Biomedicines

14 pages, 1873 KiB

Open AccessEditor’s ChoiceArticle

Inflammatory and Oxidative Stress Markers—Mirror Tools in Rheumatoid Arthritis

by Radu Răzvan Mititelu, Rodica Pădureanu, Manuela Băcănoiu, Vlad Pădureanu, Anca Oana Docea, Daniela Calina, Andreea Lili Barbulescu and Ana Maria Buga

Biomedicines 2020, 8(5), 125; https://doi.org/10.3390/biomedicines8050125 - 15 May 2020

Cited by 67 | Viewed by 5802

Abstract

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease, associated with significant morbidity, mainly due to progressive damage and consequent disability. Oxidative stress is an important part of RA pathophysiology, as in autoimmune disease the interaction between immune response and endogenous/exogenous antigens subsequently [...] Read more.

Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease, associated with significant morbidity, mainly due to progressive damage and consequent disability. Oxidative stress is an important part of RA pathophysiology, as in autoimmune disease the interaction between immune response and endogenous/exogenous antigens subsequently induce the production of reactive oxygen species. The oxidative stress process seems to be positively strongly correlated with inflammation and accelerated joint destruction. We were asking ourselves if the oxidative stress biomarkers are the mirror tools of disease activity, outcome, and inflammation level in a group of RA patients under standard or biological therapy compared to healthy age-matched controls. In order to do this, the oxidative stress damage biomarkers (lipids peroxide and protein carbonyl level), antioxidant defense capacity, and pro-inflammatory status of plasma were quantified. In this study, we took into account the complete picture of RA diseases and assessed, for the first time, the inflammatory level in correlation with the oxidative stress level and antioxidant capacity of RA patients. Our results revealed that protein oxidation through carbonylation is significantly increased in RA groups compared to controls, and both protein carbonyl Pcarb and thiobarbituric acid reactive substance (TBARS) are reliable markers of ROS damage. Therefore, it is unanimous that neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PltLR) correlated with Pcarb, and TBARS can provide a view of the complex phenomenon represented by proteins/lipids damage, key contributors to disease outcome, and an increased awareness should be attributed to these biomarkers. Full article

(This article belongs to the Special Issue Immunoglobulins in Inflammation)

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20 pages, 904 KiB

Open AccessEditor’s ChoiceReview

Non-Invasive Delivery of Therapeutics into the Brain: The Potential of Aptamers for Targeted Delivery

by Bakhtiar Bukari, Rasika M. Samarasinghe, Jinjutha Noibanchong and Sarah L. Shigdar

Biomedicines 2020, 8(5), 120; https://doi.org/10.3390/biomedicines8050120 - 14 May 2020

Cited by 31 | Viewed by 4739

Abstract

The blood-brain barrier (BBB) is a highly specialised network of blood vessels that effectively separates the brain environment from the circulatory system. While there are benefits, in terms of keeping pathogens from entering the brain, the BBB also complicates treatments of brain pathologies [...] Read more.

The blood-brain barrier (BBB) is a highly specialised network of blood vessels that effectively separates the brain environment from the circulatory system. While there are benefits, in terms of keeping pathogens from entering the brain, the BBB also complicates treatments of brain pathologies by preventing efficient delivery of macromolecular drugs to diseased brain tissue. Although current non-invasive strategies of therapeutics delivery into the brain, such as focused ultrasound and nanoparticle-mediated delivery have shown various levels of successes, they still come with risks and limitations. This review discusses the current approaches of therapeutic delivery into the brain, with a specific focus on non-invasive methods. It also discusses the potential for aptamers as alternative delivery systems and several reported aptamers with promising preliminary results. Full article

(This article belongs to the Special Issue Engineering Aptamers for Biomedical Applications II)

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19 pages, 5878 KiB

Open AccessEditor’s ChoiceArticle

RNA Sequencing in Comparison to Immunohistochemistry for Measuring Cancer Biomarkers in Breast Cancer and Lung Cancer Specimens

by Maxim Sorokin, Kirill Ignatev, Elena Poddubskaya, Uliana Vladimirova, Nurshat Gaifullin, Dmitriy Lantsov, Andrew Garazha, Daria Allina, Maria Suntsova, Victoria Barbara and Anton Buzdin

Biomedicines 2020, 8(5), 114; https://doi.org/10.3390/biomedicines8050114 - 9 May 2020

Cited by 26 | Viewed by 7018

Abstract

RNA sequencing is considered the gold standard for high-throughput profiling of gene expression at the transcriptional level. Its increasing importance in cancer research and molecular diagnostics is reflected in the growing number of its mentions in scientific literature and clinical trial reports. However, [...] Read more.

RNA sequencing is considered the gold standard for high-throughput profiling of gene expression at the transcriptional level. Its increasing importance in cancer research and molecular diagnostics is reflected in the growing number of its mentions in scientific literature and clinical trial reports. However, the use of different reagents and protocols for RNA sequencing often produces incompatible results. Recently, we published the Oncobox Atlas of RNA sequencing profiles for normal human tissues obtained from healthy donors killed in road accidents. This is a database of molecular profiles obtained using uniform protocol and reagents settings that can be broadly used in biomedicine for data normalization in pathology, including cancer. Here, we publish new original 39 breast cancer (BC) and 19 lung cancer (LC) RNA sequencing profiles obtained for formalin-fixed paraffin-embedded (FFPE) tissue samples, fully compatible with the Oncobox Atlas. We performed the first correlation study of RNA sequencing and immunohistochemistry-measured expression profiles for the clinically actionable biomarker genes in FFPE cancer tissue samples. We demonstrated high (Spearman’s rho 0.65–0.798) and statistically significant (p < 0.00004) correlations between the RNA sequencing (Oncobox protocol) and immunohistochemical measurements for HER2/ERBB2, ER/ESR1 and PGR genes in BC, and for PDL1 gene in LC; AUC: 0.963 for HER2, 0.921 for ESR1, 0.912 for PGR, and 0.922 for PDL1. To our knowledge, this is the first validation that total RNA sequencing of archived FFPE materials provides a reliable estimation of marker protein levels. These results show that in the future, RNA sequencing can complement immunohistochemistry for reliable measurements of the expression biomarkers in FFPE cancer samples. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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18 pages, 1033 KiB

Open AccessEditor’s ChoiceReview

The Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing

by Blair Z. Johnson, Andrew W. Stevenson, Cecilia M. Prêle, Mark W. Fear and Fiona M. Wood

Biomedicines 2020, 8(5), 101; https://doi.org/10.3390/biomedicines8050101 - 30 Apr 2020

Cited by 249 | Viewed by 17886

Abstract

The timely resolution of wound healing is critical for restoring the skin as a protective barrier. The switch from a proinflammatory to a reparative microenvironment must be tightly regulated. Interleukin (IL)-6 is a key modulator of the inflammatory and reparative process: it is [...] Read more.

The timely resolution of wound healing is critical for restoring the skin as a protective barrier. The switch from a proinflammatory to a reparative microenvironment must be tightly regulated. Interleukin (IL)-6 is a key modulator of the inflammatory and reparative process: it is involved in the differentiation, activation, and proliferation of leukocytes, endothelial cells, keratinocytes, and fibroblasts. This review examines the role of IL-6 in the healing of cutaneous wounds, and how dysregulation of IL-6 signaling can lead to either fibrosis or a failure to heal. The role of an IL-6/TGF-β feedback loop is discussed in the context of fibrogenesis, while IL-6 expression and responses in advanced age, diabetes, and obesity is outlined regarding the development of chronic wounds. Current research on therapies that modulate IL-6 is explored. Here, we consider IL-6′s diverse impact on cutaneous wound healing. Full article

(This article belongs to the Special Issue The Interleukin-6 Family in Disease Pathogenesis and Therapy)

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20 pages, 1185 KiB

Open AccessEditor’s ChoiceArticle

Effect of the Most Relevant CYP3A4 and CYP3A5 Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates

by Miriam Saiz-Rodríguez, Susana Almenara, Marcos Navares-Gómez, Dolores Ochoa, Manuel Román, Pablo Zubiaur, Dora Koller, María Santos, Gina Mejía, Alberto M. Borobia, Cristina Rodríguez-Antona and Francisco Abad-Santos

Biomedicines 2020, 8(4), 94; https://doi.org/10.3390/biomedicines8040094 - 22 Apr 2020

Cited by 70 | Viewed by 6835

Abstract

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, [...] Read more.

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC (p = 0.099) and a tendency of lower normalized Cl (p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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20 pages, 344 KiB

Open AccessEditor’s ChoiceReview

Cancer Vaccines and Oncolytic Viruses Exert Profoundly Lower Side Effects in Cancer Patients than Other Systemic Therapies: A Comparative Analysis

by Volker Schirrmacher

Biomedicines 2020, 8(3), 61; https://doi.org/10.3390/biomedicines8030061 - 16 Mar 2020

Cited by 45 | Viewed by 4955

Abstract

This review compares cytotoxic drugs, targeted therapies, and immunotherapies with regard to mechanisms and side effects. Targeted therapies relate to small molecule inhibitors. Immunotherapies include checkpoint inhibitory antibodies, chimeric antigen receptor (CAR) T-cells, cancer vaccines, and oncolytic viruses. All these therapeutic approaches fight [...] Read more.

This review compares cytotoxic drugs, targeted therapies, and immunotherapies with regard to mechanisms and side effects. Targeted therapies relate to small molecule inhibitors. Immunotherapies include checkpoint inhibitory antibodies, chimeric antigen receptor (CAR) T-cells, cancer vaccines, and oncolytic viruses. All these therapeutic approaches fight systemic disease, be it micro-metastatic or metastatic. The analysis includes only studies with a proven therapeutic effect. A clear-cut difference is observed with regard to major adverse events (WHO grades 3–4). Such severe side effects are not observed with cancer vaccines/oncolytic viruses while they are seen with all the other systemic therapies. Reasons for this difference are discussed. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

20 pages, 278 KiB

Open AccessEditor’s ChoiceReview

Viral Vector-Based Melanoma Gene Therapy

by Altijana Hromic-Jahjefendic and Kenneth Lundstrom

Biomedicines 2020, 8(3), 60; https://doi.org/10.3390/biomedicines8030060 - 16 Mar 2020

Cited by 18 | Viewed by 6030

Abstract

Gene therapy applications of oncolytic viruses represent an attractive alternative for cancer treatment. A broad range of oncolytic viruses, including adenoviruses, adeno-associated viruses, alphaviruses, herpes simplex viruses, retroviruses, lentiviruses, rhabdoviruses, reoviruses, measles virus, Newcastle disease virus, picornaviruses and poxviruses, have been used in [...] Read more.

Gene therapy applications of oncolytic viruses represent an attractive alternative for cancer treatment. A broad range of oncolytic viruses, including adenoviruses, adeno-associated viruses, alphaviruses, herpes simplex viruses, retroviruses, lentiviruses, rhabdoviruses, reoviruses, measles virus, Newcastle disease virus, picornaviruses and poxviruses, have been used in diverse preclinical and clinical studies for the treatment of various diseases, including colon, head-and-neck, prostate and breast cancer as well as squamous cell carcinoma and glioma. The majority of studies have focused on immunotherapy and several drugs based on viral vectors have been approved. However, gene therapy for malignant melanoma based on viral vectors has not been utilized to its full potential yet. This review represents a summary of the achievements of preclinical and clinical studies using viral vectors, with the focus on malignant melanoma. Full article

(This article belongs to the Special Issue Gene Therapy Coming of Age)

20 pages, 1010 KiB

Open AccessEditor’s ChoiceReview

New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

by Volker Schirrmacher

Biomedicines 2020, 8(3), 55; https://doi.org/10.3390/biomedicines8030055 - 6 Mar 2020

Cited by 13 | Viewed by 4236

Abstract

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity [...] Read more.

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer II)

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14 pages, 2857 KiB

Open AccessEditor’s ChoiceReview

Correlations between Microbiota Bioactivity and Bioavailability of Functional Compounds: A Mini-Review

by Emanuel Vamanu and Florentina Gatea

Biomedicines 2020, 8(2), 39; https://doi.org/10.3390/biomedicines8020039 - 20 Feb 2020

Cited by 64 | Viewed by 6387

Abstract

Numerous studies have demonstrated the role of the microbiota in supporting the physiological functions, owing to its metabolomic component. The presence of biocomponents generally leads to the correction of the microbial pattern correlated with the reduction of oxidative pressure. This study aims to [...] Read more.

Numerous studies have demonstrated the role of the microbiota in supporting the physiological functions, owing to its metabolomic component. The presence of biocomponents generally leads to the correction of the microbial pattern correlated with the reduction of oxidative pressure. This study aims to present the main processes that correlate the bioavailability and bioactivity of some functional components through the action of the human microbiota. The use of probiotics and prebiotics is an innovative manner involving alternatives that increase the bioavailability of certain natural or metabolic components has been proposed. Probiotic strains (Saccharomyces cerevisiae or Lactobacillus (L.) plantarum) may represent an intermediary for increasing the antioxidant bioactivity, and they may be administered in the form of a biomass enriched with functional compounds, such as phenolic acids. The limiting effect of gastrointestinal transit is, in several cases, the key to the biopharmaceutical value of new products (or supplements). The identification of newer ways of formulating supplements also involves the compatibility of different types of products, the testing of bioaccessibility, and the elimination of biotransformations. Full article

(This article belongs to the Special Issue Functional Products Used in Alleviation of Oxidative Stress Diseases and Interaction with Human Microbiota)

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11 pages, 1731 KiB

Open AccessEditor’s ChoiceArticle

The Co-Expression of Programmed Death-Ligand 1 (PD-L1) in Untreated EGFR-Mutated Metastatic Lung Adenocarcinoma

by Ping-Chih Hsu, Chih-Wei Wang, Scott Chih-Hsi Kuo, Shu-Min Lin, Yu-Lun Lo, Allen Chung-Cheng Huang, Li-Chung Chiu and Cheng-Ta Yang

Biomedicines 2020, 8(2), 36; https://doi.org/10.3390/biomedicines8020036 - 19 Feb 2020

Cited by 13 | Viewed by 3273

Abstract

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is the standard first-line therapy for metastatic lung adenocarcinoma harboring sensitive EGFR mutations. Tumor surface programmed death-ligand 1 (PD-L1) is expressed in some metastatic EGFR-mutated lung adenocarcinoma, but its impact on the efficacy of EGFR-TKIs [...] Read more.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is the standard first-line therapy for metastatic lung adenocarcinoma harboring sensitive EGFR mutations. Tumor surface programmed death-ligand 1 (PD-L1) is expressed in some metastatic EGFR-mutated lung adenocarcinoma, but its impact on the efficacy of EGFR-TKIs is unclear. We retrospectively investigated 117 untreated metastatic lung EGFR mutated adenocarcinoma patients with a PD-L1 immunohistochemistry test. The PD-L1 expression level was classified by tumor proportion scores (TPS). Forty-five patients had negative expression (TPS < 1%), 45 had a weak expression (TPS 1–49%), and 27 had a strong expression (≥50%). All patients recruited in this study received EGFR-TKIs as a first-line therapy. No significant differences were observed for objective response rates (68.9% versus 62.2% versus 73.1%, p = 0.807) and median time to treatment failure (TTF) (12.17 versus 13.17 versus 11.0 months, p = 0.443) of first-line EGFR-TKIS among the three groups of patients (negative versus weak versus strong). The median overall survival was 21.27 versus 20.63 versus 19.43 months among the three groups of patients (p = 0.77). Our results demonstrated that PD-L1 did not affect the efficacy of first-line EGFR-TKIs in metastatic EGFR mutated lung adenocarcinoma. Thus, EGFR-TKIs are suggested as the preferred clinical therapy for these patients, despite their PD-L1 levels. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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17 pages, 2800 KiB

Open AccessEditor’s ChoiceArticle

5-(Carbamoylmethylene)-oxazolidin-2-ones as a Promising Class of Heterocycles Inducing Apoptosis Triggered by Increased ROS Levels and Mitochondrial Dysfunction in Breast and Cervical Cancer

by Biagio Armentano, Rosita Curcio, Matteo Brindisi, Raffaella Mancuso, Vittoria Rago, Ida Ziccarelli, Luca Frattaruolo, Marco Fiorillo, Vincenza Dolce, Bartolo Gabriele and Anna Rita Cappello

Biomedicines 2020, 8(2), 35; https://doi.org/10.3390/biomedicines8020035 - 18 Feb 2020

Cited by 23 | Viewed by 3864

Abstract

Oxazolidinones are antibiotics that inhibit protein synthesis by binding the 50S ribosomal subunit. Recently, numerous worldwide researches focused on their properties and possible involvement in cancer therapy have been conducted. Here, we evaluated in vitro the antiproliferative activity of some 5-(carbamoylmethylene)-oxazolidin-2-ones on MCF-7 [...] Read more.

Oxazolidinones are antibiotics that inhibit protein synthesis by binding the 50S ribosomal subunit. Recently, numerous worldwide researches focused on their properties and possible involvement in cancer therapy have been conducted. Here, we evaluated in vitro the antiproliferative activity of some 5-(carbamoylmethylene)-oxazolidin-2-ones on MCF-7 and HeLa cells. The tested compounds displayed a wide range of cytotoxicity on these cancer cell lines, measured by MTT assay, exhibiting no cytotoxicity on non-tumorigenic MCF-10A cells. Among the nine tested derivatives, four displayed a good anticancer potential. Remarkably, OI compound showed IC₅₀ values of 17.66 and 31.10 µM for MCF-7 and HeLa cancer cells, respectively. Furthermore, we assessed OI effect on the cell cycle by FACS analysis, highlighting a G1 phase arrest after 72 h, supported by a low expression level of Cyclin D1 protein. Moreover, mitochondrial membrane potential was reduced after OI treatment driven by high levels of ROS. These findings demonstrate that OI treatment can inhibit MCF-7 and HeLa cell proliferation and induce apoptosis by caspase-9 activation and cytochrome c release in the cytosol. Hence, 5-(carbamoylmethylene)-oxazolidin-2-ones have a promising anticancer activity, in particular, OI derivative could represent a good candidate for in vivo further studies and potential clinical use. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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13 pages, 1771 KiB

Open AccessEditor’s ChoiceArticle

Impact of Statin Use on Dementia Incidence in Elderly Men and Women with Ischemic Heart Disease

by Mi-Young Kim, Minji Jung, Yoojin Noh, Sooyoung Shin, Chang Hyung Hong, Sukhyang Lee and Yi-Sook Jung

Biomedicines 2020, 8(2), 30; https://doi.org/10.3390/biomedicines8020030 - 9 Feb 2020

Cited by 12 | Viewed by 3872

Abstract

This study aimed to determine the association between statins and the prevention of dementia according to sex differences in elderly patients with ischemic heart disease (IHD). We performed a nationwide retrospective cohort study using the Korean Health Insurance Review and Assessment Service database [...] Read more.

This study aimed to determine the association between statins and the prevention of dementia according to sex differences in elderly patients with ischemic heart disease (IHD). We performed a nationwide retrospective cohort study using the Korean Health Insurance Review and Assessment Service database (2007–2015). Among the 264,036 eligible patients aged ≥65 years with IHD, statin users were compared with non–users by propensity score matching at a 1:1 ratio (71,587 in each group). The primary outcome was dementia risk by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Differential risks of dementia were assessed by sex in the subgroups of statin types, exposure duration, and patient age, implying that sex is an influential factor for the link between statin use and dementia incidence. Among seven commonly prescribed statins, rosuvastatin was associated with the greatest preventive effect on dementia incidence, with an adjusted HR of 0.82 (95% CI = 0.78–0.87). In a subgroup analysis organized by sex, the differential risk of dementia incidence was assessed in each statin group, implying that sex is an influential factor for the link between statin and dementia. This study suggests that appropriate statin use considering sex differences may have beneficial effects on the development of dementia. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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12 pages, 1078 KiB

Open AccessEditor’s ChoiceArticle

Circulating MyomiRs as Potential Biomarkers to Monitor Response to Nusinersen in Pediatric SMA Patients

by Silvia Bonanno, Stefania Marcuzzo, Claudia Malacarne, Eleonora Giagnorio, Riccardo Masson, Riccardo Zanin, Maria Teresa Arnoldi, Francesca Andreetta, Ornella Simoncini, Anna Venerando, Cinzia Gellera, Chiara Pantaleoni, Renato Mantegazza, Pia Bernasconi, Giovanni Baranello and Lorenzo Maggi

Biomedicines 2020, 8(2), 21; https://doi.org/10.3390/biomedicines8020021 - 26 Jan 2020

Cited by 31 | Viewed by 5239

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons. The paralogous SMN2 gene partially compensates full-length SMN [...] Read more.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons. The paralogous SMN2 gene partially compensates full-length SMN protein production, mitigating the phenotype. Antisense oligonucleotide nusinersen (Spinraza^®) enhances SMN2 gene expression. SMN is involved in RNA metabolism and biogenesis of microRNA (miRNA), key gene expression modulators, whose dysregulation contributes to neuromuscular diseases. They are stable in body fluids and may reflect distinct pathophysiological states, thus acting as promising biomarkers. Muscle-specific miRNAs (myomiRs) as biomarkers for clinical use in SMA have not been investigated yet. Here, we analyzed the expression of miR-133a, -133b, -206 and -1, in serum of 21 infantile SMA patients at baseline and after 6 months of nusinersen treatment, and correlated molecular data with response to therapy evaluated by the Hammersmith Functional Motor Scale Expanded (HFMSE). Our results demonstrate that myomiR serological levels decrease over disease course upon nusinersen treatment. Notably, miR-133a reduction predicted patients’ response to therapy. Our findings identify myomiRs as potential biomarkers to monitor disease progression and therapeutic response in SMA patients. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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11 pages, 1667 KiB

Open AccessEditor’s ChoiceArticle

2-deoxy-d-glucose Ameliorates Animal Models of Dermatitis

by Soo Young Choi, Min-Jeong Heo, Chanmi Lee, Yeong Min Choi, In-sook An, Seunghee Bae, Sungkwan An and Jin Hyuk Jung

Biomedicines 2020, 8(2), 20; https://doi.org/10.3390/biomedicines8020020 - 24 Jan 2020

Cited by 18 | Viewed by 4524

Abstract

Glucose metabolism is a key metabolic pathway that orchestrates cellular homeostasis by generating ATP, nucleotides, and amino acids. Abnormal glucose signaling has been found in many diseases including cancers and inflammatory diseases. According to recent report, glycolysis contributes to pathogenesis of psoriasis and [...] Read more.

Glucose metabolism is a key metabolic pathway that orchestrates cellular homeostasis by generating ATP, nucleotides, and amino acids. Abnormal glucose signaling has been found in many diseases including cancers and inflammatory diseases. According to recent report, glycolysis contributes to pathogenesis of psoriasis and ablation of Glut1 attenuates animal models of psoriasis. While we were screening a molecular target for atopic dermatitis, we found the levels of glucose transporters including Glut1 (SLC2a1) and Glut3 (SLC2a3) are highly expressed in skin biopsies of dermatitis patients from multiple datasets. We demonstrated that administration of 2-deoxy-d-glucose (2DG) ameliorates animal models of 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone induced dermatitis using morphological and histological analysis. These results suggest that inhibition of glucose metabolism ameliorates dermatitis in animal models. Full article

(This article belongs to the Section Drug Discovery and Development)

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14 pages, 3219 KiB

Open AccessEditor’s ChoiceArticle

Protective Effects of Astaxanthin Supplementation against Ultraviolet-Induced Photoaging in Hairless Mice

by Xing Li, Tomohiro Matsumoto, Miho Takuwa, Mahmood Saeed Ebrahim Shaiku Ali, Takumi Hirabashi, Hiroyo Kondo and Hidemi Fujino

Biomedicines 2020, 8(2), 18; https://doi.org/10.3390/biomedicines8020018 - 21 Jan 2020

Cited by 31 | Viewed by 7319

Abstract

Ultraviolet (UV) light induces skin photoaging, which is characterized by thickening, wrinkling, pigmentation, and dryness. Astaxanthin (AST), a ketocarotenoid isolated from Haematococcus pluvialis, has been extensively studied owing to its possible effects on skin health as well as UV protection. In addition, [...] Read more.

Ultraviolet (UV) light induces skin photoaging, which is characterized by thickening, wrinkling, pigmentation, and dryness. Astaxanthin (AST), a ketocarotenoid isolated from Haematococcus pluvialis, has been extensively studied owing to its possible effects on skin health as well as UV protection. In addition, AST attenuates the increased generation of reactive oxygen species (ROS) and capillary regression of the skeletal muscle. In this study, we investigated whether AST could protect against UV-induced photoaging and reduce capillary regression in the skin of HR-1 hairless mice. UV light induces wrinkle formation, epidermal thickening, and capillary regression in the dermis of HR-1 hairless mice. The administration of AST reduced the UV-induced wrinkle formation and skin thickening, and increased collagen fibers in the skin. AST supplementation also inhibited the generation of ROS, decreased wrinkle formation, reduced epidermal thickening, and increased the density of capillaries in the skin. We also found an inverse correlation between wrinkle formation and the density of capillaries. An association between photoaging and capillary regression in the skin was also observed. These results suggest that AST can protect against photoaging caused by UV irradiation and the inhibitory effects of AST on photoaging may be associated with the reduction of capillary regression in the skin. Full article

(This article belongs to the Section Drug Discovery and Development)

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23 pages, 7472 KiB

Open AccessEditor’s ChoiceArticle

Comparative Evaluation of the Angiogenic Potential of Hypoxia Preconditioned Blood-Derived Secretomes and Platelet-Rich Plasma: An In Vitro Analysis

by Philipp Moog, Katharina Kirchhoff, Sanjar Bekeran, Anna-Theresa Bauer, Sarah von Isenburg, Ulf Dornseifer, Hans-Günther Machens, Arndt F. Schilling and Ektoras Hadjipanayi

Biomedicines 2020, 8(1), 16; https://doi.org/10.3390/biomedicines8010016 - 16 Jan 2020

Cited by 13 | Viewed by 5273

Abstract

Blood-derived factor preparations are being clinically employed as tools for promoting tissue repair and regeneration. Here we set out to characterize the in vitro angiogenic potential of two types of frequently used autologous blood-derived secretomes: platelet-rich plasma (PRP) and hypoxia preconditioned plasma (HPP)/serum [...] Read more.

Blood-derived factor preparations are being clinically employed as tools for promoting tissue repair and regeneration. Here we set out to characterize the in vitro angiogenic potential of two types of frequently used autologous blood-derived secretomes: platelet-rich plasma (PRP) and hypoxia preconditioned plasma (HPP)/serum (HPS). The concentration of key pro-angiogenic (VEGF) and anti-angiogenic (TSP-1, PF-4) protein factors in these secretomes was analyzed via ELISA, while their ability to induce microvessel formation and sprouting was examined in endothelial cell and aortic ring cultures, respectively. We found higher concentrations of VEGF in PRP and HPP/HPS compared to normal plasma and serum. This correlated with improved induction of microvessel formation by PRP and HPP/HPS. HPP had a significantly lower TSP-1 and PF-4 concentration than PRP and HPS. PRP and HPP/HPS appeared to induce similar levels of microvessel sprouting; however, the length of these sprouts was greater in HPP/HPS than in PRP cultures. A bell-shaped angiogenic response profile was observed with increasing HPP/HPS dilutions, with peak values significantly exceeding the PRP response. Our findings demonstrate that optimization of peripheral blood cell-derived angiogenic factor signalling through hypoxic preconditioning offers an improved alternative to simple platelet concentration and release of growth factors pre-stored in platelets. Full article

(This article belongs to the Special Issue Hypoxia-Inducible Factors: Regulation and Therapeutic Potential)

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9 pages, 1438 KiB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effects of Diospyrin on Lipopolysaccharide-Induced Inflammation Using RAW 264.7 Mouse Macrophages

by Adnan Shahidullah, Ji-Young Lee, Young-Jin Kim, Syed Muhammad Ashhad Halimi, Abdur Rauf, Hyun-Ju Kim, Bong-Youn Kim and Wansu Park

Biomedicines 2020, 8(1), 11; https://doi.org/10.3390/biomedicines8010011 - 11 Jan 2020

Cited by 7 | Viewed by 5224

Abstract

Diospyrin is a bisnaphthoquinonoid medicinal compound derived from Diospyros lotus, with known anti-cancer, anti-tubercular, and anti-leishmanial activities against Leishmania donovani. However, the effects of diospyrin on lipopolysaccharide (LPS)-induced macrophage activation and inflammation are not fully reported. In this study, the anti-inflammatory [...] Read more.

Diospyrin is a bisnaphthoquinonoid medicinal compound derived from Diospyros lotus, with known anti-cancer, anti-tubercular, and anti-leishmanial activities against Leishmania donovani. However, the effects of diospyrin on lipopolysaccharide (LPS)-induced macrophage activation and inflammation are not fully reported. In this study, the anti-inflammatory effects of diospyrin on LPS-induced macrophages were examined. Diospyrin showed no toxicity in RAW 264.7 at concentrations of up to 10 μM. Diospyrin moderated the production of nitric oxide (NO), monocyte chemotactic protein-1, macrophage inflammatory protein-1β, interleukin (IL)-6, IL-10, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, vascular endothelial growth factor, leukemia inhibitory factor, and RANTES/CCL5, as well as calcium release in LPS-induced RAW 264.7, at concentrations of up to 10 μM significantly (p < 0.05). Diospyrin also significantly inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and mRNA expression of C/EBP homologous protein (CHOP), as well as tumor necrosis factor receptor superfamily member 6 (Fas), in LPS-induced RAW 264.7 cells at concentrations of up to 10 μM (p < 0.05). Diospyrin exhibits anti-inflammatory properties mediated via inhibition of NO, and cytokines in LPS-induced mouse macrophages via the ER-stressed calcium-p38 MAPK/CHOP/Fas pathway. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches)

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14 pages, 1970 KiB

Open AccessEditor’s ChoiceReview

The Gut Microbiome and Type 2 Diabetes Mellitus: Discussing A Complex Relationship

by Angelos K. Sikalidis and Adeline Maykish

Biomedicines 2020, 8(1), 8; https://doi.org/10.3390/biomedicines8010008 - 7 Jan 2020

Cited by 119 | Viewed by 20231

Abstract

Type 2 diabetes mellitus (T2DM) is a disease that affects over 9% of the United States population and is closely linked to obesity. While obesity was once thought to stem from a sedentary lifestyle and diets high in fat, recent evidence supports the [...] Read more.

Type 2 diabetes mellitus (T2DM) is a disease that affects over 9% of the United States population and is closely linked to obesity. While obesity was once thought to stem from a sedentary lifestyle and diets high in fat, recent evidence supports the idea that there is more complexity pertinent to the issue. The human gut microbiome has recently been the focus in terms of influencing disease onset. Evidence has shown that the microbiome may be more closely related to T2DM than what was originally thought. High fat diets typically result in poor microbiome heath, which then shifts the gut into a state of dysbiosis. Dysbiosis can then lead to metabolic deregulation, including increased insulin resistance and inflammation, two key factors in the development of T2DM. The purpose of this review is to discuss how microbiome relates to T2DM onset, especially considering obesity, insulin resistance, and inflammation. Full article

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10 pages, 646 KiB

Open AccessEditor’s ChoiceReview

Gastric Cancer Stem Cells: Current Insights into the Immune Microenvironment and Therapeutic Targets

by Lingfeng Fu, Luke Bu, Tadahito Yasuda, Mayu Koiwa, Takahiko Akiyama, Tomoyuki Uchihara, Hideo Baba and Takatsugu Ishimoto

Biomedicines 2020, 8(1), 7; https://doi.org/10.3390/biomedicines8010007 - 6 Jan 2020

Cited by 30 | Viewed by 6027

Abstract

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) are known to be involved in chemotherapy resistance and the development of metastases. Although CSCs harbor self-renewal and tumorigenic abilities, the immune microenvironment surrounding CSCs provides various factors [...] Read more.

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) are known to be involved in chemotherapy resistance and the development of metastases. Although CSCs harbor self-renewal and tumorigenic abilities, the immune microenvironment surrounding CSCs provides various factors and supports the maintenance of CSC properties. The current review summarizes the accumulating findings regarding the relationship between the immune microenvironment and gastric CSCs (GCSCs), which will support the possibility of developing novel therapeutic strategies for targeting GCSCs. Full article

(This article belongs to the Special Issue Gastric Cancer Research: From Basic Science to the Clinic)

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