Publications by authors named "Jin-Rong Zhou"

48 Publications

Cataloging recent advances in epigenetic alterations in major mental disorders and autism.

Epigenomics 2021 Aug 28;13(15):1231-1245. Epub 2021 Jul 28.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, 02118 MA, USA.

During the last two decades, diverse epigenetic modifications including DNA methylation, histone modifications, RNA editing and miRNA dysregulation have been associated with psychiatric disorders. A few years ago, in a review we outlined the most common epigenetic alterations in major psychiatric disorders (e.g., aberrant DNA methylation of , , , and , and increased expression of miR-34a and miR-181b). Recent follow-up studies have uncovered other DNA methylation aberrations affecting several genes in mental disorders, in addition to dysregulation of many miRNAs. Here, we provide an update on new epigenetic findings and highlight potential origin of the diversity and inconsistencies, focusing on drug effects, tissue/cell specificity of epigenetic landscape and discuss shortcomings of the current diagnostic criteria in mental disorders.
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http://dx.doi.org/10.2217/epi-2021-0074DOI Listing
August 2021

Assessment of thoracic aorta in different cardiac phases in patients with non-aorta diseases using cardiac CT.

Sci Rep 2021 Jul 26;11(1):15209. Epub 2021 Jul 26.

Department of Radiology, The Affiliated Hospital of Southwest Medical University, 25# Tai Ping Street, Luzhou, 646099, Sichuan, China.

The aim was to evaluate the thoracic aorta in different cardiac phases to obtain the correct cardiac phase for measuring the maximum diameter required to predict aortic disease. Cardiac CT was performed on 97 patients for suspected coronary artery disease. The average diameter of ascending (AAD) and descending aorta (DAD) in the plane of pulmonary bifurcation, in the plane of the sinus junction (AAD [STJ] and DAD [STJ]), descending aorta in the plane of the diaphragm (DAD [Dia]), the diameter of the main pulmonary artery (MPAD), distance from the sternum to the spine (S-SD), and distance from the sternum to the ascending aorta (S-AAD) were assessed at 20 different time points in the cardiac cycle. Differences in aortic diameter in different cardiac phases and the correlation between aortic diameter and traditional risk factors were analyzed by the general linear mixed model. The diameter of the thoracic aorta reached the minimum at the phase of 95-0%, and reached the maximum at 30-35%. The maximum values of AAD, AAD (STJ), DAD, DAD (STJ), and DAD (Dia) were 32.51 ± 3.35 mm, 28.86 ± 3.01 mm, 23.46 ± 2.88 mm, 21.85 ± 2.58 mm, and 21.09 ± 2.66 mm, respectively. The maximum values of MPAD/AAD and DAD/AAD (STJ) were 0.8140 ± 0.1029, 0.7623 ± 0.0799, respectively. The diameter of the thoracic aorta varies with the cardiac phase. Analyzing the changes in aortic diameter, which can be done using cardiac CT, could provide a more accurate clinical measurement for predicting aortic disease.
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http://dx.doi.org/10.1038/s41598-021-94677-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313572PMC
July 2021

Therapeutic Effectiveness and Safety of Repurposing Drugs for the Treatment of COVID-19: Position Standing in 2021.

Front Pharmacol 2021 14;12:659577. Epub 2021 Jun 14.

Pharmacology Department, Medical Faculty, Universiti Kebangsaan Malaysia (The National University of Malaysia), Kuala Lumpur, Malaysia.

COVID-19, transmitted by SARS-CoV-2, is one of the most serious pandemic situations in the history of mankind, and has already infected a huge population across the globe. This horrendously contagious viral outbreak was first identified in China and within a very short time it affected the world's health, transport, economic, and academic sectors. Despite the recent approval of a few anti-COVID-19 vaccines, their unavailability and insufficiency along with the lack of other potential therapeutic options are continuing to worsen the situation, with valuable lives continuing to be lost. In this situation, researchers across the globe are focusing on repurposing prospective drugs and prophylaxis such as favipiravir, remdesivir, chloroquine, hydroxychloroquine, ivermectin, lopinavir-ritonavir, azithromycin, doxycycline, ACEIs/ARBs, rivaroxaban, and protease inhibitors, which were preliminarily based on and pharmacological and toxicological study reports followed by clinical applications. Based on available preliminary data derived from limited clinical trials, the US National Institute of Health (NIH) and USFDA also recommended a few drugs to be repurposed i.e., hydroxychloroquine, remdesivir, and favipiravir. However, World Health Organization later recommended against the use of chloroquine, hydroxychloroquine, remdesivir, and lopinavir/ritonavir in the treatment of COVID-19 infections. Combining basic knowledge of viral pathogenesis and pharmacodynamics of drug molecules as well as approaches, many drug candidates have been investigated in clinical trials, some of which have been proven to be partially effective against COVID-19, and many of the other drugs are currently under extensive screening. The repurposing of prospective drug candidates from different stages of evaluation can be a handy wellspring in COVID-19 management and treatment along with approved anti-COVID-19 vaccines. This review article combined the information from completed clinical trials, case series, cohort studies, meta-analyses, and retrospective studies to focus on the current status of repurposing drugs in 2021.
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http://dx.doi.org/10.3389/fphar.2021.659577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243370PMC
June 2021

Traditional Herbal Medicines, Bioactive Metabolites, and Plant Products Against COVID-19: Update on Clinical Trials and Mechanism of Actions.

Front Pharmacol 2021 28;12:671498. Epub 2021 May 28.

Pharmacology Department, Medical Faculty, Universiti Kebangsaan Malaysia (The National University of Malaysia), Kuala Lumpur, Malaysia.

SARS-CoV-2 is the latest worldwide pandemic declared by the World Health Organization and there is no established anti-COVID-19 drug to combat this notorious situation except some recently approved vaccines. By affecting the global public health sector, this viral infection has created a disastrous situation associated with high morbidity and mortality rates along with remarkable cases of hospitalization because of its tendency to be high infective. These challenges forced researchers and leading pharmaceutical companies to find and develop cures for this novel strain of coronavirus. Besides, plants have a proven history of being notable wellsprings of potential drugs, including antiviral, antibacterial, and anticancer therapies. As a continuation of this approach, plant-based preparations and bioactive metabolites along with a notable number of traditional medicines, bioactive phytochemicals, traditional Chinese medicines, nutraceuticals, Ayurvedic preparations, and other plant-based products are being explored as possible therapeutics against COVID-19. Moreover, the unavailability of effective medicines against COVID-19 has driven researchers and members of the pharmaceutical, herbal, and related industries to conduct extensive investigations of plant-based products, especially those that have already shown antiviral properties. Even the recent invention of several vaccines has not eliminated doubts about safety and efficacy. As a consequence, many limited, unregulated clinical trials involving conventional mono- and poly-herbal therapies are being conducted in various areas of the world. Of the many clinical trials to establish such agents as credentialed sources of anti-COVID-19 medications, only a few have reached the landmark of completion. In this review, we have highlighted and focused on plant-based anti-COVID-19 clinical trials found in several scientific and authenticated databases. The aim is to allow researchers and innovators to identify promising and prospective anti-COVID-19 agents in clinical trials (either completed or recruiting) to establish them as novel therapies to address this unwanted pandemic.
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http://dx.doi.org/10.3389/fphar.2021.671498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194295PMC
May 2021

Herbal medicine WangShiBaoChiWan improves gastrointestinal health in mice via modulation of intestinal tight junctions and gut microbiota and inhibition of inflammation.

Biomed Pharmacother 2021 Jun 21;138:111426. Epub 2021 Mar 21.

Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

WangShiBoChiWan (WSBCW) is a commonly used Chinese herbal medicine for the treatment of functional gastrointestinal disorders. However, its preclinical efficacy and the mechanisms of action have not been adequately studied. The goals of this study were to evaluate the effects of WSBCW on gastrointestinal health and modulation of related biomarkers. Female C57BL mice were randomly assigned into one of the experimental groups consisting of the control, drug controls, and WSBCW at 40, 120, and 360 mg/kg BW. Whole gut transit, small intestinal motility, and intestinal barrier permeability were determined. The castor oil-induced diarrhea mouse model was used to determine the effect of WSBCW on the diarrhea type of irritable bowel syndrome (IBS-D). WSBCW increased whole gut transit and intestinal motility, improved intestinal permeability in healthy animals and alleviated diarrhea symptoms in IBS-D mice. WSBCW upregulated intestinal junction proteins, increased the abundance of Bifidobacterium genus, Desulfovibrio genus and inhibited Bacteroides fragillis group in the gut microbiota, increased intestinal villi lengths, and decreased blood levels of inflammatory cytokines. Our study provided preclinical evidence to verify the effectiveness of WSBCW in gastrointestinal health and elucidate mechanistic insights. The results warrant further investigations to evaluate the therapeutic efficacy of WSBCW on gastrointestinal disorders, such as IBS and IBD.
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http://dx.doi.org/10.1016/j.biopha.2021.111426DOI Listing
June 2021

Screening and Molecular Modeling Evaluation of Food Peptides to Inhibit Key Targets of COVID-19 Virus.

Biomolecules 2021 02 22;11(2). Epub 2021 Feb 22.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Peptide drugs, especially food-derived peptides, have a variety of functional activities including antiviral and may also have a therapeutic effect on COVID-19. In this study, comparing with the reported drugs, 79 peptides were found to bind to the key targets of COVID-19 virus with higher non-covalent interaction, while among them, six peptides showed high non-covalent interactions with the three targets, which may inhibit the COVID-19 virus. In the simulation, peptides of nine to 10 amino acids with a hydrophilic amino acid and acidic amino acid in the middle and aromatic amino acids on the side showed higher binding to angiotensin-converting enzyme 2 (ACE2). Peptides of five to six amino acids with a basic amnio acid in the head, acidic amnio acid in the neck, hydrophobicity group in the middle, and basic amino acids in the tail showed higher binding to COVID-19 virus main protease (M), while those with basic amino acids and acidic amino acids in the two sides and aromatic amino acids in the middle might have stronger interaction with COVID-19 virus RNA-dependent RNA polymerase (RdRp).
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http://dx.doi.org/10.3390/biom11020330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926797PMC
February 2021

Dietary Fermented Soy Extract and Oligo-Lactic Acid Alleviate Chronic Kidney Disease in Mice via Inhibition of Inflammation and Modulation of Gut Microbiota.

Nutrients 2020 Aug 8;12(8). Epub 2020 Aug 8.

Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Chronic kidney disease (CKD) is a global epidemic with an increasing prevalence worldwide. Effective preventive strategies are urgently needed. This study aimed to investigate the effect of nutraceutical components, a fermented soybean product (ImmuBalance, IMB) and an oligo-lactic acid product (LAP), on the prevention of adenine-induced CKD in mice. Female C57BL/6 mice were randomly assigned into following experimental groups: negative control; model control; and models treated with IMB at 250 or 1000 mg/kg body weight (BW), LAP at 1000 or 2000 mg/kg BW, and IMB/LAP combinations. The CKD model was established by intraperitoneal injection of adenine daily for 4 weeks, and treatments started 2 weeks before adenine injection and ended after 10 weeks. Compared with the model control, the treatments did not significantly alter the body weight or food intake. Both IMB and LAP, especially their combination, significantly inhibited tubular dilation, tubulointerstitial degeneration or atrophy, interstitial chronic inflammation and acute inflammation in the kidneys of CKD mice, and significantly decreased serum cystatin C levels. IMB or LAP significantly reversed CKD-associated increases of circulating and kidney levels of inflammatory cytokines, circulating levels of kidney injury biomarkers, and kidney levels of stem cell biomarkers, and significantly reversed CKD-associated reduction of cecum group. Our results suggest that dietary supplementation of IMB or LAP may significantly delay the development and/or progression of CKD.
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http://dx.doi.org/10.3390/nu12082376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468970PMC
August 2020

Dynamic assessment of the central vein throughout the cardiac cycle in adults with no right heart disease by cardiac CT.

Clin Imaging 2021 Jan 17;69:120-125. Epub 2020 Jul 17.

Department of Radiology, The Affiliated Hospital of Southwest Medical University, 25# Tai Ping Street, Luzhou, Sichuan 646000, China. Electronic address:

Purpose: The aim of this study was to investigate the effect of the cardiac cycle on the vena cava and determine the phase of measuring maximum diameters.

Methods: A total of 152 patients who underwent cardiac computed tomography (CT) were included. Patients' basic information was collected. The major axis, minor axis, and cross-sectional area (CSA) of the vena cava in 10 phases reconstructed at 10% step from 5% to 95% R-R interval were measured in four planes (SVC1 layer: the bifurcation of the pulmonary artery; SVC2 layer: the superior vena cava (SVC) into the right atrium; IVC1 layer: the intersection of the inferior vena cava (IVC) and the right atrium; IVC2 layer: the IVC into the anterior hepatic plane). The difference in vena cava diameters between cardiac cycles was determined using the linear mixed model.

Results: The variations in diameter and CSA of the SVC in cardiac cycles were statistically significant (p < 0.05), while those of the suprahepatic IVC were not. In the SVC1 layer, the maximum value of the SVC major and minor axes was observed in 85% and 45% phases, respectively, while that in the SVC2 layer was observed in 45% phases. The maximum SVC diameters in the SVC1 and SVC2 layers were 19.48 ± 2.57 mm and 17.43 ± 3.09 mm, respectively. The SVC and IVC diameters and CSA were positively correlated with the body surface area in the linear mixed model.

Conclusion: The maximum SVC diameter and CSA were mostly observed in 45% phase, which provides a reference for selecting the best phase to measure the abnormality of vena cava diameter in the future.
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http://dx.doi.org/10.1016/j.clinimag.2020.07.003DOI Listing
January 2021

Loss of a Negative Feedback Loop between IRF8 and AR Promotes Prostate Cancer Growth and Enzalutamide Resistance.

Cancer Res 2020 07 27;80(13):2927-2939. Epub 2020 Apr 27.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer but decreased in CRPC compared with normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and enzalutamide resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated prostate cancer progression and enzalutamide resistance and . Furthermore, IFNα increased expression of IRF8 and improved the efficacy of enzalutamide in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in prostate cancer pathogenesis and a potential alternative therapeutic option to overcome enzalutamide resistance. SIGNIFICANCE: These findings identify IRF8-mediated AR degradation as a mechanism of resistance to AR-targeted therapy, highlighting the therapeutic potential of IFNα in targeting IRF8-AR axis in CRPC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2927/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2549DOI Listing
July 2020

Metformin in colorectal cancer: molecular mechanism, preclinical and clinical aspects.

J Exp Clin Cancer Res 2019 Dec 12;38(1):491. Epub 2019 Dec 12.

Brain Research Institute Monash Sunway (BRIMS), Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500, Bandar Sunway, Selangor, Malaysia.

Growing evidence showed the increased prevalence of cancer incidents, particularly colorectal cancer, among type 2 diabetic mellitus patients. Antidiabetic medications such as, insulin, sulfonylureas, dipeptyl peptidase (DPP) 4 inhibitors and glucose-dependent insulinotropic peptide (GLP-1) analogues increased the additional risk of different cancers to diabetic patients. Conversely, metformin has drawn attention among physicians and researchers since its use as antidiabetic drug exhibited beneficial effect in the prevention and treatment of cancer in diabetic patients as well as an independent anticancer drug. This review aims to provide the comprehensive information on the use of metformin at preclinical and clinical stages among colorectal cancer patients. We highlight the efficacy of metformin as an anti-proliferative, chemopreventive, apoptosis inducing agent, adjuvant, and radio-chemosensitizer in various colorectal cancer models. This multifarious effects of metformin is largely attributed to its capability in modulating upstream and downstream molecular targets involved in apoptosis, autophagy, cell cycle, oxidative stress, inflammation, metabolic homeostasis, and epigenetic regulation. Moreover, the review highlights metformin intake and colorectal cancer risk based on different clinical and epidemiologic results from different gender and specific population background among diabetic and non-diabetic patients. The improved understanding of metformin as a potential chemotherapeutic drug or as neo-adjuvant will provide better information for it to be used globally as an affordable, well-tolerated, and effective anticancer agent for colorectal cancer.
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http://dx.doi.org/10.1186/s13046-019-1495-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909457PMC
December 2019

Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice.

J Nutr Biochem 2019 07 8;69:108-119. Epub 2019 Apr 8.

Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Quercetin (QCT) has been shown to have anticancer activities associated with apoptosis and autophagy induction. However, whether autophagy is functionally responsible for the inhibitory effect of QCT on hepatocellular carcinoma (HCC) remains elusive. This study aims to investigate if QCT inhibits HCC growth via autophagy induction. The in vitro experiments showed that QCT inhibited the growth of human HCC cells in dose- and time-dependent manners and had minimal cytotoxicity to normal hepatocytes. QCT increased both autophagosomes and autolysosomes in HCC cells, as determined by electron microscopy, GFP-RFP-LC3 fluorescence confocal microscopy and Western blot analysis of autophagy-related biomarkers. Functional assays using pathway-specific inhibitors, activators or siRNAs indicated that QCT stimulated autophagy in part via inhibiting the AKT/mTOR pathway and activating the MAPK pathways. Further functional experiments using autophagy inhibitors demonstrated that QCT induced apoptosis of HCC cells in part via stimulating autophagy. The in vivo studies showed that QCT significantly inhibited tumor growth associated with apoptosis induction and autophagy stimulation, and that inhibition of autophagy significantly alleviated the QCT effect on tumor growth inhibition and apoptosis induction. To the best of our knowledge, this is the first in vivo report to demonstrate that QCT inhibits HCC tumor growth and induces apoptosis in part via stimulation of autophagy. Our results provide strong experimental evidence to support that autophagy stimulation may be an important mechanism by which QCT induces cancer cell apoptosis, and pave the way for further clinical investigations by applying QCT or QCT-rich foods for HCC intervention.
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http://dx.doi.org/10.1016/j.jnutbio.2019.03.018DOI Listing
July 2019

2-Hydroxy-3-methylanthraquinone inhibits lung carcinoma cells through modulation of IL-6-induced JAK2/STAT3 pathway.

Phytomedicine 2019 Aug 28;61:152848. Epub 2019 Jan 28.

Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China; Institute of Oncology, the First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China. Electronic address:

Background: 2-hydroxy-3-methylanthraquinone (HMA), an anthraquinone monomer in traditional Chinese medicine Hedyotis diffusa, has been reported to inhibit the growth of several types of cancer, but its effect on lung cancer has not been adequately investigated.

Hypothesis/purpose: This study aimed to test the hypothesis that HMA inhibit the growth, migration, and invasion of lung cancer cells in part via downregulation of interleukin (IL)-6-induced JAK2/STAT3 pathway.

Methods: Growth and apoptosis of lung cancer cells were quantitated by CCK-8 assay and Annexin V-FITC/PI flow cytometric analysis, respectively. Migration and invasion of A549 cells were determined by wound-healing assay and transwell invasion assay, respectively. The effect of HMA on cytokines expression in A549 cells was evaluated by the cytokine antibody array assay. Gene expression and protein levels of related molecular markers were quantitated by real time-PCR and Western blot analysis, respectively.

Results: HMA significantly inhibited IL-6-stimulated growth and colony formation of A549 cells, increased the number of apoptotic cells, and inhibited invasion associated with downregulation of expression of IL-6-induced MMP-1, MMP-2, and MMP-9 genes. IL-6 increased the levels of tyrosine phosphorylation of JAK2 and STAT3 in A549 cells, which was reversed by HMA treatment. In addition, HMA reduced the expression of a series of inflammation-related cytokines in A549 cells supernatant, including IL-6, G-CSF, IL-6R, IL-8, MCP-1, RANTES, TNF-α.

Conclusion: These results suggest that HMA may inhibit the growth and invasion of lung cancer cells in part via downregulation of IL-6-induced JAK2/STAT3 pathway.
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http://dx.doi.org/10.1016/j.phymed.2019.152848DOI Listing
August 2019

Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder.

Am J Med Genet B Neuropsychiatr Genet 2019 03 23;180(2):138-149. Epub 2018 Nov 23.

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.

Although the loss of brain laterality is one of the most consistent modalities in schizophrenia (SCZ) and bipolar disorder (BD), its molecular basis remains elusive. Our limited previous studies indicated that epigenetic modifications are key to the asymmetric transcriptomes of brain hemispheres. We used whole-genome expression microarrays to profile postmortem brain samples from subjects with SCZ, psychotic BD [BD[+]] or non-psychotic BD [BD(-)], or matched controls (10/group) and performed whole-genome DNA methylation (DNAM) profiling of the same samples (3-4/group) to identify pathways associated with SCZ or BD[+] and genes/sites susceptible to epigenetic regulation. qRT-PCR and quantitative DNAM analysis were employed to validate findings in larger sample sets (35/group). Gene Set Enrichment Analysis (GSEA) demonstrated that BMP signaling and astrocyte and cerebral cortex development are significantly (FDR q < 0.25) coordinately upregulated in both SCZ and BD[+], and glutamate signaling and TGFβ signaling are significantly coordinately upregulated in SCZ. GSEA also indicated that collagens are downregulated in right versus left brain of controls, but not in SCZ or BD[+] patients. Ingenuity Pathway Analysis predicted that TGFB2 is an upstream regulator of these genes (p = .0012). While lateralized expression of TGFB2 in controls (p = .017) is associated with a corresponding change in DNAM (p ≤ .023), lateralized expression and DNAM of TGFB2 are absent in SCZ or BD. Loss of brain laterality in SCZ and BD corresponds to aberrant epigenetic regulation of TGFB2 and changes in TGFβ signaling, indicating potential avenues for disease prevention/treatment.
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http://dx.doi.org/10.1002/ajmg.b.32691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386618PMC
March 2019

Ginseng oligopeptides protect against irradiation-induced immune dysfunction and intestinal injury.

Sci Rep 2018 09 17;8(1):13916. Epub 2018 Sep 17.

Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, 100191, China.

Intestinal injury and immune dysfunction are commonly encountered after irradiation therapy. While the curative abilities of ginseng root have been reported in prior studies, there is little known regarding its role in immunoregulation of intestinal repairability in cancer patients treated with irradiation. Our current study aims to closely examine the protective effects of ginseng-derived small molecule oligopeptides (Panax ginseng C. A. Mey.) (GOP) against irradiation-induced immune dysfunction and subsequent intestinal injury, using in vitro and in vivo models. Expectedly, irradiation treatment resulted in increased intestinal permeability along with mucosal injury in both Caco-2 cells and mice, probably due to disruption of the intestinal epithelial barrier, leading to high plasma lipopolysaccharide (LPS) and pro-inflammatory cytokines levels. However, when the cells were treated with GOP, this led to diminished concentration of plasma LPS and cytokines (IL-1 and TNF-α), suggesting its dampening effect on inflammatory and oxidative stress, and potential role in restoring normal baseline intestinal permeability. Moreover, the Caco-2 cells treated with GOP showed high trans-epithelial electrical resistance (TEER) and low FITC-dextran paracellular permeability when compared to the control group. This could be explained by the higher levels of tight junction proteins (ZO-1 and Occludin) expression along with reduced expression of the apoptosis-related proteins (Bax and Caspase-3) noticed in the GOP-treated cells, highlighting its role in preserving intestinal permeability, through prevention of their degradation while maintaining normal levels of expression. Further confirmatory in vivo data showed that GOP-treated mice exhibited high concentrations of lymphocytes (CD3, CD4, CD8) in the intestine, to rescue the irradiation-induced damage and restore baseline intestinal integrity. Therefore, we propose that GOP can be used as an adjuvant therapy to attenuate irradiation-induced immune dysfunction and intestinal injury in cancer patients.
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http://dx.doi.org/10.1038/s41598-018-32188-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141576PMC
September 2018

Depression promotes prostate cancer invasion and metastasis via a sympathetic-cAMP-FAK signaling pathway.

Oncogene 2018 05 8;37(22):2953-2966. Epub 2018 Mar 8.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China.

Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.
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http://dx.doi.org/10.1038/s41388-018-0177-4DOI Listing
May 2018

Microbiome, inflammation, epigenetic alterations, and mental diseases.

Am J Med Genet B Neuropsychiatr Genet 2017 Sep 10;174(6):651-660. Epub 2017 Jul 10.

Nutrition/Metabolism Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Major mental diseases such as autism, bipolar disorder, schizophrenia, and major depressive disorder are debilitating illnesses with complex etiologies. Recent findings show that the onset and development of these illnesses cannot be well described by the one-gene; one-disease approach. Instead, their clinical presentation is thought to result from the regulative interplay of a large number of genes. Even though the involvement of many genes are likely, up regulating and activation or down regulation and silencing of these genes by the environmental factors play a crucial role in contributing to their pathogenesis. Much of this interplay may be moderated by epigenetic changes. Similar to genetic mutations, epigenetic modifications such as DNA methylation, histone modifications, and RNA interference can influence gene expression and therefore may cause behavioral and neuronal changes observed in mental disorders. Environmental factors such as diet, gut microbiota, and infections have significant role in these epigenetic modifications. Studies show that bioactive nutrients and gut microbiota can alter either DNA methylation and histone signatures through a variety of mechanisms. Indeed, microbes within the human gut may play a significant role in the regulation of various elements of "gut-brain axis," via their influence on inflammatory cytokines and production of antimicrobial peptides that affect the epigenome through their involvement in generating short chain fatty acids, vitamin synthesis, and nutrient absorption. In addition, they may participate in-gut production of many common neurotransmitters. In this review we will consider the potential interactions of diet, gastrointestinal microbiome, inflammation, and epigenetic alterations in psychiatric disorders.
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http://dx.doi.org/10.1002/ajmg.b.32567DOI Listing
September 2017

An update on the epigenetics of psychotic diseases and autism.

Epigenomics 2015 ;7(3):427-49

Departments of Medicine (Biomedical Genetics Section), Genetics & Genomics, Boston University School of Medicine, Boston, MA 02118, USA.

The examination of potential roles of epigenetic alterations in the pathogenesis of psychotic diseases have become an essential alternative in recent years as genetic studies alone are yet to uncover major gene(s) for psychosis. Here, we describe the current state of knowledge from the gene-specific and genome-wide studies of postmortem brain and blood cells indicating that aberrant DNA methylation, histone modifications and dysregulation of micro-RNAs are linked to the pathogenesis of mental diseases. There is also strong evidence supporting that all classes of psychiatric drugs modulate diverse features of the epigenome. While comprehensive environmental and genetic/epigenetic studies are uncovering the origins, and the key genes/pathways affected in psychotic diseases, characterizing the epigenetic effects of psychiatric drugs may help to design novel therapies in psychiatry.
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http://dx.doi.org/10.2217/epi.14.85DOI Listing
September 2015

Effect of soy nuts and equol status on blood pressure, lipids and inflammation in postmenopausal women stratified by metabolic syndrome status.

Metabolism 2015 Feb 5;64(2):236-43. Epub 2014 Oct 5.

Division of Cardiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA. Electronic address:

Objective: Soy has been associated with lower risk of cardiovascular disease in Asian countries which consume daily soy. Our study examined whether production of equol, an estrogen metabolite, affected the ability of soy nuts to improve cardiovascular risk factors.

Materials/methods: Sixty postmenopausal women participated in a randomized, controlled, crossover trial of a Therapeutic Lifestyle Changes (TLC) diet alone and a TLC diet in which 0.5 cup of soy nuts (25 g of soy protein and 101 mg of aglycone isoflavones) replaced 25 g of nonsoy protein daily. Each diet was followed for 8 weeks at the end of which blood pressure (BP), lipid levels, adhesion molecules and inflammatory markers were measured.

Results: Women with MetS had significantly higher baseline body mass index (BMI), BP, triglycerides (TG), and soluble intercellular adhesion molecule (sICAM) than women without MetS. In women with MetS on the soy diet, significant reductions in diastolic BP (7.7%; P=0.02), TG (22.9%; P=0.02), C-reactive protein (CRP) (21.4%; P=0.01) and sICAM (7.3%; P=0.03) were noted among equol producers compared to levels on the TLC diet. No significant changes were noted in equol nonproducers. Similarly, in women without MetS, only equol producers had significant reductions in diastolic BP (3.3%, P=0.02) and CRP (30%, P=0.04). In contrast to women with MetS, TG and sICAM levels were not affected in women without MetS, a finding possibly related to lower baseline levels.

Conclusions: Cardiovascular risk reduction with soy nuts is not uniform and may be greater among producers of equol.
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http://dx.doi.org/10.1016/j.metabol.2014.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800063PMC
February 2015

Human selenium binding protein-1 (hSP56) is a negative regulator of HIF-1α and suppresses the malignant characteristics of prostate cancer cells.

BMB Rep 2014 Jul;47(7):411-6

Laboratory for Cell and Molecular Biology, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Oncology Therapeutic Area, Quintiles Translational, Arlington, MA 02476,USA.

In the present study, we demonstrate that ectopic expression of 56-kDa human selenium binding protein-1 (hSP56) in PC-3 cells that do not normally express hSP56 results in a marked inhibition of cell growth in vitro and in vivo. Down-regulation of hSP56 in LNCaP cells that normally express hSP56 results in enhanced anchorage-independent growth. PC-3 cells expressing hSP56 exhibit a significant reduction of hypoxia inducible protein (HIF)-1α protein levels under hypoxic conditions without altering HIF-1α mRNA (HIF1A) levels. Taken together, our findings strongly suggest that hSP56 plays a critical role in prostate cells by mechanisms including negative regulation of HIF-1α, thus identifying hSP56 as a candidate anti-oncogene product.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163856PMC
http://dx.doi.org/10.5483/bmbrep.2014.47.7.104DOI Listing
July 2014

Flavonoid ampelopsin inhibits the growth and metastasis of prostate cancer in vitro and in mice.

PLoS One 2012 5;7(6):e38802. Epub 2012 Jun 5.

Department of Pharmaceuticals, Fujian Health College, Fuzhou, Fujian, People's Republic of China.

The objective of this study was to evaluate the chemopreventive effect of a novel flavonoid, ampelopsin (AMP) on the growth and metastasis of prostate cancer cells. AMP showed the more potent activity in inhibiting the proliferation of androgen-sensitive LNCaP and, to less extent, androgen-independent PC-3 human prostate cancer cell lines in vitro, primarily by induction of apoptosis associated with down-regulation of bcl-2. On the other hand, AMP showed much less activity in inhibiting the proliferation of normal prostate epithelial cells than that of prostate cancer cell lines. AMP also inhibited the migration and invasion of PC-3 cells in vitro associated with down-regulation of CXCR4 expression. In the animal study using an orthotopic prostate tumor model, AMP (150 and 300 mg/kg body weight) inhibited the growth of PC-3 tumors and lymph node and lung metastases in a dose-dependent manner. Compared to the control mice, mice treated with AMP at 300 mg/kg BW had reduced final tumor weight by 49.2% (P<0.05), lymph node metastases by 54.5% (P = 0.3) and lung metastases by 93% (P<0.05), but had no apparent alteration on food intake or body weight. The in vivo anti-growth and anti-metastasis activities of AMP were associated with induction of apoptosis and inhibition of proliferation of prostate cancer cells, reduction of prostate tumor angiogenesis, and reduction of CXCR4 expression. Our results provide supporting evidence to warrant further investigation to develop AMP as a novel efficacious and safe candidate agent against progression and metastasis of prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038802PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367907PMC
October 2012

Tanshinones inhibit the growth of breast cancer cells through epigenetic modification of Aurora A expression and function.

PLoS One 2012 2;7(4):e33656. Epub 2012 Apr 2.

Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.

The objectives of this study were to evaluate the effects of tanshinones from a Chinese herb Salvia Miltiorrhiza on the growth of breast cancer cells, and to elucidate cellular and molecular mechanisms of action. Tanshinones showed the dose-dependent effect on the growth inhibition of breast cancer cells in vitro, with tanshinone I (T1) the most potent agent. T1 was also the only tanshinone to have potent activity in inhibiting the growth of the triple-negative breast cancer cell line MDA-MB231. T1 caused cell cycle arrests of both estrogen-dependent and estrogen-independent cell lines associated with alterations of cyclinD, CDK4 and cyclinB, and induced breast cancer cell apoptosis associated with upregulation of c-PARP and downregulation of survivin and Aurora A. Among these associated biomarkers, Aurora A showed the most consistent pattern with the anti-growth activity of tanshinones. Overexpression of Aurora A was also verified in breast tumors. The gene function assay showed that knockdown of Aurora A by siRNA dramatically reduced the growth-inhibition and apoptosis-induction activities of T1, suggesting Aurora A as an important functional target of T1 action. On the other hand, tanshinones had much less adverse effects on normal mammary epithelial cells. Epigenetic mechanism studies showed that overexpression of Aurora A gene in breast cancer cells was not regulated by gene promoter DNA methylation, but by histone acetylation. T1 treatment significantly reduced acetylation levels of histone H3 associated with Aurora A gene. Our results supported the potent activity of T1 in inhibiting the growth of breast cancer cells in vitro in part by downregulation of Aurora A gene function. Our previous studies also demonstrated that T1 had potent anti-angiogenesis activity and minimal side effects in vivo. Altogether, this study warrants further investigation to develop T1 as an effective and safe agent for the therapy and prevention of breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033656PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317444PMC
July 2012

Bioactive tanshinone I inhibits the growth of lung cancer in part via downregulation of Aurora A function.

Mol Carcinog 2013 Jul 2;52(7):535-43. Epub 2012 Mar 2.

Institute of Molecular & Experimental Therapeutics, East China Normal University, Shanghai, China.

Lung cancer is the leading cause of cancer death in the world, and the searching for novel efficacious and safe agents for lung cancer prevention remains the top priority of lung cancer research. In the present study, we evaluated the effect of bioactive tanshinones from a Chinese herb Salvia miltiorrhiza, cryptotanshinone (CT), tanshinone I (T1) and tanshinone IIA (T2A), on the proliferation inhibition of lung cancer cell lines. Tanshinones inhibited the lung cancer cell proliferation in vitro, with T1 the most potent, via cell cycle arrest and apoptosis induction. Gene function assay showed that Aurora A knockdown by siRNA dramatically eliminated the T1 activity in vitro, suggesting that Aurora A is an important functional target for T1. We further evaluated the effectiveness of T1 on the growth of H1299 nonsmall lung cancer cell in a mouse model. Tanshinone I inhibited the growth of H1299 lung tumor in a dose-dependent manner. Tanshinone I at 200 mg/kg body weight significantly reduced final tumor weight by 34% (P < 0.05) associated with inhibiting proliferation and inducing apoptosis of lung cancer cells by 54% (P < 0.001) and 193% (P < 0.001), respectively, inhibiting lung tumor angiogenesis by 72% (P < 0.001), and reducing Aurora A expression by 67% (P < 0.001). On the other hand, T1 did not significantly alter food intake or body weight. Our results provided experimental evidence to suggest that T1 may be an efficacious and safe agent for the prevention of lung cancer progression and Aurora A may be an important molecular target for T1 action against lung cancer.
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http://dx.doi.org/10.1002/mc.21888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376178PMC
July 2013

Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-κB inhibitors in ovarian cancer therapy.

PLoS One 2011 12;6(9):e24285. Epub 2011 Sep 12.

Medical Biochemistry Division, Faculty of Health Sciences, International Center for Genetic Engineering and Biotechnology, University of Cape Town, Cape Town, South Africa.

Several epidemiological studies have correlated the use of non-steroidal anti-inflammatory drugs (NSAID) with reduced risk of ovarian cancer, the most lethal gynecological cancer, diagnosed usually in late stages of the disease. We have previously established that the pro-apoptotic cytokine melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) is a crucial mediator of NSAID-induced apoptosis in prostate, breast, renal and stomach cancer cells. In this report we evaluated various structurally different NSAIDs for their efficacies to induce apoptosis and mda-7/IL-24 expression in ovarian cancer cells. While several NSAIDs induced apoptosis, Sulindac Sulfide and Diclofenac most potently induced apoptosis and reduced tumor growth. A combination of these agents results in a synergistic effect. Furthermore, mda-7/IL-24 induction by NSAIDs is essential for programmed cell death, since inhibition of mda-7/IL-24 by small interfering RNA abrogates apoptosis. mda-7/IL-24 activation leads to upregulation of growth arrest and DNA damage inducible (GADD) 45 α and γ and JNK activation. The NF-κB family of transcription factors has been implicated in ovarian cancer development. We previously established NF-κB/IκB signaling as an essential step for cell survival in cancer cells and hypothesized that targeting NF-κB could potentiate NSAID-mediated apoptosis induction in ovarian cancer cells. Indeed, combining NSAID treatment with NF-κB inhibitors led to enhanced apoptosis induction. Our results indicate that inhibition of NF-κB in combination with activation of mda-7/IL-24 expression may lead to a new combinatorial therapy for ovarian cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024285PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171406PMC
March 2012

JunD-mediated repression of GADD45α and γ regulates escape from cell death in prostate cancer.

Cell Cycle 2011 Aug 1;10(15):2583-91. Epub 2011 Aug 1.

International Center for Genetic Engineering and Biotechnology (ICGEB), Cancer Genomics Group, Cape Town, South Africa.

The AP-1 transcription factor complex has been implicated in a variety of biological processes including cell differentiation, proliferation, apoptosis and oncogenic transformation. We previously established that activation of the AP-1 family member JunD contributes to deregulated expression of the anti-apoptotic IL-6 gene in prostate cancer cells. We now show that inhibition of JunD in prostate cancer cells results in GADD45α- and γ-dependent induction of cell death and inhibition of tumor growth that is mediated at least partially via c-Jun N-terminal kinase (JNK) and p38 kinase activation. Apoptosis induction by dominant negative JunD and JNK and p38 kinase activation are impeded upon knock down of GADD45α and γ expression by small interfering RNA, most vividly demonstrating the central role of GADD45α and γ in JunD-mediated escape of prostate cancer cells from programmed cell death.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180197PMC
http://dx.doi.org/10.4161/cc.10.15.16057DOI Listing
August 2011

Smad4 inactivation promotes malignancy and drug resistance of colon cancer.

Cancer Res 2011 Feb 18;71(3):998-1008. Epub 2011 Jan 18.

Department of Medicine, Genetics & Genomics Graduate Program, Boston University School of Medicine, Boston, Massachusetts, USA.

SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity in advanced stage colon cancers. Although Smad4 is regarded as a signaling mediator of the TGFβ signaling pathway, its role as a major suppressor of colorectal cancer progression and the molecular events underlying this phenomenon remain elusive. Here, we describe the establishment and use of colon cancer cell line model systems to dissect the functional roles of TGFβ and Smad4 inactivation in the manifestation of a malignant phenotype. We found that loss of function of Smad4 and retention of intact TGFβ receptors could synergistically increase the levels of VEGF, a major proangiogenic factor. Pharmacologic inhibition studies suggest that overactivation of the TGFβ-induced MEK-Erk and p38-MAPK (mitogen-activated protein kinase) auxiliary pathways are involved in the induction of VEGF expression in SMAD4 null cells. Overall, SMAD4 deficiency was responsible for the enhanced migration of colon cancer cells with a corresponding increase in matrix metalloprotease 9 enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis, and resistance to 5'-fluoruracil-mediated apoptosis. Interestingly, Smad4 specifically interacts with hypoxia-inducible factor (HIF) 1α under hypoxic conditions providing a molecular basis for the differential regulation of target genes to suppress a malignant phenotype. In summary, our results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression. These findings are also consistent with targeting TGFβ-induced auxiliary pathways, such as MEK-ERK, and p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-3269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075468PMC
February 2011

Bioactive tanshinones in Salvia miltiorrhiza inhibit the growth of prostate cancer cells in vitro and in mice.

Int J Cancer 2011 Sep 3;129(5):1042-52. Epub 2010 Nov 3.

Nutrition/Metabolism Laboratory, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Searching for efficacious and safe agents for the chemoprevention and therapy of prostate cancer has become the top priority of research. The objective of this study was to determine the effects of a group of tanshinones from a Chinese herb Salvia Miltiorrhiza, cryptotanshinone (CT), tanshinone IIA (T2A) and tanshinone I (T1) on prostate cancer. The in vitro studies showed that these tanshinones inhibited the growth of human prostate cancer cell lines in a dose-dependent manner via cell cycle arrest and apoptosis induction. Among three compounds, T1 had the most potent activity with IC(50) s around 3-6 μM. On the other hand, tanshinones had much less adverse effects on the growth of normal prostate epithelial cells. The epigenetic pathway focused array assay identified Aurora A kinase as a possible target of tanshinone actions. The expression of Aurora A was overexpressed in prostate cancer cell lines. Moreover, knockdown of Aurora A in prostate cancer cells significantly decreased cell growth. Tanshinones significantly downregulated the Aurora A expression, suggesting Aurora A may be a functional target of tanshinones. Tanshinones, especially T1, also showed potent anti-angiogenesis activity in vitro and in vivo. Furthermore, T1 inhibited the growth of DU145 prostate tumor in mice associated with induction of apoptosis, decrease of proliferation, inhibition of angiogenesis and downregulation of Aurora A, whereas it did not alter food intake or body weight. Our results support that T1 may be an efficacious and safe chemopreventive or therapeutic agent against prostate cancer progression.
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http://dx.doi.org/10.1002/ijc.25678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032031PMC
September 2011

Polymorphisms of the ribonucleotide reductase M1 gene and sensitivity to platin-based chemotherapy in non-small cell lung cancer.

Lung Cancer 2009 Dec 21;66(3):344-9. Epub 2009 Mar 21.

School of Clinical Medical Science, Southeast University, 87 Dingjiaqiao Street, Nanjing 210009, PR China.

Ribonucleotide reductase catalyzes the rate limiting step of deoxyribonucleotide formation, a crucially important step in DNA synthesis and repair. The regulatory subunit M1 of ribonucleotide reductase (RRM1) is the necessary part of the RR function and controls substrate specificity and global on/off enzyme activity. Despite recent research progress, the role of RRM1 in lung cancer sensitivity to chemotherapeutics remains to be elucidated. This study was to investigate the relationship between polymorphisms of the RRM1 gene and sensitivity to platinum-based chemotherapy in non-small cell lung cancer (NSCLC). Genomic DNA samples from 214 NSCLC patients treated with platinum-based chemotherapy were used to determine the RRM1 promoter allelotypes. The RR37CC-RR524TT was the most frequent allelotype (38.50%), followed by RR37AC-RR524CT (26.76%) and RR37CC-RR524CT (14.95%). The average response rate for chemotherapy was 44.4%. The response rates to the treatment regimens in the RR37CC-RR524TT, RR37AC-RR524CT and RR37CC-RR524CT allelotypes were 43.9%, 52.6%, and 51.6%, respectively. The response rates to therapy among patients with RRM1 (-)524 allelotypes were significantly different (p=0.046), whereas that among patients with RRM1 (-)37 allelotypes were not significant. Further analysis showed that the response rate in the patients with RR524CT allelotype (52.3%) was the highest, compared with that with RR37CC-RR524TT allelotype (43.9%, p=0.28), or the Others (RR524CC and RR37AC-RR524TT, 30.2%, p=0.02). Our results suggest that the RR524CT allelotype may be associated with an increased sensitivity to platinum-based chemotherapy in NSCLC. Further research on determining RR524CT as a clinical marker for predicting response to platinum-based therapy in NSCLC patients is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2009.02.015DOI Listing
December 2009

Inflammation and foveolar hyperplasia are reduced by supplemental dietary glutamine during Helicobacter pylori infection in mice.

J Nutr 2009 May 4;139(5):912-8. Epub 2009 Mar 4.

Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

We recently showed that L-Gln protects cultured gastric cells from ammonia-induced cell death and predicted that Gln may also protect during Helicobacter pylori infection in vivo. Thus, the aim of this study was to test whether supplemental dietary Gln protects against H. pylori-associated pathology. For this, C57BL/6 mice were fed a purified diet consisting of 20.3% protein (1.9% Gln), 66% carbohydrate, and 5% fat or 25.3% protein (5% supplemental L-Gln; 6.9% total Gln), 61% carbohydrate, and 5% fat. After a 2-wk prefeeding period, mice were divided into sham-(uninfected) or H. pylori-infected groups. Body weight and food consumption were recorded weekly. Tissue histopathology, H. pylori colonization, serum IgG, and pro- and antiinflammatory cytokine mRNA expression were determined at 6, 12, and 20 wk postinfection (wkPI). Inflammation, antiinflammatory cytokine, and interleukin-1beta mRNA expression were significantly greater at 6 wkPI in H. pylori-infected mice fed supplemental Gln compared with those fed the control diet. At 20 wkPI, however, inflammation and foveolar hyperplasia were significantly lower in H. pylori-infected mice fed supplemental Gln compared with those fed the control diet. Body weight gain, food consumption, H. pylori colonization, and serum IgG did not differ in H. pylori-infected mice fed supplemental Gln compared with the control diet. Our data demonstrate that H. pylori-infected mice fed supplemental dietary Gln have reduced H. pylori-associated pathology in vivo that is accompanied by beneficial changes in the immune response to H. pylori early in infection. Thus, Gln supplementation may be an alternative therapy for reducing H. pylori-associated pathology.
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http://dx.doi.org/10.3945/jn.108.097790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714391PMC
May 2009

Epigenetic and pharmacoepigenomic studies of major psychoses and potentials for therapeutics.

Pharmacogenomics 2008 Dec;9(12):1809-23

Laboratory of Nutrition and Metabolism at BIDMC, Harvard Medical School, Boston, MA, USA.

Individuals with neuropsychiatric diseases have epigenetic programming disturbances, both in the brain, which is the primary affected organ, and in secondary tissues. Epigenetic modulations are molecular modifications made to DNA, RNA and proteins that fine-tune genotype into phenotype and do not include DNA base changes. For instance, gene-expression modulation is linked to epigenetic codes in chromatin that consist of post-replication DNA methylation and histone protein modifications (e.g., methylation, acetylation and so on), particularly in gene-promoter regions. Epigenetic coding is modulated globally, and in a gene-specific manner by environmental exposures that include nutrition, toxins, drugs and so on. Analysis of epigenetic aberrations in diseases helps to identify dysfunctional genes and pathways, establish more robust cause-effect relationships than genetic studies alone, and identify new pharmaceutical targets and drugs, including nucleic acid reagents such as inhibitory RNAs. The emerging science of pharmacoepigenomics can impact the treatment of psychiatric and other complex diseases. In fact, some therapeutics now in use target epigenetic programming. In the near future, epigenetic interventions should help stabilize affected individuals and lead to prevention strategies.
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http://dx.doi.org/10.2217/14622416.9.12.1809DOI Listing
December 2008

Effect of soy nuts on adhesion molecules and markers of inflammation in hypertensive and normotensive postmenopausal women.

Am J Cardiol 2008 Jul 16;102(1):84-6. Epub 2008 Apr 16.

Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Recently, it was shown that substituting soy nuts for nonsoy protein in a therapeutic lifestyle change (TLC) diet lowered systolic and diastolic blood pressure by 9.9% and 6.8%, respectively, in postmenopausal women with hypertension and by 5.2% and 2.9%, respectively, in normotensive postmenopausal women. In this study, to examine mechanisms for these reductions, markers of inflammation were measured, including soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, C-reactive protein, interleukin-6, and matrix metalloproteinase-9. Sixty healthy postmenopausal women (48 normotensive and 12 with hypertension) were randomized in a crossover design to a TLC diet alone or a TLC diet in which 0.5 cups of soy nuts (25 g soy protein and 101 mg aglycone isoflavones) replaced 25 g of nonsoy protein daily. Each diet was followed for 8 weeks. Compared with the TLC diet alone, levels of soluble vascular cell adhesion molecule-1 were significantly lower on the soy diet in women with hypertension (623.6 +/- 153.8 vs 553.8 +/- 114.4 ng/ml, respectively, p = 0.003), whereas no significant differences were observed in normotensive women. Soy nuts were associated with a trend toward reduction in C-reactive protein in normotensive women. No effect on levels of soluble intercellular adhesion molecule-1, interleukin-6, or matrix metalloproteinase-9 was observed. In conclusion, the reduction in soluble vascular cell adhesion molecule-1 with soy nuts in women with hypertension suggests an improvement in endothelial function that may reflect an overall improvement in the underlying inflammatory process underlying atherosclerosis.
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http://dx.doi.org/10.1016/j.amjcard.2008.02.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229929PMC
July 2008
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