, aminoboronic acid, carboranes, and BODIPY, for the treatment of different human diseases.In addition, we also describe the synthesis, key structure-activity relationship, and associated biological activities, such as antimicrobial, antituberculosis, antitumor, antiparasitic, antiprotozoal, anti-inflammatory, antifolate, antidepressant, antiallergic, anesthetic, and anti-Alzheimer's agents, as well as proteasome and lipogenic inhibitors. This compilation could be very useful in the exploration of novel boron-derived compounds against different diseases, with promising efficacy and lesser side effects.

High risk of relapse with intermediate dose cytarabine for consolidation in young favourable-risk acute myeloid leukaemia patients following induction with 7+3: a retrospective multicentre analysis and critical review of the literature.

Following the 2017 European LeukemiaNet (ELN) guidelines, we changed our practice from using high-dose cytarabine (HIDAC-3 g/m2 q12h-D1,3,5) to intermediate-dose cytarabine (IDAC-1·5 g/m2 q12h-D1,3,5/D1-3) for consolidation in young(<60 years) favourable-risk acute myeloid leukaemia (AML) patients. We assessed the clinical impact of this practice change. Of 80 patients, 51 received HIDAC prior to the protocol change, and subsequently, 29 received IDAC. The three-year risk of relapse was significantly higher with IDAC [61%; 95% confidence interval (CI) 40-82] compared with HIDAC (22%; 10-34), P < 0·01. Our findings suggest HIDAC, rather than IDAC, is the preferred dose for single-agent cytarabine consolidation in young, favourable-risk AML following 7+3 induction.

BF175 inhibits endometrial carcinoma through SREBP-regulated metabolic pathways in vitro.

Elevated lipogenesis is an important metabolic hallmark of rapidly proliferating tumor such as endometrial carcinoma (EC). The sterol regulatory element-binding protein 1 (SREBP1) is a master regulator of lipogenesis and involved in EC proliferation. BF175 is a novel chemical inhibitor of SREBP pathway, and has shown potent anti-lipogenic effects. However, the effect of BF175 on EC cells are yet to be determined. In the present study, we found that BF175 decreased cell viability, colony formation and migratory capacity, inducing autophagy and mitochondrial related apoptosis in EC cell line AN3CA. Z-VAD-FMK partially attenuated the effect of BF175 on AN3CA. In addition, BF175 significantly downregulated SREBPs and their downstream genes. The levels of free fatty acids and total cholesterol were also inhibited. Microarray analysis suggested BF175 treatment obviously affected lipid metabolic pathways in EC. Taken together, we validated BF175 exhibited anti-tumor activity by targeting SREBP-dependent lipogenesis and inducing apoptosis which mitochondrial pathway involved in, suggesting that it's potential as a novel therapeutic reagent for EC.

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review.

Small-cell lung carcinoma (SCLC) is one of the most aggressive solid tumors, and the prognosis has not improved significantly in 25 years. Despite a recent understanding of the genomic aberrations seen in SCLC, these insights have not led to any breakthroughs in treatment. We present a patient with SCLC harboring a novel MYCL1 fusion protein who experienced a prolonged disease course due to the use of Aurora A kinase inhibitor and subsequently nivolumab. MYC family genes are master regulators of several cellular pathways including proliferation, differentiation, and apoptosis and recently have been shown to be involved in tumor immune evasion. Large studies have shown that a significant proportion of patients with SCLC have amplification or overexpression of MYC family genes. Preclinical data have exposed vulnerability of MYC-driven tumors to Aurora kinase inhibitors, bromodomain and extraterminal domain inhibitors, and recently to immune checkpoint blockers. Further studies using these agents with selective enrolling of patients with MYC-altered tumors are warranted to exploit these vulnerabilities.

Impact of adjuvant chemotherapy on outcomes in appendiceal cancer.

BACKGROUND: The impact of using adjuvant chemotherapy following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal adenocarcinoma is not known. The aim of this study was to assess the impact of adjuvant chemotherapy following complete cytoreduction in patients with appendiceal adenocarcinoma. METHODS: Retrospective medical record review of all patients with appendiceal adenocarcinoma treated at our institution between 2006 and 2015. Kaplan-Meier plots were used to summarize overall survival (OS) and relapse-free survival over time, and log-rank tests and Cox proportional hazards models were used to test for differences in survival between groups. RESULTS: A total of 103 patients with appendiceal adenocarcinoma received care at our institution during the study period. Complete cytoreduction (cytoreductive score 0-1) was achieved in 68 patients (66%). Of these 68 patients, 26 received adjuvant chemotherapy. The most common regimens were capecitabine (n = 11), capecitabine plus oxaliplatin (n = 7), and 5-FU plus oxaliplatin (n = 6). Tumor histopathology and grade, and the ability to achieve complete cytoreduction were significant predictors of overall survival. The median OS for non-low-grade and well-differentiated tumor patients who received adjuvant chemotherapy following complete cytoreduction was 9.03 years, compared to 2.88 years for patients who did not receive adjuvant chemotherapy (P = .02). Among low-grade and well-differentiated tumor patients who underwent complete cytoreduction, there was no statistically significant difference in OS between those who received adjuvant chemotherapy and those who did not. CONCLUSION: Adjuvant chemotherapy seems to have benefit in appendiceal cancer patients with non-low-grade or well-differentiated tumor type but not in low-grade or well-differentiated tumors.

SMARC-B1 deficient sinonasal carcinoma metastasis to the brain with next generation sequencing data: a case report of perineural invasion progressing to leptomeningeal invasion.

BACKGROUND: SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread. CASE PRESENTATION: A 42 year old female presented with facial pain and had resection of a tumor along the V2 division of the trigeminal nerve on the right. She underwent adjuvant stereotactic radiation. She developed further neurological symptoms and imaging demonstrated the tumor had infiltrated into the cavernous sinus as well as intradurally. She had surgical resection for removal of her brain metastasis and decompression of the cavernous sinus. Following her second surgery, she had adjuvant radiation and chemotherapy. Several months later she had quadriparesis and imaging was consistent with leptomeningeal spread. She underwent palliative radiation and ultimately transitioned quickly to comfort care and expired. Overall survival from time of diagnosis was 13 months. Next generation sequencing was carried out on her primary tumor and brain metastasis. The brain metastatic tissue had an increased tumor mutational burden in comparison to the primary. CONCLUSIONS: This is the first report of SDSC with perineural invasion progressing to leptomeningeal carcinomatosis. Continued next generation sequencing of the primary and metastatic tissue by clinicians is encouraged toprovide further insights into metastatic progression of rare solid tumors.

Discovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-ß.

Disorders of bone healing and remodeling are indications with an unmet need for effective pharmacological modulators. We used a high-throughput screen to identify activators of the bone marker alkaline phosphatase (ALP), and discovered 6,8-dimethyl-3-(4-phenyl-1H-imidazol-5-yl)quinolin-2(1H)-one (DIPQUO). DIPQUO markedly promotes osteoblast differentiation, including expression of Runx2, Osterix, and Osteocalcin. Treatment of human mesenchymal stem cells with DIPQUO results in osteogenic differentiation including a significant increase in calcium matrix deposition. DIPQUO stimulates ossification of emerging vertebral primordia in developing zebrafish larvae, and increases caudal fin osteogenic differentiation during adult zebrafish fin regeneration. The stimulatory effect of DIPQUO on osteoblast differentiation and maturation was shown to be dependent on the p38 MAPK pathway. Inhibition of p38 MAPK signaling or specific knockdown of the p38-ß isoform attenuates DIPQUO induction of ALP, suggesting that DIPQUO mediates osteogenesis through activation of p38-ß, and is a promising lead candidate for development of bone therapeutics.

Involvement of AMP-activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain.

Microglial activation followed by neuroinflammation is a defense mechanism of the brain to eliminate harmful endogenous and exogenous materials including pathogens and damaged tissues, while excessive or chronic neuroinflammation may cause or exacerbate neurodegeneration observed in brain injuries and neurodegenerative diseases. Depending on conditions/environments during activation, microglia acquire distinct phenotypes, such as pro-inflammatory, anti-inflammatory, and disease-associated phenotypes, and show their ability to phagocytose various objects and produce pro-and anti-inflammatory mediators. Prevention of excessive inflammation by regulating the microglia's pro/anti-inflammatory balance is important for alleviating progression of brain injuries and diseases. Among many factors involved in the regulation of microglial phenotypes, cellular energy status plays an important role. Adenosine monophosphate-activated protein kinase (AMPK), which serves as a master sensor and regulator of energy balance, is considered a candidate molecule. Accumulating evidence from adult rodent studies indicates that AMPK activation promotes anti-inflammatory responses in microglia exposed to danger signals or various stressors mainly through inhibition of the nuclear factor κB (NF-κB) signaling and activation of the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway. However, AMPK activation in neurons exposed to stressors/insults may exacerbate neuronal damage if AMPK activation is excessive or prolonged. While AMPK affects microglial activation states and neuronal cell survival rates in both the adult and the developing brain, studies in the developing brain are still scarce, even though activated AMPK is highly expressed especially in the neonatal brain. More in depth studies in the developing brain are important, because neuroinflammation/neurodegeneration occurred during development can result in long-lasting brain damage.

Magmas inhibition as a potential treatment strategy in malignant glioma.

PURPOSE: Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a nuclear gene that encodes the mitochondrial import inner membrane translocase subunit Tim16. Magmas is highly conserved, ubiquitously expressed in mammalian cells, and is essential for cell viability. Magmas expression levels are increased in prostate cancers and pituitary adenomas. Moreover, silencing Magmas by RNAi sensitizes pituitary adenoma cells to pro-apoptotic stimuli and induces a G0/G1 accumulation. The aim of this study was to examine whether inhibition of Magmas by small molecule inhibitors could be beneficial for the treatment of malignant gliomas. METHODS: We evaluated the expression of Magmas in patient-derived glioblastoma tissue samples and xenograft models. We studied the feasibility of a small molecule Magmas inhibitor (BT#9) as a therapeutic agent in stable human glioma cell lines and high-grade patient derived glioma stem-like cells. RESULTS: Magmas was overexpressed in tissue sections from glioma patients and xenografts. In vivo studies revealed that BT#9 could cross the blood-brain barrier in the animal model. Magmas inhibition by BT#9 in glioma cell lines significantly decreased cell proliferation, induced apoptosis along with vacuole formation, and blocked migration and invasion. In addition, BT#9 treatment decreased the respiratory function of glioma cells, supporting the role that Magmas serves as a reactive oxygen species regulator. CONCLUSIONS: This is the first study on the role of Magmas in glioma. Our findings suggest that Magmas plays a key role in glioma cell survival and targeting Magmas by small molecule inhibitors may be a therapeutic strategy in gliomas.

Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma.

Autophagy is an evolutionarily conserved catabolic process that plays an essential role in maintaining cellular homeostasis by degrading unneeded cell components. When exposed to hostile environments, such as hypoxia or nutrient starvation, cells hyperactivate autophagy in an effort to maintain their longevity. In densely packed solid tumors, such as glioblastoma, autophagy has been found to run rampant due to a lack of oxygen and nutrients. In recent years, targeting autophagy as a way to strengthen current glioblastoma treatment has shown promising results. However, that protective autophagy inhibition or autophagy overactivation is more beneficial, is still being debated. Protective autophagy inhibition would lower a cell's previously activated defense mechanism, thereby increasing its sensitivity to treatment. Autophagy overactivation would cause cell death through lysosomal overactivation, thus introducing another cell death pathway in addition to apoptosis. Both methods have been proven effective in the treatment of solid tumors. This systematic review article highlights scenarios where both autophagy inhibition and activation have proven effective in combating chemoresistance and radioresistance in glioblastoma, and how autophagy may be best utilized for glioblastoma therapy in clinical settings.

Association of VDBP and CYP2R1 gene polymorphisms with vitamin D status in women with polycystic ovarian syndrome: a north Indian study.

PURPOSE: Polycystic ovarian syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age and is usually associated with oligo-ovulation/anovulation, obesity, and insulin resistance. Hypovitaminosis D may also be a primary factor in the initiation and development of PCOS. However, little is known about the role of genetic variation in vitamin D metabolism in PCOS aetiology. Therefore, we studied the genetic polymorphisms of CYP2R1 and vitamin D binding protein (VDBP) in an Indian population. METHODS: Serum vitamin D was measured by ELISA. Genotyping of VDBP single nucleotide polymorphisms (SNPs) rs7041 (HaeIII; G>T) and rs4588 (StyI; A>C) and CYP2R1 SNP rs2060793 (HinfI; A>G) was carried out by restriction fragment length polymorphism in 50 cases of PCOS that were compared with 50 age-matched healthy women. RESULTS: Vitamin D levels were found to be significantly lower in women with PCOS (p = 0.008) than in age-matched controls. There was no significant difference in genotype frequencies of all three polymorphisms (rs7041, rs4588, and rs2060793) between PCOS and control women. In women with a vitamin D deficiency (<20 ng/ml), the GT allele of the VDBP SNP rs7041 (p value =0.04), the VDBP allelic combination Gc1F/1F (T allele of rs4588 and C allele of rs7041) (p value =0.03), and the GA allele of the CYP2R1 SNP rs2060793 (p = 0.05) were associated with an increased risk of developing PCOS. CONCLUSIONS: The present study shows that the GT allele of VDBP SNP rs7041, the VDBP allelic combination (GC1F/1F), and GA allele of CYP2R1 SNP rs2060793 in vitamin D deficient women increase the risk of PCOS.

Neuroprotective effects of estrogen in CNS injuries: insights from animal models.

Among the estrogens that are biosynthesized in the human body, 17ß-estradiol (estradiol or E2) is the most common and the best estrogen for neuroprotection in animal models of the central nervous system (CNS) injuries such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic brain injury (IBI). These CNS injuries are not only serious health problems, but also enormous economic burden on the patients, their families, and the society at large. Studies from animal models of these CNS injuries provide insights into the multiple neuroprotective mechanisms of E2 and also suggest the possibility of translating the therapeutic efficacy of E2 in the treatment SCI, TBI, and IBI in humans in the near future. The pathophysiology of these injuries includes loss of motor function in the limbs, arms and their extremities, cognitive deficit, and many other serious consequences including life-threatening paralysis, infection, and even death. The potential application of E2 therapy to treat the CNS injuries may become a trend as the results are showing significant therapeutic benefits of E2 for neuroprotection when administered into the animal models of SCI, TBI, and IBI. This article describes the plausible mechanisms how E2 works with or without the involvement of estrogen receptors and provides an overview of the known neuroprotective effects of E2 in these three CNS injuries in different animal models. Because activation of estrogen receptors has profound implications in maintaining and also affecting normal physiology, there are notable impediments in translating E2 therapy to the clinics for neuroprotection in CNS injuries in humans. While E2 may not yet be the sole molecule for the treatment of CNS injuries due to the controversies surrounding it, the neuroprotective effects of its metabolite and derivative or combination of E2 with another therapeutic agent are showing significant impacts in animal models that can potentially shape the new treatment strategies for these CNS injuries in humans.

Cardiac Imaging Methods for Chemotherapy-related Cardiotoxicity Screening and Related Radiation Exposure: Current Practice and Trends.

BACKGROUND: Radiation exposure is a serious concern with usage of serial multigated acquisition (MUGA) scans (7.8mSv/study) for chemotherapy-related cardiotoxicity (CRC) screening. The current practice with respect to the imaging modalities chosen for cardiotoxicity screening and related radiation exposure has not been studied. MATERIALS AND METHODS: We performed a serial cross-sectional study from 2011 to 2014, evaluating the relative usage of the three imaging modalities for CRC screening. RESULTS: MUGA scan usage decreased from 30.4% to 16.7%, echocardiogram (Echo) utilization increased from 68.7% to 80.4% and cardiac magnetic resonance (CMR) usage increased from 0.9% to 2.9% in the 4-year period. Estimated total radiation exposure and secondary cancer risk can increase significantly in certain subgroups when MUGA scan is employed for serial cardiac imaging. CONCLUSION: Increased awareness of radiation risks from MUGA, as well as increasing focus on early detection of cardiotoxicity using Echo and CMR, are possible reasons behind the observed trends.

Corrigendum: What Is the Link between Stringent Response, Endoribonuclease Encoding Type II Toxin-Antitoxin Systems and Persistence?

[This corrects the article on p. 1882 in vol. 7, PMID: 27933045.].

Radiolabeling and initial biological evaluation of [18F]KBM-1 for imaging RAR-α receptors in neuroblastoma.

Retinoic acid receptor alpha (RAR-α) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high-risk neuroblastoma are treated13-cis-retinoic acid, which reduces risk of cancer recurrence. Neuroblastoma cell death is mediated via RAR-α, and expression of RAR-α is upregulated after treatment. A molecular imaging probe that binds RAR-α will help clinicians to diagnose and stratify risk for patients with neuroblastoma, who could benefit from retinoid-based therapy. In this study, we report the radiolabeling, and initial in vivo evaluation of [18F]KBM-1, a novel RAR-α agonist. The radiochemical synthesis of [18F]KBM-1 was carried out through KHF2 assisted substitution of [18F]- from aryl-substituted pinacolatoesters-based retinoid precursor. In vitro cell uptake assay in human neuroblastoma cell line showed that the uptake of [18F]KBM-1 was significantly inhibited by all three blocking agents (KBM-1, ATRA, BD4) at all the selected incubation times. Standard biodistribution in mice bearing neuroblastoma tumors demonstrated increased tumor uptake from 5min to 60min post radiotracer injection and the uptake ratios for target to non-target (tumor: muscle) increased 2.2-fold to 3.7-fold from 30min to 60min post injection. Tumor uptake in subset of 30min blocking group was 1.7-fold lower than unblocked. These results demonstrate the potential utility of [18F]KBM-1 as a RAR-α imaging agent.