PReD-Bench/PRed-Bench huggingface dataset:
Coadministration of Polypeptide-k and Curcumin Through Solid Self-Nanoemulsifying Drug Delivery System for Better Therapeutic Effect Against Diabetes Mellitus: Formulation, Optimization, Biopharmaceutical Characterization, and Pharmacodynamic Assessment
Authors: Sheetu Wadhwa
Ankit Kumar Yadav
Gowthamarajan Kuppusamy
Rajesh Kumar
Nethravathi Puttappa
Anindita De
Narendra Kumar Pandey
Varun Garg
Monica Gulati
Sachin Kumar Singh
Puneet Kaur
Bimlesh Kumar
Journal: Assay and Drug Development Technologies (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: diabetes; diffusion; dissolution; solid SNEDDS; spray drying
Affiliations: School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India., Department of Pharmaceutical Sciences, Washington State University, College of Pharmacy, Spokane, Washington., Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research (Deemed To Be University), Ootacamund, Tamilnadu, India.

Abstract:  An attempt has been made to prepare solid self-nanoemulsifying drug delivery system (SNEDDS) of polypeptide-k (PPK) and curcumin (CRM) using Labrafil M1944 CS as oil, Tween-80 as surfactant, Transcutol P as cosurfactant and Aerosil-200 (A-200) as porous hydrophobic carrier for improving their antidiabetic potential through oral delivery. Box-Behnken Design was used to optimize the liquid formulation based on the results of the mean droplet size, polydispersity index, percentage drug loading, and zeta potential. The formulation was adsorbed on Aerosil-200 through spray drying. The formulation showed desirable micromeritic, disintegration, and dissolution properties. About fivefold rise in the dissolution and permeation rate for drugs was observed from formulations vis a vis their unprocessed forms. The formulation was found to be stable with variation in pH, dilution, and temperature. The individual solid SNEDDS formulation of PPK and CRM and their combination were evaluated for antidiabetic potential and the results were compared with their naive forms on streptozotocin-induced diabetic rats. The results revealed better control of serum glucose level and other biochemical tests, such as liver parameters, lipid profiles, and antioxidant levels, as well as histological evaluation of pancreatic tissues in all the solid SNEDDS formulation as compared with their naive forms. 

Retracted: No

PubPeer comments:
 ![file] In Figure 12, I think the histopathology image panels were duplicated, especially with sub-panels (b, c, e, f, g) are duplicated for various treatment groups. There images were shown and reused in black color. Surprisingly, the same histopathological images were used as H E stained color images in their previous publication (Fig. 10) as below- http: dx.doi.org 10.1016 j.ejps.2017.08.022 ![file] ,
The therapeutic effect of monocyte chemoattractant protein-1 delivered by an electrospun scaffold for hyperglycemia and nephrotic disorders
Authors: Hong Fu
Cai Yong
Zhiren Fu
Zhengxin Wang
Zhijia Ni
Xiaomin Shi
Xing Zhang
Guoshan Ding
Hao Yin
Journal: International Journal of Nanomedicine (2014)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: MCP-1; diabetes; electrospinning; islet transplantation.
Affiliations: Department of Transplantation, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, People's Republic of China., Department of Surgery, Organ Transplant Center, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China., Department of Surgery, University of Chicago, Chicago, IL, USA., Department of Surgery, Organ Transplant Center, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China ; Department of Surgery, University of Chicago, Chicago, IL, USA.

Abstract:  Here, we investigated in diabetic mice the therapeutic effect of monocyte chemoattractant protein-1 (MCP-1), locally delivered by an electrospun scaffold, on transplanted islets. This therapeutic scheme is expected to exert a synergistic effect to ameliorate hyperglycemia and its associated nephrotic disorders. The cumulative amount of MCP-1 released from the scaffold in vitro within a 3-week window was 267.77 ± 32.18 ng, without a compromise in bioactivity. After 8 weeks following the transplantation, the islet population stimulated by MCP-1 was 35.14%± 7.23% larger than the non-stimulated islet population. Moreover, MCP-1 increased concentrations of blood insulin and C-peptide 2 by 49.83%± 5.29% and 43.49%± 9.21%, respectively. Consequently, the blood glucose concentration in the MCP-1 group was significantly lower than that in the control group at week 2 post-surgery. MCP-1 also enhanced the tolerance of sudden oral glucose challenge. The rapid decrease of blood creatinine, urine creatinine, and blood urea nitrogen suggested that the recovery of renal functions compromised by hyperglycemia could also be attributed to MCP-1. Our study shed new light on a synergistic strategy to alleviate hyperglycemia and nephrotic disorders in diabetic patients. 

Retracted: No

PubPeer comments:
 Figure 3A. Much more similar than you would expect. ![file] , 
 Too many dupliactions of in vivo images by the same team. ![file] , 
 Figure 7 B demonstated muine albumin depletion by urine in 24 hrs. Could the author explain how to collect all murine urine in a whole day? It seems to be an impossible mission. ![file] ,
Bmi‑1‑targeting suppresses osteosarcoma aggressiveness through the NF‑κB signaling pathway
Authors: Bin Luo
Jiaguo Liu
Meng Zhao
Journal: Molecular Medicine Reports (2017)
Discipline: CLINICAL MEDICINE
Keywords: Bone cancer; Bmi-1; osteosarcoma; antibody; therapy
Affiliations: Department of Orthopedics, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.

Abstract:  Bone cancer is one of the most lethal malignancies and the specific causes of tumor initiation are not well understood. B‑cell‑specific Moloney murine leukemia virus integration site 1 protein (Bmi‑1) has been reported to be associated with the initiation and progression of osteosarcoma, and as a prognostic indicator in the clinic. In the current study, a full‑length antibody targeting Bmi‑1 (AbBmi‑1) was produced and the preclinical value of Bmi‑1‑targeted therapy was evaluated in bone carcinoma cells and tumor xenograft mice. The results indicated that the Bmi‑1 expression level was markedly upregulated in bone cancer cell lines, and inhibition of Bmi‑1 by AbBmi‑1 reduced the invasiveness and migration of osteosarcoma cells. Overexpression of Bmi‑1 promoted proliferation and angiogenesis, and increased apoptosis resistance induced by cisplatin via the nuclear factor‑κB (NF‑κB) signal pathway. In addition, AbBmi‑1 treatment inhibited the tumorigenicity of osteosarcoma cells in vivo. Furthermore, AbBmi‑1 blocked NF‑κB signaling and reduced MMP‑9 expression. Furthermore, Bmi‑1 promoted osteosarcoma tumor growth, whereas AbBmi‑1 significantly inhibited osteosarcoma tumor growth in vitro and in vivo. Notably, AbBmi‑1 decreased the percentages of Ki67‑positive cells and terminal deoxynucleotidyl transferase dUTP nick end labeling‑positive cells in tumors compared with Bmi‑1‑treated and PBS controls. Notably, MMP‑9 and NF‑κB expression were downregulated by treatment with AbBmi‑1 in MG‑63 osteosarcoma cells. In conclusion, the data provides evidence that AbBmi‑1 inhibited the progression of osteosarcoma, suggesting that AbBmi‑1 may be a novel anti‑cancer agent through the inhibition of Bmi‑1 via activating the NF‑κB pathway in osteosarcoma. 

Retracted: No

PubPeer comments:
 Figure 2B. * Red boxes: Two panels appear to look more similar than expected ![file] ,
miR-144 suppresses the growth and metastasis of laryngeal squamous cell carcinoma by targeting IRS1
Authors: Chang-Lei Cui
Xiang-Yan Cui
Wei-Lun Chen
Zhong-Ying Fu
Xu Gong
Xin Wu
Journal: American journal of translational research (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: IRS1; growth; laryngeal squamous cell carcinoma; metastasis; miR-144.
Affiliations: Department of Otorhinolaryngology-Head and Neck Surgery, The First Hospital of Jilin University 3302 Jilin Main Road, Changchun 130021, China., Department of Anesthesiology, The First Hospital of Jilin University 3302 Jilin Main Road, Changchun 130021, China., Department of Hand Surgery, The First Hospital of Jilin University 3302 Jilin Main Road, Changchun 130021, China.

Abstract:  Increasing evidence has been suggested that microRNA-144 (miR-144) involved in tumor initiation, development and metastasis in various cancers. However, the biological roles and potential mechanisms of miR-144 in laryngeal squamous cell carcinoma (LSCC) remain unclear. In the present study, we discovered that miR-144 expression levels in LSCC tissues were significantly lower than those of adjacent normal tissues. Furthermore, overexpression of miR-144 in LSCC cells inhibited cell proliferation, colony formation, migration, and invasion in vitro. Consistently, stable overexpression of miR-144 suppressed the growth of LSCC cell xenografts in vivo. Bioinformatic algorithms and luciferase reporter assays confirmed that insulin receptor substrate 1 (IRS1) is a direct target of miR-144. Overexpreesion of miR-144 obviously decreased IRS1 expression thereby suppressing phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation. Further functional studies suggested that downregulation of IRS1 had similar effects as that of miR-144 overexpression, and upregulation of IRS1 partially reversed the inhibitory effects of miR-144. These findings suggested that miR-144 functioned as a tumor suppressor in LSCC by targeting IRS1, and that miR-144 might serve as a potential target for LSCC treatment. 

Retracted: No

PubPeer comments:
 Fig 2.  MiR-144 overexpression reduces proliferation and colony formation in Hep2 cells. A. qRT-PCR determined miR-144 expression in Hep2 cells transfected with miR-144 mimic or miR-NC. B. CCK8 assay were performed to determined cell proliferation in Hep2 cells transfected with miR-144 mimic or miR-NC. C. Colony formation was determined in Hep2 cells transfected with miR-144 mimic or miR-NC . ![file] Fig 2 from [Wu et al (2015)] .  Overexpression of miR-128 inhibits CRC cells proliferation and colony formation. (A) miR-128 mimic restored miR-128 expression in SW480 cells. (B) Cell proliferation was determined by CCK8 assay in SW480 cells following transfection with miR-128 mimic or miR-NC. (C) Cell colony formation was determined in SW480 cells following transfection with miR-128 mimics or miR-NC. ![file] Could the authors comment on the similarity of some of these panels? UPDATE: see also Figs 2C, 5C from [Yang et al (2018)] . ![file] ,
The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation
Authors: Qiuyu Wang
Jiandie D Lin
Lin Jiang
Siming Li
Liangyou Rui
Haifei Shi
Qi Zhu
Yuanyuan Xiao
Xuelian Xiong
Liang Guo
Hong Shen
Vishal P Sharma
Kunimasa Ohta
Journal: Nature metabolism (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Thermogenesis; Energy expenditure; Metabolic homeostasis; Tsukushi (TSK); Liver
Affiliations: Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109., Department of Molecular & Integrated Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109., Physiology and Neuroscience, Department of Biology, Miami University, OH 45056., Department of Developmental Neurobiology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.

Abstract:  Thermogenesis is an important contributor to whole body energy expenditure and metabolic homeostasis. Although circulating factors that promote energy expenditure are known, endocrine molecules that suppress energy expenditure have remained largely elusive. Here we show that Tsukushi (TSK) is a liver-enriched secreted factor that is highly inducible in response to increased energy expenditure. Hepatic Tsk expression and plasma TSK levels are elevated in obesity. TSK deficiency increases sympathetic innervation and norepinephrine release in adipose tissue, leading to enhanced adrenergic signaling and thermogenesis, attenuation of brown fat whitening and protection from diet-induced obesity in mice. Our work reveals TSK as part of a negative feedback mechanism that gates thermogenic energy expenditure and highlights TSK as a potential target for therapeutic intervention in metabolic disease. 

Retracted: No

PubPeer comments:
 Data from this article could not be reproduced by Mouchiroud et al., 2019 (The Hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis https: www.sciencedirect.com science article pii S2212877819309172)  TSK overexpression had no impact on BAT activation, body weight regulation, and glucose homeostasis , 
 The obesity-resistant phenotype of TSK knockout mice is extremely robust and has been observed in high-fat diet, western diet, and NASH diet models. TSK deficiency also corrects obesity and associated metabolic disorders caused by MC4R mutation. ,
Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice
Authors: Christin Schaaf
Craig H Selzman
Marcio Buffolo
Karla Maria Pires
E Dale Abel
J David Symons
James Cox
Sihem Boudina
Journal: Journal of Molecular and Cellular Cardiology (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Akt; Autophagy; Cardiac function; IGF-1 receptors; Insulin receptors
Affiliations: Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA., Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA., Department of Biochemistry, University of Utah, Salt Lake City, UT, USA., Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA., Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA. Electronic address: .

Abstract:  Autophagy plays an important role in the maintenance of normal heart function. However, the role of autophagy in the inulin resistant and diabetic heart is not well understood. Furthermore, the upstream signaling and the downstream targets involved in cardiac autophagy regulation during obesity and type 2 diabetes mellitus (T2DM) are not fully elucidated. The aim of this study was to measure autophagic flux and to dissect the upstream and downstream signaling involved in cardiac autophagy regulation in the hearts of obese T2DM mice. Our study demonstrated that cardiac autophagic flux is suppressed in the heart of obese diabetic (ob/ob) mice due to impaired autophagosome formation. We showed that suppression of autophagy was due to sustained activation of mTOR as we could restore cardiac autophagy by inhibiting mTOR. Moreover, the novel finding of this study is that while IGF-1 receptor-mediated Akt activation contributes to cardiac hypertrophy, it is not involved in mTOR activation and autophagy suppression in obesity and T2DM. In contrast, inhibition of ERK signaling abolished mTOR activation and restored autophagy in the heart of obese diabetic (ob/ob) mice. The study identifies mechanisms regulating cardiac autophagy in obesity and T2DM that are mediated by ERK/mTOR but are distinct from Akt. The findings are of significant importance as they demonstrate for the first time the contribution of IGF-1 receptors (IGF-1R) and Akt signaling in cardiac hypertrophy but not in cardiac autophagy regulation in obesity and T2DM. 

Retracted: No

PubPeer comments:
 Figure 2 - two copies of one XRD pattern, little vertical compression applied. ![file] ,
Defective Regulation of Autophagy upon Leucine Deprivation Reveals a Targetable Liability of Human Melanoma Cells In Vitro and In Vivo
Authors: Roberto Zoncu
David M Sabatini
Dohoon Kim
Joon-Ho Sheen
Journal: Cancer Cell (2011)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Autophagy; Cancer therapy; Leucine deprivation; Apoptosis; Melanoma cells
Affiliations: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.

Abstract:  Autophagy is of increasing interest as a target for cancer therapy. We find that leucine deprivation causes the caspase-dependent apoptotic death of melanoma cells because it fails to appropriately activate autophagy. Hyperactivation of the RAS-MEK pathway, which is common in melanoma, prevents leucine deprivation from inhibiting mTORC1, the main repressor of autophagy under nutrient-rich conditions. In an in vivo tumor xenograft model, the combination of a leucine-free diet and an autophagy inhibitor synergistically suppresses the growth of human melanoma tumors and triggers widespread apoptosis of the cancer cells. Together, our study represents proof of principle that anticancer effects can be obtained with a combination of autophagy inhibition and strategies to deprive tumors of leucine. 

Retracted: No

PubPeer comments:
 Fig. 3E contains two panels with the exact same pattern. Can the authors check whether it is a duplication? ![file] , 
 Hello, I am the first author on this manuscript. In a revised Figure 3E, we replaced the mistakenly placed image of Mel-STR control media data with the correct Mel-STMK control media data. The error does not impact the conclusions drawn from the experiments using the dual-color autophagy index reporter. I made this correction in consultation with David Sabatini. ![file] ,
miR-124 inhibits proliferation, migration and invasion of malignant melanoma cells via targeting versican
Authors: Ping Yang
Pingyuan Bu
Chengyuan Li
Journal: Experimental and Therapeutic Medicine (2017)
Discipline: CLINICAL MEDICINE
Keywords: melanoma; microRNA; tumor suppressor.
Affiliations: Department of Burn Surgery, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China., Department of Hematology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.

Abstract:  MicroRNA (miR)-124 has been implicated in malignant melanoma (MM). However, the detailed regulatory mechanism of miR-124 in the malignant phenotypes of MM cells has remained largely elusive. A total of 68 pairs of MM tissues and adjacent tissues were collected. Reverse-transcription quantitative polymerase chain reaction was used to examine the mRNA expression of versican as well as the expression of miR-124, and the protein expression of versican was assessed by western blot analysis. MTT, wound healing and Transwell assays were used to determine cell proliferation, migration and invasion, respectively. A bioinformatics analysis and a luciferase reporter assay were used to confirm the targeting association between miR-124 and versican. miR-124 was significantly downregulated in MM tissues compared with that in adjacent non-tumorous tissues, and decreased expression of miR-124 was associated with increased tumor thickness, advanced clinical stage and node metastasis of MM. Furthermore, the expression levels of miR-124 were also reduced in MM cell lines compared with normal human skin HACAT cells. Forced overexpression of miR-124 caused a significant reduction in the proliferation, migration and invasion of MM A375 cells. Versican was significantly upregulated in MM tissues and cell lines, and was identified as a novel target of miR-124 in A375 cells using a luciferase reporter gene assay, and miR-124 was revealed to negatively regulate the protein expression of versican in A375 cells. Overexpression of versican impaired the suppressive effects of miR-124 on the proliferation, migration and invasion of A375 cells. In conclusion, miR-124 inhibited the malignant phenotypes of MM cells at least partly via inhibition of versican. Therefore, the miR-124/versican axis may be used as a promising therapeutic target for inhibiting MM growth and metastasis. 

Retracted: No

PubPeer comments:
 Figs 2D, 5E. ![file] Colored rectangles for consistency with Figs 3C, 4D, 5D from [Hu et al (2016)] ... ![file] ...Figs 3 C,D and 8 C,D from [Liu et al (2017)] . ![file] Other manifestations are linked in those threads. ,
A novel route for F-box protein-mediated ubiquitination links CHIP to glycoprotein quality control
Authors: Henry L Paulson
Hsiang Wen
Kevin A Glenn
Victor M Miller
Rick F Nelson
Journal: Journal of Biological Chemistry (2006)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: SCF ubiquitin ligases; F-box proteins; substrate specificity; Fbx2; CHIP
Affiliations: Medical Scientist Training Program, Graduate Program in Neuroscience, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.

Abstract:  In SCF (Skp1/Cullin/F-box protein) ubiquitin ligases, substrate specificity is conferred by a diverse array of F-box proteins. Only in fully assembled SCF complexes, it is believed, can substrates bound to F-box proteins become ubiquitinated. Here we show that Fbx2, a brain-enriched F-box protein implicated in the ubiquitination of glycoproteins discarded from the endoplasmic reticulum, binds the co-chaperone/ubiquitin ligase CHIP (C terminus of Hsc-70-interacting protein) through a unique N-terminal PEST domain in Fbx2. CHIP facilitates the ubiquitination and degradation of Fbx2-bound glycoproteins, including unassembled NMDA receptor subunits. These findings indicate that CHIP acts with Fbx2 in a novel ubiquitination pathway that links CHIP to glycoprotein quality control in neurons. In addition, they expand the repertoire of pathways by which F-box proteins can regulate ubiquitination and suggest a new role for PEST domains as a protein interaction motif. 

Retracted: No

PubPeer comments:
 In Figure S2, the bands in blue boxes are duplicated. Although they are from the some group, the other bands for these two groups are different. Why are they the same? ![file] , 
 I agree with the concern about Figure S2 and have illustrated this with a false color image below. I also added the last author s email address in hopes that he will reply. *** ![file] ,
Expression of Death Receptor 4 Is Positively Regulated by MEK/ERK/AP-1 Signaling and Suppressed upon MEK Inhibition
Authors: Wei Zhou
Ping Yue
Henry Huang
Shi-Yong Sun
Jiusheng Deng
Weilong Yao
You-Take Oh
Liang Deng
Journal: Journal of Biological Chemistry (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: AP1 transcription factor (AP-1); DR4; MEK; Trail; apoptosis
Affiliations: From the Xiangya School of Medicine, Central South University, Changsha, Hunan, China 410008 and., the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322., the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322 .

Abstract:  Death receptor 4 (DR4) is a cell surface receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and triggers apoptosis upon ligation with TRAIL or aggregation. MEK/ERK signaling is a well known and the best-studied effector pathway downstream of Ras and Raf. This study focuses on determining the impact of pharmacological MEK inhibition on DR4 expression and elucidating the underlying mechanism. We found that several MEK inhibitors including MEK162, AZD6244, and PD0325901 effectively decreased DR4 protein levels including cell surface DR4 in different cancer cell lines. Accordingly, pre-treatment of TRAIL-sensitive cancer cell lines with a MEK inhibitor desensitized them to TRAIL-induced apoptosis. These results indicate that MEK inhibition negatively regulates DR4 expression and cell response to TRAIL-induced apoptosis. MEK inhibitors did not alter DR4 protein stability, rather decreased its mRNA levels, suggesting a transcriptional regulation. In contrast, enforced activation of MEK/ERK signaling by expressing ectopic B-Raf (V600E) or constitutively activated MEK1 (MEK1-CA) or MEK2 (MEK2-CA) activated ERK and increased DR4 expression; these effects were inhibited when a MEK inhibitor was present. Promoter analysis through deletion and mutation identified the AP-1 binding site as an essential response element for enhancing DR4 transactivation by MEK1-CA. Furthermore, inhibition of AP-1 by c-Jun knockdown abrogated the ability of MEK1-CA to increase DR4 promoter activity and DR4 expression. These results suggest an essential role of AP-1 in mediating MEK/ERK activation-induced DR4 expression. Our findings together highlight a previously undiscovered mechanism that positively regulates DR4 expression through activation of the MEK/ERK/AP-1 signaling pathway. 

Retracted: No

PubPeer comments:
 ![file] ,
Morphological and biochemical alterations in the jejunum following iodoacetamide-induced colitis in rats
Authors: Naim Khoury
Jean Marie Reimund
Michele Kedinger
Mona Diab Assef
Abdo Jurjus
Charlotte Jourdainne Foltzer
Kassem Barada
Journal: Canadian Journal of Physiology and Pharmacology (2006)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: morphological alterations; small intestine; large intestine; enterocyte enzymes; carriers
Affiliations: Faculty of Medicine, American University of Beirut, Riad El Solh, Beirut 1107-2020, Lebanon. , Faculty of Medicine, American University of Beirut, Riad El Solh, Beirut 1107-2020, Lebanon., INSERM Unité 381, Strasbourg, France.

Abstract:  This study aims to describe the morphological alterations in the small and large intestines as well as the expression of some enterocyte enzymes and carriers in a rat model of iodoacetamide-induced colitis. Biopsies from the large and small intestines were taken at 1, 2, 4, 8, and 16 days postinduction and studied by light microscopy. The expressions of lactase, sucrase, aminopeptidase, and Glut-5 in the jejunum were studied by immunohistochemistry. Gene expressions of enterocyte lactase and sucrase were determined by RT-PCR using specific oligonucleotides. Microscopic examination of the large intestines revealed manifestations concordant with inflammation. Such alterations peaked at 2 days, were maintained to a lesser extent for 4 days, regressed by 8 days, and healed by 16 days. In the jejunum, the expression of lactase, sucrase, and aminopeptidase decreased 2 days after colitis induction, and recovered 2 days later. Similarly, Glut-5 expression decreased transiently with partial recovery by day 8. Compared with sham, gene expression of jejunal brush border enzymes sucrase and lactase showed a 4-fold increase in lactase and a 9-fold increase in sucrase after 4 days. We conclude that colitis can induce significant functional abnormalities in distant noninflamed small bowel regions. 

Retracted: No

PubPeer comments:
 Figures 7 and 8. * Some sets of three lanes look more similar than expected, as marked with red and green boxes * The markers are shown separately, not attached to the lanes, making it hard to know the sizing of the bands. ![file] ,
Doxorubicin-induced apoptosis in H9c2 cardiomyocytes by NF-κB dependent PUMA upregulation
Authors: D Li
Y Yang
J Li
Y An
S-Q Zhang
Journal: European review for medical and pharmacological sciences (2013)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: doxorubicin; cardiotoxicity; apoptosis; NF-κB; PUMA
Affiliations: Department of Internal Medicine-Cardiovascular, The Affiliated Hospital of Medical College Qingdao University, Qingdao, Shandong, R.P. China. .

Abstract:  Objective: The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of solid tumors and malignant hematologic disease. Although the mechanism by which it causes cardiac injury is not yet known, apoptosis has been regarded as one of mechanisms underlying the cardiotoxic effects of doxorubicin. In the present study, we investigates the mechanisms of doxorubicin-induced apoptosis in H9c2 cardiomyocytes by NF-κB dependent PUMA upregulation. Materials and methods: H9c2 cardiac myocytes was treated with 5-50 mM concentration of doxorubicin for 72 hours. p65 siRNA or PUMA siRNA was transfected into H9c2 cardiac myocytes, then treated with 50 mM doxorubicin for 72 hours. Apoptotic cells were detected using Flow cytometric analysis. MTT cytotoxicity test was used to detect the effect of doxorubicin on H9c2 cardiac myocytes. PUMA expression was detected by western blot assay. NF-kappaB binding activities was detected using electrophoretic mobility shift assays (EMSA). Results: Doxorubicin promotes apoptosis and inhibits proliferation in H9c2 cardiac myocytes in a dose and time-dependent way. Doxorubicin treatment increased NF-kappaB binding activities and PUMA expression. Inhibition of p65 by p65 siRNA decreased PUMA expression of doxorubicin-induced. Furthermore, p65 siRNA or PUMA siRNA-mediated suppression of p65 or PUMA results in inhibition of apoptosis of doxorubicin-induced. Conclusions: It is demonstrated that PUMA is a direct target of NF-κB and mediates doxorubicin-induced apoptosis in vitro. 

Retracted: No

PubPeer comments:
 Finally - something I have been saying [since 2017] , they should have cited me - and even a [pubpeer thread] . Basically, they found that tumor RNA is not transferred to platelets. ** Our observations suggest that the phenomenon of tumour RNA transfer to platelets occurs below detection limit since even a very sensitive qPCR assay did not allow for a reliable detection of BRAF V600E in the platelet fraction. In contrast, EV fractions derived from the same patients allowed for detection of BRAF V600E in 10 of 12 blood specimens. ** ,
p14(ARF) regulates E2F activity
Authors: Nicholas B La Thangue
Oonagh Loughran
Sarah L Mason
Journal: Oncogene (2002)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: ARF protein; oncogenic signals; growth arrest; p53 pathway; MDM2
Affiliations: Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Davidson Building, University of Glasgow, Glasgow G12 8QQ, UK.

Abstract:  The ARF protein product of the ink4a/arf locus is induced by a variety of oncogenic signals. ARF facilitates growth arrest through the p53 pathway by hindering the down-regulation of p53 activity mediated by MDM2, through the formation of a protein complex with MDM2. Here we have explored the possibility that human p14(ARF) activity is integrated with growth regulating pathways other than p53, and report our results that p14(ARF) can control the activity of the E2F transcription factor. p14(ARF) regulates E2F activity in different cell-types, including p53(-/-)/mdm(-/-) MEFs, thus excluding that the effects of p14(ARF) are indirectly caused through MDM2 modulation. p14(ARF) down-regulates E2F-dependent transcription, and in cells undergoing E2F-dependent apoptosis prompts cell cycle arrest. p14(ARF) possesses multiple binding domains for E2F-1, one of which resides within the N-terminal region and coincides with the regulation of E2F activity. A mutational analysis of p14(ARF) indicates that the E2F-1 and MDM2 binding domains can be distinguished. These results highlight the potential interplay between p14(ARF) and E2F, and establish p14(ARF) as a pleiotrophic regulator of cell growth that acts by targetting at least two key pathways in the control of proliferation, namely E2F and p53. 

Retracted: No

PubPeer comments:
 Figure 2e. Vertical and horizontal changes in signal in E2F-1 panel, but not in p14 panel. ![file] ,
A combinatorial approach of a polypharmacological adjuvant 2-deoxy-D-glucose with low dose radiation therapy to quell the cytokine storm in COVID-19 management
Authors: Amitava Adhikary
Amit Verma
Gayle Woloschak
Rao V L Papineni
Bilikere S Dwarakanath
Journal: International Journal of Radiation Biology (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: 2-azido-2-deoxy-D-glucose; 2-deoxy-D-glucose (2-DG); COVID-19; Low dose radiation therapy (LDRT); severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Affiliations: PACT & Health LLC, Branford, CT, USA, Department of Chemistry, Oakland University, Rochester, MI, USA;, Department of Radiobiology, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA;, Department of Research and Development, Shanghai Proton and Heavy Ion Center, Shanghai, People's Republic of China;, Department of Surgery, University of Kansas Medical Center (Adjunct), and PACT & Health LLC, Branford, CT, USA

Abstract:  COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease and is the major cause of deaths worldwide. The clinical complexities (inflammation, cytokine storm, and multi-organ dysfunction) associated with COVID-19 poses constraints to effective management of critically ill COVID-19 patients. Low dose radiation therapy (LDRT) has been evaluated as a potential therapeutic modality for COVID-19 pneumonia. However, due to heterogeneity in disease manifestation and inter-individual variations, effective planning for LDRT is limited for this large-scale event. 2-deoxy-D-glucose (2-DG) has emerged as a polypharmacological agent for COVID-19 treatment due to its effects on the glycolytic pathway, anti-inflammatory action, and interaction with viral proteins. We suggest that 2-DG will be a potential adjuvant to enhance the efficacy of LDRT in the treatment of COVID-19 pneumonia. Withal, azido analog of 2-DG, 2-azido-2-DG can produce rapid catastrophic oxidative stress and quell the cytokine storm in critically ill COVID-19 patients. 

Retracted: No

PubPeer comments:
 Interestingly, this is another perspective paper suggesting the use of 2-deoxy-D -glucose in combination with low dose radiation therapy. Low dose radiation therapy for COVID-19 was supported by NIH NCI last year there was a preliminary report on this which has its own controversy. Use of 2-DG was speculated here. I am more concerned about this perspective, the authors speculate the use of 2-DG without having any experimental evidence (this paper was submitted in June 2020). Authors listed reference 40 - Papineni. 2020. Polypharmacological Agent(s) in combination with Radiation Therapy for Cancer and COVID-19 Treatment [USPTO Patent (in Prep)]. The google scholar link takes me to the current paper i am discussing here. A patent application in preparation is not accessible to authors at all - and how it can be a reference? Just yesterday, Drug Controller General of India has approved oral use of 2-DG in COVID-19 patients to reduce the use of oxygen. ,
Sulfur availability regulates plant growth via glucose-TOR signaling
Authors: Eric Linster
Markus Wirtz
Rüdiger Hell
Anna Speiser
Gernot Poschet
Mutsumi Wanatabe
Marleen Silbermann
Ilaria Forieri
Carsten Sticht
Yihan Dong
Arman Allboje Samami
Kazuki Saito
Aurelio A Teleman
Jean-Marc Deragon
Journal: Nature Communications (2017)
Discipline: Multidisciplinary
Keywords: TOR; amino acid sensing; metazoa; plants; Arabidopsis
Affiliations: Centre for Organismal Studies (COS), University of Heidelberg, Im Neuenheimer Feld 360, 69120, Heidelberg, Germany., Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan., Center for Medical Research, University of Mannheim, 68167, Mannheim, Germany., German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany., Laboratory of Genomes and Plant Development, Centre National de la Recherche Scientifique, University of Perpignan, 66100, Perpignan, France., Centre for Organismal Studies (COS), University of Heidelberg, Im Neuenheimer Feld 360, 69120, Heidelberg, Germany. .

Abstract:  Growth of eukaryotic cells is regulated by the target of rapamycin (TOR). The strongest activator of TOR in metazoa is amino acid availability. The established transducers of amino acid sensing to TOR in metazoa are absent in plants. Hence, a fundamental question is how amino acid sensing is achieved in photo-autotrophic organisms. Here we demonstrate that the plant Arabidopsis does not sense the sulfur-containing amino acid cysteine itself, but its biosynthetic precursors. We identify the kinase GCN2 as a sensor of the carbon/nitrogen precursor availability, whereas limitation of the sulfur precursor is transduced to TOR by downregulation of glucose metabolism. The downregulated TOR activity caused decreased translation, lowered meristematic activity, and elevated autophagy. Our results uncover a plant-specific adaptation of TOR function. In concert with GCN2, TOR allows photo-autotrophic eukaryotes to coordinate the fluxes of carbon, nitrogen, and sulfur for efficient cysteine biosynthesis under varying external nutrient supply. 

Retracted: No

PubPeer comments:
 The opening sentence of this article refers to the death of George Floyd as a  murder , which is something that has yet to be determined in court. The death was ruled a  homicide by the coroner; however, we are still waiting to see if the court rules it to have been  murder .  Homicide and  murder are not the same thing. In days of more responsible authorship and editorship, this would be referred to as a  killing or an  alleged murder until the trial in the courts has finished. **We aren t supposed to do trial by media in America.** (Further, the authors and the journal open themselves up to a libel claim in the case that Chauvin is found guilty of manslaughter, but not of murder, or if he is found not guilty altogether.) ,
Overexpression of Epsin 3 enhances migration and invasion of glioma cells by inducing epithelial‑mesenchymal transition
Authors: Xiuhua Yao
Biao Zhang
Qiaoli Wu
Pengcheng Kan
Zhuolin Ma
Yaru Wang
Wen Song
Chao Huang
Journal: Oncology Reports (2018)
Discipline: CLINICAL MEDICINE
Keywords: Epsin 3; Glioma; Glioblastoma; Oncogene; Migration
Affiliations: Graduate School, Tianjin Medical University, Tianjin 300021, P.R. China., Graduate School, Tianjin Medical University, Tianjin 300021, P.R. China., Clinical Laboratory, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin Huanhu Hospital, Tianjin 300350, P.R. China.

Abstract:  Epsin 3 (EPN3) expression is limited to gastric parietal cells and wounded or pathological tissue rather than normal brain tissue, and although it has been identified as an oncogene in estrogen receptor‑positive breast cancer and non‑small cell lung cancer, its function in cancer is poorly understood. The present study aimed to investigate the association of EPN3 expression with the clinicopathological features of patients with glioma, as well as the effects of EPN3 on glioblastoma cells and the potential molecular mechanisms for its effects on glioblastoma cell behavior. EPN3 expression was assessed by immunohistochemistry in tissue samples from 167 patients with glioma, as well as by western blotting in 5 glioblastoma cell lines. The U87 and U251 glioblastoma cell lines were used to investigate the effects of EPN3 on glioblastoma cell invasion and migration through gain and loss of EPN3 expression experiments; expression levels were further investigated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses. The results demonstrated that EPN3 expression levels were upregulated in high‑grade glioma tissues compared with low‑grade tissues, and there were varying expression levels of EPN3 in the five glioblastoma cell lines. No significant differences were observed in EPN3 expression in relation to patient age, sex or tumor size. Overexpression of EPN3 promoted glioblastoma cell migration and invasion, which we hypothesized was through affecting epithelial‑mesenchymal transition (EMT). RT‑qPCR and western blotting revealed that EPN3 upregulation increased the expression of Notch1 intracellular domain, β‑catenin, Slug, Twist and zinc‑finger E‑box‑binding homeobox (ZEB)‑1. These results suggested that EPN3 enhances the migration and invasion of glioblastoma cells by activating the transcription factors Slug, Twist and ZEB1, but not Snail 1 or ZEB2, to induce EMT in glioma cells; EPN3 involvement in the Notch and WNT/β‑catenin signaling pathways may contribute to this process. 

Retracted: No

PubPeer comments:
 Figure 3B appears to have an overlapping image: ![file] , 
 #1 Thank you very much for pointing out the error. We have carefully checked the raw data. and we had inadvertently mistake during the figure preparation. We are going tou00a0contact the journal and request for a correction.We aplogize for the mistake and any inconeniences caused. Thanks again. ,
FBX8 is a metastasis suppressor downstream of miR-223 and targeting mTOR for degradation in colorectal carcinoma
Authors: Y Ding
J L Hu
Y Q Ding
Y R Yan
J Yu
W T Liao
W J Zhou
Z C Zeng
X H Zhu
L Liang
F F Wang
X J Zhang
Journal: Cancer Letters (2017)
Discipline: CLINICAL MEDICINE
Keywords: Colorectal carcinoma; FBX8; Ubiquitin degradation; mTOR; miR-223.
Affiliations: Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China., Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Department of Pathology, Shenzhen University, Shenzhen 518060, People's Republic of China., Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China., Department of Radiotherapy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China., Department of Pathology, Southern Medical University, Guangzhou 510515, Guangdong Province, People's Republic of China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, Guangzhou 510515, Guangdong Province, People's Republic of China. Electronic address: .

Abstract:  F-box proteins are critical components of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligases and involved in the ubiquitin-dependent proteolytic pathway. Dysregulation of F-box protein-mediated proteolysis often leads to human malignancies. F-box only protein 8 (FBX8), a novel component of F-box proteins, is down-regulated in several tumors and closely correlates with tumor progression. However, little is known about its function, regulatory mechanisms and substrates in the progression of colorectal carcinoma (CRC). Combining microRNA (miRNA) assay, functional characterization, mechanistic studies with clinical validation, we identify FBX8 as a CRC metastasis suppressor downstream of miR-223, a metastasis promoting miRNA that is transcriptionally regulated by Myocyte enhancer factor (MEF2A). mTOR is a substrate of FBX8 for ubiquitin-mediated degradation and is required for FBX8 induced cell proliferation and invasion in CRC cells. FBX8 is down-regulated in human CRC tissues and correlates with MEF2A, miR-223 and mTOR expression levels. Notably, low FBX8 expression status in CRC tissues was a significant prognostic factor for poor overall survival of patients. These findings illustrate FBX8 as a metastasis suppressor that functions through mTOR signaling pathway and has significant prognostic power. 

Retracted: No

PubPeer comments:
 Figure 2J and Figure 3J appear to overlap. *** ![file] ,
Role of NOD2 and RIP2 in host–microbe interactions with Gram-negative bacteria: insights from the periodontal disease model
Authors: Dario S Zamboni
Dana T Graves
Mario J Ávila-Campos
Joao Ac Souza
Fernanda Rg Rocha
Sabrina G de Aquino
Marcell C Medeiros
Carlos Rossa Junior
Luis C Spolidorio
Journal: Innate Immunity (2016)
Discipline: IMMUNOLOGY
Keywords: Bone resorption; NOD2 signaling adaptor protein; inflammation; innate immunity; macrophages.
Affiliations: 1 Department of Diagnosis and Surgery, School of Dentistry at Araraquara-Univ Estadual Paulista (UNESP), Araraquara, SP, Brazil., 2 Department of Microbiology, Institute of Biomedical Sciences-Univ de Sao Paulo (USP), Sao Paulo, SP, Brazil., 3 Department of Physiology and Pathology, School of Dentistry at Araraquara-Univ Estadual Paulista (UNESP), Araraquara, SP, Brazil., 4 Department of Cell, Molecular Biology and Biopathogenic Agents, School of Medicine at Ribeirao Preto-Univ de Sao Paulo (USP), Ribeirao Preto, SP, Brazil., 5 Department of Periodontics, School of Dental Medicine-University of Pennsylvania, Philadelphia, PA, USA.

Abstract:  NOD2 is a member of the NLR family of proteins that participate in the activation of the innate immune response. RIP2 is a downstream kinase activated by both NOD1 and NOD2. There is scarcity of information regarding the relevance of NOD2 in periodontitis, a chronic inflammatory condition characterized by inflammatory bone resorption. We used NOD2-KO and RIP2-KO mice in a model of microbial-induced periodontitis. Heat-killed Aggregatibacter actinomycetemcomitans was injected in the gingival tissues three times/wk for 4 wk. Bone resorption was assessed by μCT analysis; osteoclasts were identified by immunohistochemical staining for TRAP and inflammation was assessed using a severity score system in H/E-stained sections. In vitro studies using primary macrophages assessed the response macrophages using qPCR-based array and multi-ligand ELISA. Bone resorption and osteoclastogenesis were significantly reduced in NOD2-KO mice. Severity of inflammation was not affected. qPCR-focused arrays and multi-ligand ELISA showed that expression of pro-inflammatory mediators was reduced in NOD2- and RIP2-deficient cells. RANKL-induced osteoclastogenesis was impaired in NOD2- and RIP2-deficient macrophages. We conclude that NOD2 is important for osteoclast differentiation and inflammatory bone resorption in vivo and also for the macrophage response to Gram-negative bacteria. 

Retracted: No

PubPeer comments:
 Publications share same set of images for control animals. Papers donu2019t even cite each other ![file] ![file] ,