International Journal of Molecular Sciences

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Open AccessReview

The Occurrence, Biosynthesis, and Molecular Structure of Proanthocyanidins and Their Effects on Legume Forage Protein Precipitation, Digestion and Absorption in the Ruminant Digestive Tract

by Arjan Jonker and Peiqiang Yu

Int. J. Mol. Sci. 2017, 18(5), 1105; https://doi.org/10.3390/ijms18051105 - 22 May 2017

Cited by 49 | Viewed by 9057

Abstract

Forages grown in temperate regions, such as alfalfa (Medicago sativa L.) and white clover (Trefolium repens L.), typically have a high nutritional value when fed to ruminants. Their high protein content and degradation rate result, however, in poor utilization of protein [...] Read more.

Forages grown in temperate regions, such as alfalfa (Medicago sativa L.) and white clover (Trefolium repens L.), typically have a high nutritional value when fed to ruminants. Their high protein content and degradation rate result, however, in poor utilization of protein from the forage resulting in excessive excretion of nitrogen into the environment by the animal. Proanthocyanindins (also known as condensed tannins) found in some forage legumes such as birdsfoot trefoil (Lotus corniculatus L.), bind to dietary protein and can improve protein utilization in the animal. This review will focus on (1) the occurrence of proanthocyanidins; (2) biosynthesis and structure of proanthocyanidins; (3) effects of proanthocyanidins on protein metabolism; (4) protein precipitating capacity of proanthocyanidins and their effects on true intestinal protein adsorption by ruminants; and (5) effect on animal health, animal performance and environmental emissions. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle

Dual-Component Gelatinous Peptide/Reactive Oligomer Formulations as Conduit Material and Luminal Filler for Peripheral Nerve Regeneration

by Caroline Kohn-Polster, Divya Bhatnagar, Derek J. Woloszyn, Matthew Richtmyer, Annett Starke, Alexandra H. Springwald, Sandra Franz, Michaela Schulz-Siegmund, Hilton M. Kaplan, Joachim Kohn and Michael C. Hacker

Int. J. Mol. Sci. 2017, 18(5), 1104; https://doi.org/10.3390/ijms18051104 - 21 May 2017

Cited by 15 | Viewed by 7669

Abstract

Toward the next generation of nerve guidance conduits (NGCs), novel biomaterials and functionalization concepts are required to address clinical demands in peripheral nerve regeneration (PNR). As a biological polymer with bioactive motifs, gelatinous peptides are promising building blocks. In combination with an anhydride-containing [...] Read more.

Toward the next generation of nerve guidance conduits (NGCs), novel biomaterials and functionalization concepts are required to address clinical demands in peripheral nerve regeneration (PNR). As a biological polymer with bioactive motifs, gelatinous peptides are promising building blocks. In combination with an anhydride-containing oligomer, a dual-component hydrogel system (cGEL) was established. First, hollow cGEL tubes were fabricated by a continuous dosing and templating process. Conduits were characterized concerning their mechanical strength, in vitro and in vivo degradation and biocompatibility. Second, cGEL was reformulated as injectable shear thinning filler for established NGCs, here tyrosine-derived polycarbonate-based braided conduits. Thereby, the formulation contained the small molecule LM11A-31. The biofunctionalized cGEL filler was assessed regarding building block integration, mechanical properties, in vitro cytotoxicity, and growth permissive effects on human adipose tissue-derived stem cells. A positive in vitro evaluation motivated further application of the filler material in a sciatic nerve defect. Compared to the empty conduit and pristine cGEL, the functionalization performed superior, though the autologous nerve graft remains the gold standard. In conclusion, LM11A-31 functionalized cGEL filler with extracellular matrix (ECM)-like characteristics and specific biochemical cues holds great potential to support PNR. Full article

(This article belongs to the Special Issue Peripheral Nerve Regeneration: From Bench to Bedside 2017)

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Open AccessReview

Immunobiology of Newcastle Disease Virus and Its Use for Prophylactic Vaccination in Poultry and as Adjuvant for Therapeutic Vaccination in Cancer Patients

by Volker Schirrmacher

Int. J. Mol. Sci. 2017, 18(5), 1103; https://doi.org/10.3390/ijms18051103 - 20 May 2017

Cited by 33 | Viewed by 6930

Abstract

Newcastle disease (ND) is one of the most important diseases of poultry worldwide. In the last decades, molecular research has gained a lot of new information about its causative agent, newcastle disease virus (NDV). In poultry industry, certain strains of NDV have [...] Read more.

Newcastle disease (ND) is one of the most important diseases of poultry worldwide. In the last decades, molecular research has gained a lot of new information about its causative agent, newcastle disease virus (NDV). In poultry industry, certain strains of NDV have been used for preventive vaccination for more than 60 years. NDV has also been applied to cancer patients with beneficial effects for about 50 years, but this is less well known. The molecular basis for these differential effects of NDV in birds and man have been elucidated in the last decades and are explained in this review. The anti-neoplastic and immune-stimulatory properties in non-permissive hosts such as mouse and man have to do with the strong type I interferon responses induced in these foreign species. Additionally, NDV has the potential to break various types of tumor resistances and also to affect liver fibrosis. A main section is devoted to the benefits of clinical application of NDV and NDV-based vaccines to cancer patients. Reverse genetics technology allowed developing NDV into a vector suitable for gene therapy. Examples will be provided in which genetically engineered NDV is being used successfully as vector against new emerging viruses. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessReview

Nanoparticles as Theranostic Vehicles in Experimental and Clinical Applications—Focus on Prostate and Breast Cancer

by Jörgen Elgqvist

Int. J. Mol. Sci. 2017, 18(5), 1102; https://doi.org/10.3390/ijms18051102 - 20 May 2017

Cited by 61 | Viewed by 11477

Abstract

Prostate and breast cancer are the second most and most commonly diagnosed cancer in men and women worldwide, respectively. The American Cancer Society estimates that during 2016 in the USA around 430,000 individuals were diagnosed with one of these two types of cancers, [...] Read more.

Prostate and breast cancer are the second most and most commonly diagnosed cancer in men and women worldwide, respectively. The American Cancer Society estimates that during 2016 in the USA around 430,000 individuals were diagnosed with one of these two types of cancers, and approximately 15% of them will die from the disease. In Europe, the rate of incidences and deaths are similar to those in the USA. Several different more or less successful diagnostic and therapeutic approaches have been developed and evaluated in order to tackle this issue and thereby decrease the death rates. By using nanoparticles as vehicles carrying both diagnostic and therapeutic molecular entities, individualized targeted theranostic nanomedicine has emerged as a promising option to increase the sensitivity and the specificity during diagnosis, as well as the likelihood of survival or prolonged survival after therapy. This article presents and discusses important and promising different kinds of nanoparticles, as well as imaging and therapy options, suitable for theranostic applications. The presentation of different nanoparticles and theranostic applications is quite general, but there is a special focus on prostate cancer. Some references and aspects regarding breast cancer are however also presented and discussed. Finally, the prostate cancer case is presented in more detail regarding diagnosis, staging, recurrence, metastases, and treatment options available today, followed by possible ways to move forward applying theranostics for both prostate and breast cancer based on promising experiments performed until today. Full article

(This article belongs to the Special Issue Diagnostic, Prognostic and Predictive Biomarkers in Prostate Cancer)

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Open AccessArticle

Analysis of Gene Expression Signatures in Cancer-Associated Stroma from Canine Mammary Tumours Reveals Molecular Homology to Human Breast Carcinomas

by Julia Ettlin, Elena Clementi, Parisa Amini, Alexandra Malbon and Enni Markkanen

Int. J. Mol. Sci. 2017, 18(5), 1101; https://doi.org/10.3390/ijms18051101 - 20 May 2017

Cited by 39 | Viewed by 11111

Abstract

Cancer-associated stroma (CAS) plays a key role in cancer initiation and progression. Spontaneously occurring canine mammary carcinomas are viewed as excellent models of human breast carcinomas. Considering the importance of CAS for human cancer, it likely plays a central role in canine tumours [...] Read more.

Cancer-associated stroma (CAS) plays a key role in cancer initiation and progression. Spontaneously occurring canine mammary carcinomas are viewed as excellent models of human breast carcinomas. Considering the importance of CAS for human cancer, it likely plays a central role in canine tumours as well. So far, however, canine CAS lacks characterisation, and it remains unclear whether the biology between CAS from canine and human tumours is comparable. In this proof-of-principle study, using laser-capture microdissection, we isolated CAS and normal stroma from 13 formalin-fixed paraffin embedded canine simple mammary carcinomas and analysed the expression of seven known human CAS markers by RT-qPCR (Reverse Transcription quantitative PCR) and validated some targets by immunohistochemistry. We found that Col1a1 (Collagen1α1), αSMA (alpha Smooth Muscle Actin), FAP (Fibroblast activation protein), PDGFRβ (Platelet-derived growth factor receptor beta), and Caveolin-1 were significantly upregulated in canine CAS, and the expression of CXCL12 (Stromal cell derived factor 1) significantly decreased, whereas MMP2 (Matrix Metalloproteinase 1) and IL6 (Interleukin 6) did not change. Our results suggest strong similarities in CAS biology in canine and human mammary carcinomas but also reveal some differences. To the best of our knowledge, this is the first report to provide a comprehensive expression analysis of the most important CAS markers in canine simple mammary carcinomas and further supports the validity of the dog as model for human cancer. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessReview

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

by Salvatore Giovanni Vitale, Antonio Simone Laganà, Stella Capriglione, Roberto Angioli, Valentina Lucia La Rosa, Salvatore Lopez, Gaetano Valenti, Fabrizio Sapia, Giuseppe Sarpietro, Salvatore Butticè, Carmelo Tuscano, Daniele Fanale, Alessandro Tropea and Diego Rossetti

Int. J. Mol. Sci. 2017, 18(5), 1100; https://doi.org/10.3390/ijms18051100 - 20 May 2017

Cited by 35 | Viewed by 8201

Abstract

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due [...] Read more.

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms “uterine carcinosarcoma”, “uterine Malignant Mixed Müllerian Tumors”, “target therapies”, “angiogenesis therapy”, “cancer stem cell therapy”, “prognostic biomarker”, and “novel antibody-drug”. Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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Open AccessArticle

High-Mobility Group Box 1 Disrupts Metabolic Function with Cigarette Smoke Exposure in a Ceramide-Dependent Manner

by Oliver J. Taylor, Mikayla O. Thatcher, Sheryl T. Carr, Jonathan L. Gibbs, Annie M. Trumbull, Mitchell E. Harrison, Duane R. Winden, Mackenzie J. Pearson, Trevor S. Tippetts, William L. Holland, Paul R. Reynolds and Benjamin T. Bikman

Int. J. Mol. Sci. 2017, 18(5), 1099; https://doi.org/10.3390/ijms18051099 - 20 May 2017

Cited by 10 | Viewed by 6130

Abstract

We have previously found that cigarette smoke disrupts metabolic function, in part, by increasing muscle ceramide accrual. To further our understanding of this, we sought to determine the role of the cytokine high-mobility group box 1 (HMGB1), which is increased with smoke exposure, [...] Read more.

We have previously found that cigarette smoke disrupts metabolic function, in part, by increasing muscle ceramide accrual. To further our understanding of this, we sought to determine the role of the cytokine high-mobility group box 1 (HMGB1), which is increased with smoke exposure, in smoke-induced muscle metabolic perturbations. To test this theory, we determined HMGB1 from lungs of human smokers, as well as from lung cells from mice exposed to cigarette smoke. We also treated cells and mice directly with HMGB1, in the presence or absence of myriocin, an inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in ceramide biosynthesis. Outcomes included assessments of insulin resistance and muscle mitochondrial function. HMGB1 was significantly increased in both human lungs and rodent alveolar macrophages. Further testing revealed that HMGB1 treatment elicited a widespread increase in ceramide species and reduction in myotube mitochondrial respiration, an increase in reactive oxygen species, and reduced insulin-stimulated Akt phosphorylation. Inhibition of ceramide biosynthesis with myriocin was protective. In mice, by comparing treatments of HMGB1 injections with or without myriocin, we found that HMGB1 injections resulted in increased muscle ceramides, especially C16 and C24, which were necessary for reduced muscle mitochondrial respiration and compromised insulin and glucose tolerance. In conclusion, HMGB1 may be a necessary intermediate in the ceramide-dependent metabolic consequences of cigarette smoke exposure. Full article

(This article belongs to the Special Issue Inhaled Pollutants Modulate Respiratory and Systemic Diseases)

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Open AccessArticle

The Lys-Asp-Tyr Triad within the Mite Allergen Der p 1 Propeptide Is a Critical Structural Element for the pH-Dependent Initiation of the Protease Maturation

by Andy Chevigné, Vincenzo Campizi, Martyna Szpakowska, David Bourry, Marie-Eve Dumez, José C. Martins, André Matagne, Moreno Galleni and Alain Jacquet

Int. J. Mol. Sci. 2017, 18(5), 1087; https://doi.org/10.3390/ijms18051087 - 20 May 2017

Cited by 6 | Viewed by 5456

Abstract

The major house dust mite allergen, Der p 1, is a papain-like cysteine protease expressed as an inactive precursor, proDer p 1, carrying an N-terminal propeptide with a unique structure. The maturation of the zymogen into an enzymatically-active form of Der p 1 [...] Read more.

The major house dust mite allergen, Der p 1, is a papain-like cysteine protease expressed as an inactive precursor, proDer p 1, carrying an N-terminal propeptide with a unique structure. The maturation of the zymogen into an enzymatically-active form of Der p 1 is a multistep autocatalytic process initiated under acidic conditions through conformational changes of the propeptide, leading to the loss of its inhibitory ability and its subsequent gradual cleavage. The aims of this study were to characterize the residues present in the Der p 1 propeptide involved in the initiation of the zymogen maturation process, but also to assess the impact of acidic pH on the propeptide structure, the activity of Der p 1 and the fate of the propeptide. Using various complementary enzymatic and structural approaches, we demonstrated that a structural triad K17p-D51p-Y19p within the N-terminal domain of the propeptide is essential for its stabilization and the sensing of pH changes. Particularly, the protonation of D51p under acidic conditions unfolds the propeptide through disruption of the K17p-D51p salt bridge, reduces its inhibition capacity and unmasks the buried residues K17p and Y19p constituting the first maturation cleavage site of the zymogen. Our results also evidenced that this triad acts in a cooperative manner with other propeptide pH-responsive elements, including residues E56p and E80p, to promote the propeptide unfolding and/or to facilitate its proteolysis. Furthermore, we showed that acidic conditions modify Der p 1 proteolytic specificity and confirmed that the formation of the first intermediate represents the limiting step of the in vitro Der p 1 maturation process. Altogether, our results provide new insights into the early events of the mechanism of proDer p 1 maturation and identify a unique structural triad acting as a stabilizing and a pH-sensing regulatory element. Full article

(This article belongs to the Special Issue Proteolysis in Allergic Sensitization and Th2 Response)

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Open AccessArticle

How Ketamine Affects Livers of Pregnant Mice and Developing Mice?

by Hoi Man Cheung, Tony Chin Hung Chow and David Tai Wai Yew

Int. J. Mol. Sci. 2017, 18(5), 1098; https://doi.org/10.3390/ijms18051098 - 19 May 2017

Cited by 4 | Viewed by 5904

Abstract

It is well known that ketamine abuse can induce liver damage in adult addicts, but the effects of ketamine abuse in pregnant mothers on their offspring have received less attention. In this study, we investigated the effects of 5-day ketamine injections (30 mg/kg) [...] Read more.

It is well known that ketamine abuse can induce liver damage in adult addicts, but the effects of ketamine abuse in pregnant mothers on their offspring have received less attention. In this study, we investigated the effects of 5-day ketamine injections (30 mg/kg) to pregnant Institute for Cancer Research (ICR) mice during early gestation or mid-gestation on the aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities of the mothers and the offspring. We also looked into whether administering ketamine treatment to the mothers had any effects on the extent of fibrosis, cell proliferation and cell death in the livers of the newborns. No significant biochemical differences were found between treatment and control groups in the mothers. In the offspring, ketamine treatment mildly suppressed the gradual increase of hepatic AST activity in neonates during liver maturation. Measurements of hepatic ALP activity and lactic acid dehydrogenase (LDH) immunoreactivity revealed that ketamine treatment may lead to increased cell death. Proliferation of liver cells of the newborns was also retarded as shown by reduced proliferative cell nuclear antigen (PCNA) immunoreactivity in the ketamine groups. No obvious fibrosis was evident. Thus, we demonstrated that ketamine administration to pregnant mice suppressed hepatic development and also induced liver cell death of the offspring. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessArticle

The 1-Tosylpentan-3-one Protects against 6-Hydroxydopamine-Induced Neurotoxicity

by Chien-Jen Kao, Wu-Fu Chen, Bo-Lin Guo, Chien-Wei Feng, Han-Chun Hung, Wen-Ya Yang, Chun-Sung Sung, Kuan-Hao Tsui, Hsin Chu, Nan-Fu Chen and Zhi-Hong Wen

Int. J. Mol. Sci. 2017, 18(5), 1096; https://doi.org/10.3390/ijms18051096 - 19 May 2017

Cited by 13 | Viewed by 7130

Abstract

Previous studies have demonstrated that the marine compound austrasulfone, isolated from the soft coral Cladiella australis, exerts a neuroprotective effect. The intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, attenuates several inflammatory responses. The present study uses in vitro and in [...] Read more.

Previous studies have demonstrated that the marine compound austrasulfone, isolated from the soft coral Cladiella australis, exerts a neuroprotective effect. The intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, attenuates several inflammatory responses. The present study uses in vitro and in vivo methods to investigate the neuroprotective effect of dihydroaustrasulfone alcohol-modified 1-tosylpentan-3-one (1T3O). Results from in vitro experiments show that 1T3O effectively inhibits 6-hydroxydopamine-induced (6-OHDA-induced) activation of both p38 mitogen-activated protein kinase (MAPK) and caspase-3 in SH-SY5Y cells; and enhances nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling. Hoechst staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining results reveal that 1T3O significantly inhibits 6-OHDA-induced apoptosis. In addition, the addition of an Akt or HO-1 inhibitor decreases the protective effect of 1T3O. Thus, we hypothesize that the anti-apoptotic activity of 1T3O in neuronal cells is mediated through the regulation of the Akt and HO-1 signaling pathways. In vivo experiments show that 1T3O can reverse 6-OHDA-induced reduction in locomotor behavior ability in zebrafish larvae, and inhibit 6-OHDA-induced tumor necrosis factor-alpha (TNF-α) increase at the same time. According to our in vitro and in vivo results, we consider that 1T3O exerts its anti-apoptotic activities at SH-SY5Y cells after 6-OHDA challenges, probably via the regulation of anti-oxidative signaling pathways. Therefore, this compound may be a promising therapeutic agent for neurodegenerations. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2017)

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Open AccessArticle

Isorhynchophylline, a Potent Plant Alkaloid, Induces Apoptotic and Anti-Metastatic Effects in Human Hepatocellular Carcinoma Cells through the Modulation of Diverse Cell Signaling Cascades

by Hanwool Lee, Seung Ho Baek, Jong Hyun Lee, Chulwon Kim, Jeong-Hyeon Ko, Seok-Geun Lee, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Woong Mo Yang, Jae-Young Um, Gautam Sethi and Kwang Seok Ahn

Int. J. Mol. Sci. 2017, 18(5), 1095; https://doi.org/10.3390/ijms18051095 - 19 May 2017

Cited by 47 | Viewed by 7129

Abstract

Isorhynchophylline (Rhy) is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of [...] Read more.

Isorhynchophylline (Rhy) is an active pharmacological component of Uncaria rhynchophylla that has been reported previously to exert significant antihypertensive and neuroprotective effects. However, very little is known about its potential anti-cancer activities. This study was carried out to evaluate the anticancer effects of Rhy against various human carcinoma cell lines. We found that Rhy exhibited substantial cytotoxic effect against human hepatocellular carcinoma HepG2 cells when compared with other human carcinoma cell lines including those of lung, pancreas, prostate, head and neck, breast, multiple myeloma, brain and renal cell carcinoma. Rhy induced apoptosis as characterized by accumulation of cells in sub G1 phase; positive Annexin V binding; activation of caspase-8, -9, and -3; and cleavage of PARP (poly-ADP ribose polymerase). This effect of Rhy correlated with the down-regulation of various proteins that mediated cell proliferation, cell survival, metastasis, and angiogenesis. Moreover, cell proliferation, migration, and constitutive CXCR4 (C-X-C chemokine receptor type 4), MMP-9 (Matrix metallopeptidase-9), and MMP-2 expression were inhibited upon Rhy treatment. We further investigated the effect of Rhy on the oncogenic cell signaling cascades through phospho-kinase array profiling assay. Rhy was found to abrogate phospho-p38, ERK, JNK, CREB, c-Jun, Akt, and STAT3 signals, but interestingly enhanced phospho-p53 signal. Overall, our results indicate, for the first time, that Rhy could exert anticancer and anti-metastatic effects through regulation of multiple signaling cascades in hepatocellular carcinoma cells. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals and Functional Food Ingredients in Fruits and Vegetables 2017)

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Open AccessArticle

The Impact of SMAD4 Loss on Outcome in Patients with Advanced Pancreatic Cancer Treated with Systemic Chemotherapy

by Steffen Ormanns, Michael Haas, Anna Remold, Stephan Kruger, Stefan Holdenrieder, Thomas Kirchner, Volker Heinemann and Stefan Boeck

Int. J. Mol. Sci. 2017, 18(5), 1094; https://doi.org/10.3390/ijms18051094 - 19 May 2017

Cited by 20 | Viewed by 6440

Abstract

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and [...] Read more.

The role of the tumor suppressor mothers against decapentaplegic homolog 4 (SMAD4) has not yet been defined in patients (pts) with advanced pancreatic cancer (aPC). This translational research study was designed to evaluate the impact of tumoral SMAD4 loss on clinicopathological parameters and outcome in PC patients receiving palliative chemotherapy. Using immunohistochemistry, we examined SMAD4 expression in tumor tissue of 143 aPC pts treated within completed prospective clinical and biomarker trials. In uni- and multivariate analyses, SMAD4 expression status was correlated to clinicopathological patient characteristics and outcome. At chemotherapy initiation, 128 pts had metastatic PC; most pts (n = 99) received a gemcitabine-based regimen. SMAD4 loss was detected in 92 pts (64%); patient characteristics such as gender, age, tumor grading, disease stage or number of metastatic sites had no significant impact on tumoral SMAD4 status. In univariate analyses, SMAD4 loss had no impact on overall survival (hazard ratio (HR) 1.008, p = 0.656); however, we observed a prolonged progression-free survival (HR 1.565, p = 0.038) in pts with tumoral SMAD4 loss. This finding was confirmed in multivariate analyses (HR 1.790, p = 0.040), but only for gemcitabine-treated pts. In contrast to previous studies in resectable PC, loss of SMAD4 expression was not associated with a negative outcome in patients with advanced PC receiving systemic chemotherapy. Full article

(This article belongs to the Special Issue Pancreatic Disorders)

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Open AccessReview

A Review of the Impact of Maternal Obesity on the Cognitive Function and Mental Health of the Offspring

by Laura Contu and Cheryl A. Hawkes

Int. J. Mol. Sci. 2017, 18(5), 1093; https://doi.org/10.3390/ijms18051093 - 19 May 2017

Cited by 118 | Viewed by 14041

Abstract

Globally, more than 20% of women of reproductive age are currently estimated to be obese. Children born to obese mothers are at higher risk of developing obesity, coronary heart disease, diabetes, stroke, and asthma in adulthood. Increasing clinical and experimental evidence suggests that [...] Read more.

Globally, more than 20% of women of reproductive age are currently estimated to be obese. Children born to obese mothers are at higher risk of developing obesity, coronary heart disease, diabetes, stroke, and asthma in adulthood. Increasing clinical and experimental evidence suggests that maternal obesity also affects the health and function of the offspring brain across the lifespan. This review summarizes the current findings from human and animal studies that detail the impact of maternal obesity on aspects of learning, memory, motivation, affective disorders, attention-deficit hyperactivity disorder, autism spectrum disorders, and neurodegeneration in the offspring. Epigenetic mechanisms that may contribute to this mother–child interaction are also discussed. Full article

(This article belongs to the Special Issue Nutrigenomics of Risk Factors for Disease)

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Open AccessArticle

A Novel Combination of Withaferin A and Sulforaphane Inhibits Epigenetic Machinery, Cellular Viability and Induces Apoptosis of Breast Cancer Cells

by Kendra J. Royston, Neha Udayakumar, Kayla Lewis and Trygve O. Tollefsbol

Int. J. Mol. Sci. 2017, 18(5), 1092; https://doi.org/10.3390/ijms18051092 - 19 May 2017

Cited by 72 | Viewed by 8854

Abstract

With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction [...] Read more.

With cancer often classified as a disease that has an important epigenetic component, natural compounds that have the ability to regulate the epigenome become ideal candidates for study. Humans have a complex diet, which illustrates the need to elucidate the mechanisms of interaction between these bioactive compounds in combination. The natural compounds withaferin A (WA), from the Indian winter cherry, and sulforaphane (SFN), from cruciferous vegetables, have numerous anti-cancer effects and some report their ability to regulate epigenetic processes. Our study is the first to investigate the combinatorial effects of low physiologically achievable concentrations of WA and SFN on breast cancer cell proliferation, histone deacetylase1 (HDAC1) and DNA methyltransferases (DNMTs). No adverse effects were observed on control cells at optimal concentrations. There was synergistic inhibition of cellular viability in MCF-7 cells and a greater induction of apoptosis with the combinatorial approach than with either compound administered alone in both MDA-MB-231 and MCF-7 cells. HDAC expression was down-regulated at multiple levels. Lastly, we determined the combined effects of these bioactive compounds on the pro-apoptotic BAX and anti-apoptotic BCL-2 and found decreases in BCL-2 and increases in BAX. Taken together, our findings demonstrate the ability of low concentrations of combinatorial WA and SFN to promote cancer cell death and regulate key epigenetic modifiers in human breast cancer cells. Full article

(This article belongs to the Special Issue Cancer Epigenetics)

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Open AccessArticle

Exploration of the Esophageal Mucosal Barrier in Non-Erosive Reflux Disease

by Nicolaas F. Rinsma, Ricard Farré, Fred J. Troost, Montserrat Elizalde, Daniel Keszthelyi, Zsuzsanna Helyes, Ad A. Masclee and José M. Conchillo

Int. J. Mol. Sci. 2017, 18(5), 1091; https://doi.org/10.3390/ijms18051091 - 19 May 2017

Cited by 13 | Viewed by 5491

Abstract

In the absence of visible mucosal damage, it is hypothesized that the esophageal mucosal barrier is functionally impaired in patients with non-erosive reflux disease (NERD). The aim of the present study was to perform an exploratory analysis of the mucosal barrier in NERD [...] Read more.

In the absence of visible mucosal damage, it is hypothesized that the esophageal mucosal barrier is functionally impaired in patients with non-erosive reflux disease (NERD). The aim of the present study was to perform an exploratory analysis of the mucosal barrier in NERD compared to erosive esophagitis (EE) and controls. A second aim was to explore TRPV1 gene transcription in relation to the mucosal barrier function and heartburn symptoms. In this prospective study, 10 NERD patients, 11 patients with active erosive esophagitis and 10 healthy volunteers were included. Biopsies from non-eroded mucosa were obtained for (1) ex vivo analyses (Ussing chamber) of transepithelial electrical resistance (TEER) and permeability (2) gene transcription of tight-junction proteins and transient receptor potential vanilloid subfamily member 1 (TRPV1). No differences in TEER or permeability were found between NERD and healthy volunteers, whereas TEER was lower in patients with erosive esophagitis. TRPV1 gene transcription was not significantly different between EE, NERD and controls. Conclusions: esophageal mucosal barrier function and TRPV1 transcription is not significantly altered in NERD patients. Future research is needed to explore other potential mechanisms that may account for the high symptom burden in these patients. Full article

(This article belongs to the Special Issue Gastroesophageal Reflux Disease: It Is More than Just Heartburn)

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Open AccessArticle

Synthesis and Characterization of Dual-Sensitive Fluorescent Nanogels for Enhancing Drug Delivery and Tracking Intracellular Drug Delivery

by Szu-Yuan Wu, Tilahun Ayane Debele, Yu-Chih Kao and Hsieh-Chih Tsai

Int. J. Mol. Sci. 2017, 18(5), 1090; https://doi.org/10.3390/ijms18051090 - 19 May 2017

Cited by 11 | Viewed by 5991

Abstract

Here, dual-sensitive fluorescent branched alginate-polyethyleneimine copolymer (bAPSC) nanogels were synthesized from thiolated alginate and stearoyl-derivatized branched polyethyleneimine. The formation of bAPSC conjugates was confirmed through proton nuclear magnetic resonance and Fourier transform infrared spectroscopy, whereas dynamic light scattering was used to measure the [...] Read more.

Here, dual-sensitive fluorescent branched alginate-polyethyleneimine copolymer (bAPSC) nanogels were synthesized from thiolated alginate and stearoyl-derivatized branched polyethyleneimine. The formation of bAPSC conjugates was confirmed through proton nuclear magnetic resonance and Fourier transform infrared spectroscopy, whereas dynamic light scattering was used to measure the particle size and ζ potential of the nanogels. The fluorescent properties of the nanogels were confirmed through fluorescent spectroscopy and microscopy. In addition to the excitation-dependent fluorescence behavior, the fluorescence emission intensity of bAPSC was altered by both pH and γ-irradiation. This intensity was higher at a lower pH than at a higher pH, and it slightly decreased after γ-irradiation. The drug loading and encapsulation efficiency of bAPSC were 25.9% and 11.2%, respectively. An in vitro drug release study revealed that the synthesized nanogels release their doxorubicin (Dox) contents in a time-dependent manner, and the drug release was higher after 96 h of incubation. Approximately 43.74% and 88.36% of Dox was released after 96 h of incubation at pH 5.5 in the absence and presence of glutathione (GSH), respectively. However, relatively lower drug release, approximately 21.6% and 16%, was observed in the presence and absence of GSH at pH 7.4, respectively. Fluorescence microscopy confirmed that Dox-loaded bAPSC nanogels were internalized by HeLa cells, and drug distribution was easily tracked using fluorescent materials without additional probing agents. Moreover, cellular cytotoxicity and hemolysis results revealed less cytotoxicity and hemocompatibility of the synthesized nanogels, confirming that they are the most favorable alternative drug carriers for drug delivery systems. Full article

(This article belongs to the Section Materials Science)

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Open AccessArticle

Autophagy Regulates Proteasome Inhibitor-Induced Pigmentation in Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells

by Kati Juuti-Uusitalo, Ali Koskela, Niko Kivinen, Johanna Viiri, Juha M. T. Hyttinen, Mika Reinisalo, Arto Koistinen, Hannu Uusitalo, Debasish Sinha, Heli Skottman and Kai Kaarniranta

Int. J. Mol. Sci. 2017, 18(5), 1089; https://doi.org/10.3390/ijms18051089 - 19 May 2017

Cited by 11 | Viewed by 7759

Abstract

The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal [...] Read more.

The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal degradation with MG-132 or autophagy with bafilomycin A1 increased the accumulation of premelanosomes and autophagic structures in human embryonic stem cell (hESC)-derived RPE cells. Consequently, upregulation of the autophagy marker p62 (also known as sequestosome-1, SQSTM1) was confirmed in Western blot and perinuclear staining. Interestingly, cells treated with the adenosine monophosphatedependent protein kinase activator, AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), decreased the proteasome inhibitor-induced accumulation of premelanosomes, increased the amount of autophagosomes and eradicated the protein expression of p62 and LC3 (microtubule-associated protein 1A/1B-light chain 3). These results revealed that autophagic machinery is functional in hESC-RPE cells and may regulate cellular pigmentation with proteasomes. Full article

(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)

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Open AccessArticle

Ginsenoside Rb2 Alleviates Hepatic Lipid Accumulation by Restoring Autophagy via Induction of Sirt1 and Activation of AMPK

by Qi Huang, Ting Wang, Liu Yang and He-Yao Wang

Int. J. Mol. Sci. 2017, 18(5), 1063; https://doi.org/10.3390/ijms18051063 - 19 May 2017

Cited by 97 | Viewed by 8022

Abstract

Although Panax ginseng is a famous traditional Chinese medicine and has been widely used to treat a variety of metabolic diseases including hyperglycemia, hyperlipidemia, and hepatosteatosis, the effective mediators and molecular mechanisms remain largely unknown. In this study we found that ginsenoside Rb2, [...] Read more.

Although Panax ginseng is a famous traditional Chinese medicine and has been widely used to treat a variety of metabolic diseases including hyperglycemia, hyperlipidemia, and hepatosteatosis, the effective mediators and molecular mechanisms remain largely unknown. In this study we found that ginsenoside Rb2, one of the major ginsenosides in Panax ginseng, was able to prevent hepatic lipid accumulation through autophagy induction both in vivo and in vitro. Treatment of male db/db mice with Rb2 significantly improved glucose tolerance, decreased hepatic lipid accumulation, and restored hepatic autophagy. In vitro, Rb2 (50 µmol/L) obviously increased autophagic flux in HepG2 cells and primary mouse hepatocytes, and consequently reduced the lipid accumulation induced by oleic acid in combination with high glucose. Western blotting analysis showed that Rb2 partly reversed the high fatty acid in combination with high glucose (OA)-induced repression of autophagic pathways including AMP-activated protein kinase (AMPK) and silent information regulator 1 (sirt1). Furthermore, pharmacological inhibition of the sirt1 or AMPK pathways attenuated these beneficial effects of Rb2 on hepatic autophagy and lipid accumulation. Taken together, these results suggested that Rb2 alleviated hepatic lipid accumulation by restoring autophagy via the induction of sirt1 and activation of AMPK, and resulted in improved nonalcoholic fatty liver disease (NAFLD) and glucose tolerance. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle

Inhibition of Autophagy Promotes Salinomycin-Induced Apoptosis via Reactive Oxygen Species-Mediated PI3K/AKT/mTOR and ERK/p38 MAPK-Dependent Signaling in Human Prostate Cancer Cells

by Kwang-Youn Kim, Kwang-Il Park, Sang-Hun Kim, Sun-Nyoung Yu, Sul-Gi Park, Young Woo Kim, Young-Kyo Seo, Jin-Yeul Ma and Soon-Cheol Ahn

Int. J. Mol. Sci. 2017, 18(5), 1088; https://doi.org/10.3390/ijms18051088 - 18 May 2017

Cited by 164 | Viewed by 12272

Abstract

Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly [...] Read more.

Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly elucidated the underlying mechanisms. Therefore, in this study, we assessed whether salinomycin, a promising anticancer drug, induces apoptosis and elucidated potential antitumor mechanisms in chemo-resistant prostate cancer cells. Cell viability assay, Western blot, annexin V/propidium iodide assay, acridine orange (AO) staining, caspase-3 activity assay, reactive oxygen species (ROS) production, and mitochondrial membrane potential were assayed. Our data showed that salinomycin alters the sensitivity of prostate cancer cells to autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, enhanced the salinomycin-induced apoptosis. Notably, salinomycin decreased phosphorylated of AKT and phosphorylated mammalian target of rapamycin (mTOR) in prostate cancer cells. Pretreatment with LY294002, an autophagy and PI3K inhibitor, enhanced the salinomycin-induced apoptosis by decreasing the AKT and mTOR activities and suppressing autophagy. However, pretreatment with PD98059 and SB203580, an extracellular signal-regulated kinases (ERK), and p38 inhibitors, suppressed the salinomycin-induced autophagy by reversing the upregulation of ERK and p38. In addition, pretreatment with N-acetyl-l-cysteine (NAC), an antioxidant, inhibited salinomycin-induced autophagy by suppressing ROS production. Our results suggested that salinomycin induces apoptosis, which was related to ROS-mediated autophagy through regulation of the PI3K/AKT/mTOR and ERK/p38 MAPK signaling pathways. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)

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Open AccessArticle

Cellular Repair of DNA–DNA Cross-Links Induced by 1,2,3,4-Diepoxybutane

by Lisa N. Chesner, Amanda Degner, Dewakar Sangaraju, Shira Yomtoubian, Susith Wickramaratne, Bhaskar Malayappan, Natalia Tretyakova and Colin Campbell

Int. J. Mol. Sci. 2017, 18(5), 1086; https://doi.org/10.3390/ijms18051086 - 18 May 2017

Cited by 11 | Viewed by 5800

Abstract

Xenobiotic-induced interstrand DNA–DNA cross-links (ICL) interfere with transcription and replication and can be converted to toxic DNA double strand breaks. In this work, we investigated cellular responses to 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links induced by 1,2,3,4-diepoxybutane (DEB). High pressure liquid chromatography [...] Read more.

Xenobiotic-induced interstrand DNA–DNA cross-links (ICL) interfere with transcription and replication and can be converted to toxic DNA double strand breaks. In this work, we investigated cellular responses to 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) cross-links induced by 1,2,3,4-diepoxybutane (DEB). High pressure liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI⁺-MS/MS) assays were used to quantify the formation and repair of bis-N7G-BD cross-links in wild-type Chinese hamster lung fibroblasts (V79) and the corresponding isogenic clones V-H1 and V-H4, deficient in the XPD and FANCA genes, respectively. Both V-H1 and V-H4 cells exhibited enhanced sensitivity to DEB-induced cell death and elevated bis-N7G-BD cross-links. However, relatively modest increases of bis-N7G-BD adduct levels in V-H4 clones did not correlate with their hypersensitivity to DEB. Further, bis-N7G-BD levels were not elevated in DEB-treated human clones with defects in the XPA or FANCD2 genes. Comet assays and γ-H2AX focus analyses conducted with hamster cells revealed that ICL removal was associated with chromosomal double strand break formation, and that these breaks persisted in V-H4 cells as compared to control cells. Our findings suggest that ICL repair in cells with defects in the Fanconi anemia repair pathway is associated with aberrant re-joining of repair-induced double strand breaks, potentially resulting in lethal chromosome rearrangements. Full article

(This article belongs to the Section Biochemistry)

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Open AccessArticle

Assembly of Hepatocyte Spheroids Using Magnetic 3D Cell Culture for CYP450 Inhibition/Induction

by Pujan K. Desai, Hubert Tseng and Glauco R. Souza

Int. J. Mol. Sci. 2017, 18(5), 1085; https://doi.org/10.3390/ijms18051085 - 18 May 2017

Cited by 43 | Viewed by 9783

Abstract

There is a significant need for in vitro methods to study drug-induced liver injury that are rapid, reproducible, and scalable for existing high-throughput systems. However, traditional monolayer and suspension cultures of hepatocytes are difficult to handle and risk the loss of phenotype. Generally, [...] Read more.

There is a significant need for in vitro methods to study drug-induced liver injury that are rapid, reproducible, and scalable for existing high-throughput systems. However, traditional monolayer and suspension cultures of hepatocytes are difficult to handle and risk the loss of phenotype. Generally, three-dimensional (3D) cell culture platforms help recapitulate native liver tissue phenotype, but suffer from technical limitations for high-throughput screening, including scalability, speed, and handling. Here, we developed a novel assay for cytochrome P450 (CYP450) induction/inhibition using magnetic 3D cell culture that overcomes the limitations of other platforms by aggregating magnetized cells with magnetic forces. With this platform, spheroids can be rapidly assembled and easily handled, while replicating native liver function. We assembled spheroids of primary human hepatocytes in a 384-well format and maintained this culture over five days, including a 72 h induction period with known CYP450 inducers/inhibitors. CYP450 activity and viability in the spheroids were assessed and compared in parallel with monolayers. CYP450 activity was induced/inhibited in spheroids as expected, separate from any toxic response. Spheroids showed a significantly higher baseline level of CYP450 activity and induction over monolayers. Positive staining in spheroids for albumin and multidrug resistance-associated protein (MRP2) indicates the preservation of hepatocyte function within spheroids. The study presents a proof-of-concept for the use of magnetic 3D cell culture for the assembly and handling of novel hepatic tissue models. Full article

(This article belongs to the Special Issue Three-dimensional (3D) Bioprinting of Tissues and Organs)

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Open AccessReview

Idiopathic Inflammatory Myopathies: A Review of the Classification and Impact of Pathogenesis

by Dana E. Mandel, Charles J. Malemud and Ali D. Askari

Int. J. Mol. Sci. 2017, 18(5), 1084; https://doi.org/10.3390/ijms18051084 - 18 May 2017

Cited by 43 | Viewed by 9730

Abstract

Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune muscle diseases with significant morbidity and mortality. This review details and updates the pathogenesis and emerging importance of myositis-specific antibodies in the development of IIMs. An increase in the understanding of how these myositis-specific [...] Read more.

Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune muscle diseases with significant morbidity and mortality. This review details and updates the pathogenesis and emerging importance of myositis-specific antibodies in the development of IIMs. An increase in the understanding of how these myositis-specific antibodies play a role in IIMs has led to the further categorization of IIMs from the traditional polymyositis versus dermatomyositis, to additional subcategories of IIMs such as necrotizing autoimmune myositis (NAM). The diagnosis of IIMs, including manual muscle testing, laboratory studies, and non-invasive imaging have become important in classifying IIM subtypes and for identifying disease severity. Treatment has evolved from an era where glucocorticoid therapy was the only option to a time now that includes traditional steroid-sparing agents along with immunoglobulin therapy and biologics, such as rituximab. Full article

(This article belongs to the Special Issue Musculoskeletal Diseases Therapy)

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Open AccessReview

SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

by Daiji Kawanami, Keiichiro Matoba, Yusuke Takeda, Yosuke Nagai, Tomoyo Akamine, Tamotsu Yokota, Kazunori Sango and Kazunori Utsunomiya

Int. J. Mol. Sci. 2017, 18(5), 1083; https://doi.org/10.3390/ijms18051083 - 18 May 2017

Cited by 131 | Viewed by 12830

Abstract

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering [...] Read more.

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain

by Lindolfo Da Silva Meirelles, Daniel Simon and Andrea Regner

Int. J. Mol. Sci. 2017, 18(5), 1082; https://doi.org/10.3390/ijms18051082 - 18 May 2017

Cited by 49 | Viewed by 6831

Abstract

Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic [...] Read more.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic forces; this primary injury triggers a secondary wave of biochemical cascades together with metabolic and cellular changes, called secondary neural injury. In the scenario of the acutely injured brain, the ongoing secondary injury results in ischemia and edema culminating in an uncontrollable increase in intracranial pressure. These areas of secondary injury progression, or areas of “traumatic penumbra”, represent crucial targets for therapeutic interventions. Neurotrophins are a class of signaling molecules that promote survival and/or maintenance of neurons. They also stimulate axonal growth, synaptic plasticity, and neurotransmitter synthesis and release. Therefore, this review focuses on the role of neurotrophins in the acute post-injury response. Here, we discuss possible endogenous neuroprotective mechanisms of neurotrophins in the prevailing environment surrounding the injured areas, and highlight the crosstalk between neurotrophins and inflammation with focus on neurovascular unit cells, particularly pericytes. The perspective is that neurotrophins may represent promising targets for research on neuroprotective and neurorestorative processes in the short-term following TBI. Full article

(This article belongs to the Special Issue Neurotrophic Factors—Historical Perspective and New Directions)

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Open AccessArticle

Chemical Diversity, Biological Activity, and Genetic Aspects of Three Ocotea Species from the Amazon

by Joyce Kelly Da Silva, Rafaela Da Trindade, Edith Cibelle Moreira, José Guilherme S. Maia, Noura S. Dosoky, Rebecca S. Miller, Leland J. Cseke and William N. Setzer

Int. J. Mol. Sci. 2017, 18(5), 1081; https://doi.org/10.3390/ijms18051081 - 18 May 2017

Cited by 26 | Viewed by 5499

Abstract

Ocotea species present economic importance and biological activities attributed to their essential oils (EOs) and extracts. For this reason, various strategies have been developed for their conservation. The chemical compositions of the essential oils and matK DNA sequences of O. caudata, O. [...] Read more.

Ocotea species present economic importance and biological activities attributed to their essential oils (EOs) and extracts. For this reason, various strategies have been developed for their conservation. The chemical compositions of the essential oils and matK DNA sequences of O. caudata, O. cujumary, and O. caniculata were subjected to comparison with data from O. floribunda, O. veraguensis, and O. whitei, previously reported. The multivariate analysis of chemical composition classified the EOs into two main clusters. Group I was characterized by the presence of α-pinene (9.8–22.5%) and β-pinene (9.7–21.3%) and it includes O. caudata, O. whitei, and O. floribunda. In group II, the oils of O. cujumary and O. caniculata showed high similarity due amounts of β-caryophyllene (22.2% and 18.9%, respectively). The EO of O. veraguensis, rich in p-cymene (19.8%), showed minor similarity among all samples. The oils displayed promising antimicrobial and cytotoxic activities against Escherichia coli (minimum inhibitory concentration (MIC) < 19.5 µg·mL⁻¹) and MCF-7 cells (median inhibitory concentration (IC₅₀) ≅ 65.0 µg·mL⁻¹), respectively. The analysis of matK gene displayed a good correlation with the main class of chemical compounds present in the EOs. However, the matK gene data did not show correlation with specific compounds. Full article

(This article belongs to the Special Issue Effective Mechanisms of Plant Bioactive Essential Fats and Oils)

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Bordetella holmesii: Lipid A Structures and Corresponding Genomic Sequences Comparison in Three Clinical Isolates and the Reference Strain ATCC 51541

by Valérie Bouchez, Sami AlBitar-Nehmé, Alexey Novikov, Nicole Guiso and Martine Caroff

Int. J. Mol. Sci. 2017, 18(5), 1080; https://doi.org/10.3390/ijms18051080 - 18 May 2017

Cited by 6 | Viewed by 5311

Abstract

Bordetella holmesii can cause invasive infections but can also be isolated from the respiratory tract of patients with whooping-cough like symptoms. For the first time, we describe the lipid A structure of B. holmesii reference strain ATCC 51541 (alias NCTC12912 or CIP104394) and [...] Read more.

Bordetella holmesii can cause invasive infections but can also be isolated from the respiratory tract of patients with whooping-cough like symptoms. For the first time, we describe the lipid A structure of B. holmesii reference strain ATCC 51541 (alias NCTC12912 or CIP104394) and those of three French B. holmesii clinical isolates originating from blood (Bho1) or from respiratory samples (FR4020 and FR4101). They were investigated using chemical analyses, gas chromatography–mass spectrometry (GC–MS), and matrix-assisted laser desorption ionization–mass spectrometry (MALDI–MS). The analyses revealed a common bisphosphorylated β-(1→6)-linked d-glucosamine disaccharide with hydroxytetradecanoic acid in amide linkages. Similar to B. avium, B. hinzii and B. trematum lipids A, the hydroxytetradecanoic acid at the C-2′ position are carrying in secondary linkage a 2-hydroxytetradecanoic acid residue resulting of post-traductional biosynthesis modifications. The three clinical isolates displayed characteristic structural traits compared to the ATCC 51541 reference strain: the lipid A phosphate groups are more or less modified with glucosamine in the isolates and reference strain, but the presence of 10:0(3-OH) is only observed in the isolates. This trait was only described in B. pertussis and B. parapertussis strains, as well as in B. petrii isolates by the past. The genetic bases for most of the key structural elements of lipid A were analyzed and supported the structural data. Full article

(This article belongs to the Special Issue Lipopolysaccharides (LPSs))

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[¹⁸F]-Fluorinated Carboplatin and [¹¹¹In]-Liposome for Image-Guided Drug Delivery

by Narottam Lamichhane, Gajanan K. Dewkar, Gobalakrishnan Sundaresan, Rebecca N. Mahon and Jamal Zweit

Int. J. Mol. Sci. 2017, 18(5), 1079; https://doi.org/10.3390/ijms18051079 - 18 May 2017

Cited by 32 | Viewed by 5977

Abstract

Radiolabeled liposomes have been employed as diagnostic tools to monitor in vivo distribution of liposomes in real-time, which helps in optimizing the therapeutic efficacy of the liposomal drug delivery. This work utilizes the platform of [¹¹¹In]-Liposome as a drug delivery vehicle, [...] Read more.

Radiolabeled liposomes have been employed as diagnostic tools to monitor in vivo distribution of liposomes in real-time, which helps in optimizing the therapeutic efficacy of the liposomal drug delivery. This work utilizes the platform of [¹¹¹In]-Liposome as a drug delivery vehicle, encapsulating a novel ¹⁸F-labeled carboplatin drug derivative ([¹⁸F]-FCP) as a dual-molecular imaging tool as both a radiolabeled drug and radiolabeled carrier. The approach has the potential for clinical translation in individual patients using a dual modal approach of clinically-relevant radionuclides of ¹⁸F positron emission tomography (PET) and ¹¹¹In single photon emission computed tomography (SPECT). [¹¹¹In]-Liposome was synthesized and evaluated in vivo by biodistribution and SPECT imaging. The [¹⁸F]-FCP encapsulated [¹¹¹In]-Liposome nano-construct was investigated, in vivo, using an optimized dual-tracer PET and SPECT imaging in a nude mouse. The biodistribution data and SPECT imaging showed spleen and liver uptake of [¹¹¹In]-Liposome and the subsequent clearance of activity with time. Dual-modality imaging of [¹⁸F]-FCP encapsulated [¹¹¹In]-Liposome showed significant uptake in liver and spleen in both PET and SPECT images. Qualitative analysis of SPECT images and quantitative analysis of PET images showed the same pattern of activity during the imaging period and demonstrated the feasibility of dual-tracer imaging of a single dual-labeled nano-construct. Full article

(This article belongs to the Special Issue Cancer Molecular Imaging in the Era of Precision Medicine)

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Parents’ Attitudes toward Clinical Genetic Testing for Autism Spectrum Disorder—Data from a Norwegian Sample

by Jarle Johannessen, Terje Nærland, Sigrun Hope, Tonje Torske, Anne Lise Høyland, Jana Strohmaier, Arvid Heiberg, Marcella Rietschel, Srdjan Djurovic and Ole A. Andreassen

Int. J. Mol. Sci. 2017, 18(5), 1078; https://doi.org/10.3390/ijms18051078 - 18 May 2017

Cited by 29 | Viewed by 9673

Abstract

Clinical genetic testing (CGT) of children with autism spectrum disorder (ASD) may have positive and negative effects. Knowledge about parents’ attitudes is needed to ensure good involvement of caregivers, which is crucial for accurate diagnosis and effective clinical management. This study aimed to [...] Read more.

Clinical genetic testing (CGT) of children with autism spectrum disorder (ASD) may have positive and negative effects. Knowledge about parents’ attitudes is needed to ensure good involvement of caregivers, which is crucial for accurate diagnosis and effective clinical management. This study aimed to assess parents’ attitudes toward CGT for ASD. Parent members of the Norwegian Autism Society were given a previously untested questionnaire and 1455 answered. Linear regression analyses were conducted to evaluate contribution of parent and child characteristics to attitude statements. Provided it could contribute to a casual explanation of their child’s ASD, 76% would undergo CGT. If it would improve the possibilities for early interventions, 74% were positive to CGT. Between 49–67% agreed that CGT could have a negative impact on health insurance, increase their concern for the child’s future and cause family conflicts. Parents against CGT (9%) were less optimistic regarding positive effects, but not more concerned with negative impacts. The severity of the children’s ASD diagnosis had a weak positive association with parent’s positive attitudes to CGT (p-values range from <0.001 to 0.975). Parents prefer that CGT is offered to those having a child with ASD (65%), when the child’s development deviates from normal (48%), or before pregnancy (36%). A majority of the parents of children with ASD are positive to CGT due to possibilities for an etiological explanation. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome

by Opal Ousley, A. Nichole Evans, Samuel Fernandez-Carriba, Erica L. Smearman, Kimberly Rockers, Michael J. Morrier, David W. Evans, Karlene Coleman and Joseph Cubells

Int. J. Mol. Sci. 2017, 18(5), 1071; https://doi.org/10.3390/ijms18051071 - 18 May 2017

Cited by 35 | Viewed by 7069

Abstract

22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15–50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD [...] Read more.

22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15–50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA), which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observational Schedule (ADOS), and a clinician’s best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults (n = 56) with 22q11.2DS, who were ascertained irrespective of parents’ behavioral or developmental concerns, and found that 17.9% (n = 10) of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood. Full article

(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders 2017)

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Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

by Rodrigo Fernandes Da Silva, Adriana Yoshida, Daniela Maira Cardozo, Rodrigo Menezes Jales, Silke Paust, Sophie Derchain and Fernando Guimarães

Int. J. Mol. Sci. 2017, 18(5), 856; https://doi.org/10.3390/ijms18050856 - 17 May 2017

Cited by 18 | Viewed by 5273

Abstract

Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the [...] Read more.

Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the functional characteristics of natural killer (NK) cells from EOC-associated ascites in terms of their expression of activating receptors and ascites’ contents of lymphocyte subtypes, cytokine profile and presence of EOC cells. NK cell function was evaluated by the expression of the degranulation marker CD107a in resting and interleukin (IL)-2 stimulated NK cells from ascites and blood. Degranulation of NK cells from EOC cell-free ascites was significantly (p < 0.05) higher than all the other groups, either in their resting state or after IL-2 stimulation, suggesting a previous local stimulation. In contrast, treatment with IL-2 had no effect on NK cells from ascites with EOC cells. The amount of regulatory T cells was significantly higher in ascites with EOC cells compared to EOC cell-free ascites. Ascites with EOC cells also had higher levels of tumor necrosis factor (TNF)-α, suggesting inflammation related to the malignancy. In conclusion, the functional performance of NK cells was distinct between EOC cell-free ascites and ascites with EOC cells. The impairment of NK cell response to IL-2 in ascites with EOC cells was consistent with an immunosuppressive tumor microenvironment. Full article

(This article belongs to the Special Issue Natural Killer (NK) Cells)

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