Biomedicines

11 pages, 1140 KiB

Open AccessArticle

Does Medication-Related Osteonecrosis of the Jaw Influence the Quality of Life of Cancer Patients?

by Gianluca Tenore, Ahmed Mohsen, Antonella Francesca Rossi, Gaspare Palaia, Federica Rocchetti, Andrea Cassoni, Valentino Valentini, Livia Ottolenghi, Antonella Polimeni and Umberto Romeo

Biomedicines 2020, 8(4), 95; https://doi.org/10.3390/biomedicines8040095 - 24 Apr 2020

Cited by 18 | Viewed by 2644

Abstract

The aim of this study is to observe the influence of Medication-Related Osteonecrosis of the Jaw (MRONJ) on the physical and mental conditions of cancer patients using a Quality of Life (QoL) questionnaire during regular dental practice measures. Twenty cancer patients (8 males [...] Read more.

The aim of this study is to observe the influence of Medication-Related Osteonecrosis of the Jaw (MRONJ) on the physical and mental conditions of cancer patients using a Quality of Life (QoL) questionnaire during regular dental practice measures. Twenty cancer patients (8 males and 12 females) with established MRONJ were enrolled in the “MoMax” (Oral Medicine and Maxillofacial) project of the Department of Oral Sciences and Maxillofacial Surgery at “Sapienza” University of Rome, and were included in the study. The 12-item Short Form Survey was used to evaluate the QoL. Statistical analysis revealed a significant difference for Mental Component Summary (MCS) scores based on age (p = 0.018). The regression analysis revealed that the Physical Component Summary (PCS) scores were negatively influenced by the anti-resorptive medication duration (p = 0.031 and β = −1.137). No significant differences were observed with the other variables considered. The QoL of cancer patients is generally deteriorated and MRONJ may cause a further negative impact. This study highlights the possible need to include psychosocial and physical evaluations in the management process of MRONJ in cancer patients. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to 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 58 | Viewed by 5826

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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3 pages, 182 KiB

Open AccessReply

Comment in Response to “Temozolomide in Glioblastoma Therapy: Role of Apoptosis, Senescence and Autophagy etc. by B. Kaina”

by Mike-Andrew Westhoff, Tim Baisch, Verena J. Herbener, Georg Karpel-Massler, Klaus-Michael Debatin and Hannah Strobel

Biomedicines 2020, 8(4), 93; https://doi.org/10.3390/biomedicines8040093 - 20 Apr 2020

Cited by 5 | Viewed by 2143

Abstract

It is with great pleasure that we acknowledge the fact that our review on Temozolomide (TMZ) has initiated a discussion [...] Full article

(This article belongs to the Special Issue Principal Challenges in the Adjuvant Treatment of Glioblastoma)

11 pages, 1602 KiB

Open AccessArticle

Aerobic Exercise Training Inhibits Neointimal Formation via Reduction of PCSK9 and LOX-1 in Atherosclerosis

by Wei Li, Heegeun Park, Erling Guo, Wooyeon Jo, Kyu Min Sim and Sang Ki Lee

Biomedicines 2020, 8(4), 92; https://doi.org/10.3390/biomedicines8040092 - 19 Apr 2020

Cited by 6 | Viewed by 2988

Abstract

The purpose of this study was to investigate whether aerobic exercise training inhibits atherosclerosis via the reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in balloon-induced common carotid arteries of a high-fat-diet rats. Male SD (Sprague Dawley) rats fed an eight-weeks high-fat [...] Read more.

The purpose of this study was to investigate whether aerobic exercise training inhibits atherosclerosis via the reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in balloon-induced common carotid arteries of a high-fat-diet rats. Male SD (Sprague Dawley) rats fed an eight-weeks high-fat diet were randomly divided into three groups; these were the sham-operated control (SC), the balloon-induced control (BIC) and the balloon-induced exercise (BIE). The aerobic exercise training groups were performed on a treadmill. The major findings were as follows: first, body weight gain was significantly decreased by aerobic exercise training compared to the BIC without change of energy intake. Second, neointimal formation was significantly inhibited by aerobic exercise training in the balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. Third, low-density lipoprotein (LDL) receptor (LDLr) expression was significantly increased by aerobic exercise training in the livers of the high-fat diet group compared to the BIC, but not the proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Fourth, aerobic exercise training significantly decreased the expression of PCSK9, the lectin-like oxidized LDL receptor-1 (LOX-1), and vascular cell adhesion molecule-1 (VCAM-1) in balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. In conclusion, our results suggest that aerobic exercise training increases LDLr in the liver and inhibits neointimal formation via the reduction of PCSK9 and LOX-1 in balloon-induced common carotid arteries of high-fat-diet-induced rats. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 3150 KiB

Open AccessArticle

Immunogenicity and Protective Effect of a Virus-Like Particle Containing the SAG1 Antigen of Toxoplasma gondii as a Potential Vaccine Candidate for Toxoplasmosis

by Won Hyung Choi and Ji Sun Park

Biomedicines 2020, 8(4), 91; https://doi.org/10.3390/biomedicines8040091 - 18 Apr 2020

Cited by 6 | Viewed by 2596

Abstract

This study was carried out to evaluate the vaccination effect of a virus-like particle (VLP) including the surface antigen 1 (SAG1) of Toxoplasma gondii as a potential vaccine for toxoplasmosis. The SAG1 virus-like particles (SAG1-VLPs) were expressed by Sf9 cells, and their expression [...] Read more.

This study was carried out to evaluate the vaccination effect of a virus-like particle (VLP) including the surface antigen 1 (SAG1) of Toxoplasma gondii as a potential vaccine for toxoplasmosis. The SAG1 virus-like particles (SAG1-VLPs) were expressed by Sf9 cells, and their expression was confirmed through cloning, RT-PCR analysis, and western blot method. The immunogenicity and vaccine efficacy of SAG1-VLPs were assessed by the antibody response, cytokine analysis, neutralization activity, splenocyte assay, and survival rates through a mouse model. In particular, IgG, IgG1, IgG2a, and IgA were markedly increased after immunization, and the survival rates of T. gondii were strongly inhibited by the immunized sera. Furthermore, the immunization of SAG1-VLPs effectively decreased the production of specific cytokines, such as IL-1β, IL-6, TNF-α, and IFN-γ, after parasite infection. In particular, the immunized group showed strong activity and viability compared with the non-immunized infection group, and their survival rate was 75%. These results demonstrate that SAG1-VLP not only has the immunogenicity to block T. gondii infection by effectively inducing the generation of specific antibodies against T. gondii, but is also an effective antigen delivery system for preventing toxoplasmosis. This study indicates that SAG1-VLP can be effectively utilized as a promising vaccine candidate for preventing or inhibiting T. gondii infection. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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19 pages, 1159 KiB

Open AccessReview

The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches

by Solomon Habtemariam

Biomedicines 2020, 8(4), 90; https://doi.org/10.3390/biomedicines8040090 - 18 Apr 2020

Cited by 21 | Viewed by 5951

Abstract

Berberine is a quaternary isoquinoline alkaloid that has been isolated from numerous plants which are still in use today as medicine and herbal supplements. The great deal of enthusiasm for intense research on berberine to date is based on its diverse pharmacological effects [...] Read more.

Berberine is a quaternary isoquinoline alkaloid that has been isolated from numerous plants which are still in use today as medicine and herbal supplements. The great deal of enthusiasm for intense research on berberine to date is based on its diverse pharmacological effects via action on multiple biological targets. Its poor bioavailability resulting from low intestinal absorption coupled with its efflux by the action of P-glycoprotein is, however, the major limitation. In this communication, the chemical approach of improving berberine’s bioavailability and pharmacological efficacy is scrutinised with specific reference to type-2 diabetes and associated diseases such as hyperlipidaemia and obesity. The application of modern delivery systems, research from combination studies to preparation of berberine structural hybrids with known biologically active compounds (antidiabetic, antihyperlipidaemic and antioxidant), as well as synthesis approaches of berberine derivative are presented. Improvement of bioavailability and efficacy through in vitro and ex vivo transport studies, as well as animal models of bioavailability/efficacy in lipid metabolism and diabetes targets are discussed. Full article

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19 pages, 4011 KiB

Open AccessArticle

PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation

by Naoto Matsumoto, Yuki Miyamoto, Kohei Hattori, Akihiro Ito, Hironori Harada, Hiroaki Oizumi, Katsuya Ohbuchi, Kazushige Mizoguchi and Junji Yamauchi

Biomedicines 2020, 8(4), 89; https://doi.org/10.3390/biomedicines8040089 - 16 Apr 2020

Cited by 10 | Viewed by 2803

Abstract

Myelin sheaths created by oligodendroglial cells encase neuronal axons to achieve saltatory conduction and protect axons. Pelizaeus-Merzbacher disease (PMD) is a prototypic, hereditary demyelinating oligodendroglial disease of the central nervous system (CNS), and is currently known as hypomyelinating leukodystrophy 1 (HLD1). HLD12 is [...] Read more.

Myelin sheaths created by oligodendroglial cells encase neuronal axons to achieve saltatory conduction and protect axons. Pelizaeus-Merzbacher disease (PMD) is a prototypic, hereditary demyelinating oligodendroglial disease of the central nervous system (CNS), and is currently known as hypomyelinating leukodystrophy 1 (HLD1). HLD12 is an autosomal recessive disorder responsible for the gene that encodes vacuolar protein sorting-associated protein 11 homolog (VPS11). VPS11 is a member of the molecular group controlling the early endosome antigen 1 (EEA1)- and Rab7-positive vesicle-mediated protein trafficking to the lysosomal compartments. Herein, we show that the HLD12-associated Cys846-to-Gly (C846G) mutation of VPS11 leads to its aggregate formation with downregulated signaling through 70 kDa S6 protein kinase (p70S6K) in the oligodendroglial cell line FBD-102b as the model. In contrast, wild-type proteins are localized in both EEA1- and Rab7-positive vesicles. Cells harboring the C846G mutant constructs decrease differentiated phenotypes with web-like structures following differentiation, whereas parental cells exhibit them suitably. It is of note that we identify PP1C and PP2A as the protein phosphatases for phosphorylated Thr-389 of p70S6K essential for kinase activation in cells. The respective knockdown experiments or inhibitor treatment stimulates phosphorylation of p70S6K and ameliorates the inhibition of morphological differentiation, as well as the formation of protein aggregates. These results indicate that inhibition of p70S6K phosphatases PP1C and PP2A improves the defective morphological differentiation associated with HLD12 mutation, thereby hinting at amelioration based on a possible molecular and cellular pathological mechanism underlying HLD12. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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15 pages, 1755 KiB

Open AccessArticle

A Non-Coding RNA Landscape of Bronchial Epitheliums of Lung Cancer Patients

by Yanli Lin, Van Holden, Pushpawallie Dhilipkannah, Janaki Deepak, Nevins W. Todd and Feng Jiang

Biomedicines 2020, 8(4), 88; https://doi.org/10.3390/biomedicines8040088 - 13 Apr 2020

Cited by 15 | Viewed by 2321

Abstract

We propose to systematically identify a non-coding RNA (ncRNA) profile of exfoliated bronchial epitheliums of sputum from lung cancer patients. Bronchial epithelial cells enriched from sputum of 32 lung cancer patients and 33 cancer-free smokers were analyzed by next-generation sequencing to comprehensively characterize [...] Read more.

We propose to systematically identify a non-coding RNA (ncRNA) profile of exfoliated bronchial epitheliums of sputum from lung cancer patients. Bronchial epithelial cells enriched from sputum of 32 lung cancer patients and 33 cancer-free smokers were analyzed by next-generation sequencing to comprehensively characterize the ncRNA profiles. In addition, 108 miRNAs, 88 small nucleolar RNAs, 13 piwi-interacting RNAs, 6 transfer RNAs, 4 ribosomal RNAs, 19 small nuclear RNAs, and 25 long-noncoding (lnc) RNAs displayed a significantly different level in bronchial epitheliums of sputum of lung cancer patients versus cancer-free smokers (all <0.001). PCR analysis confirmed their different expression levels in the sputum specimens. A high expression of SNHG9, an lncRNA, was validated in 78 lung tumor tissues, and the expression was inversely associated with overall survival of lung cancer patients (p = 0.002). Knockdown of SNHG9 in cancer cells reduced the cell growth, proliferation, and invasion in vitro and tumorigenesis in vivo. The multiple differentially expressed ncRNAs in bronchial epitheliums may contribute to the development and progression of lung cancer and provide potential biomarkers and therapeutic targets for the disease. Full article

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

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11 pages, 1754 KiB

Open AccessArticle

Enhancement of Amyloid β_1–43 Production in the Lens Epithelium of Japanese Type 2 Diabetic Patients

by Yu Mano, Hiroko Otake, Teppei Shibata, Eri Kubo, Hiroshi Sasaki and Noriaki Nagai

Biomedicines 2020, 8(4), 87; https://doi.org/10.3390/biomedicines8040087 - 13 Apr 2020

Viewed by 1936

Abstract

We investigated whether the accumulation of amyloid β-protein (Aβ) is enhanced in the lenses of diabetic patients. Lens epithelium samples were collected from Japanese patients during cataract surgery, and the Aβ levels and gene expression of Aβ-producing and -degrading enzymes in the samples [...] Read more.

We investigated whether the accumulation of amyloid β-protein (Aβ) is enhanced in the lenses of diabetic patients. Lens epithelium samples were collected from Japanese patients during cataract surgery, and the Aβ levels and gene expression of Aβ-producing and -degrading enzymes in the samples were measured by ELISA and real-time RT-PCR, respectively. The Aβ_1–43 levels in lenses of non-diabetic patients were low (0.11 pmol/g protein), while the levels in lenses of diabetic patients were significantly (6-fold) higher. Moreover, the Aβ_1–43/total-Aβ ratio in the lenses of diabetic patients was also significantly higher than non-diabetic patients (p < 0.05). In addition, the mRNA levels for Aβ-producing enzymes were also enhanced in the lenses of diabetic patients. In contrast to the results for Aβ-producing enzymes, the mRNAs for the Aβ-degrading enzymes in the lenses of diabetic patients were significantly lower than in non-diabetic patients (p < 0.05). Furthermore, Aβ_1–43/total-Aβ ratio in lenses was found to increase with plasma glucose level. In conclusion, these results suggest that high glucose levels cause both an increase in Aβ production and a decrease in Aβ degradation, and these changes lead to the enhancement in Aβ_1–43 accumulation in the lenses of diabetic patients. These findings are useful for developing therapies for diabetic cataracts and for developing anti-cataract drugs. Full article

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

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13 pages, 7692 KiB

Open AccessArticle

Tussilagone Reduces Tumorigenesis by Diminishing Inflammation in Experimental Colitis-Associated Colon Cancer

by Sang-Hyeon Nam and Jin-Kyung Kim

Biomedicines 2020, 8(4), 86; https://doi.org/10.3390/biomedicines8040086 - 11 Apr 2020

Cited by 12 | Viewed by 2482

Abstract

Background: Tussilagone, a major component of Tussilago farfara L., has anti-angiogenic and anti-inflammatory effects. However, the therapeutic and preventive activity of tussilagone in colitis-associated colon carcinogenesis is unknown. Methods: We intended to investigate the therapeutic effects and the potential mechanism of action underlying [...] Read more.

Background: Tussilagone, a major component of Tussilago farfara L., has anti-angiogenic and anti-inflammatory effects. However, the therapeutic and preventive activity of tussilagone in colitis-associated colon carcinogenesis is unknown. Methods: We intended to investigate the therapeutic effects and the potential mechanism of action underlying the pharmacological activity of tussilagone on colitis-associated colon cancer induced in mice using azoxymethane (AOM)/dextran sulfate sodium (DSS). We injected BALB/c mice with AOM and administered 2% DSS in drinking water. The mice were given tussilagone (2.5 and 5 mg/kg body weight) and colon tissues was collected at 72 days. We used Western blotting, immunohistochemistry and real-time RT-PCR analyses to examine the tumorigenesis and inflammatory status of the colon. Results: Tussilagone administration significantly reduced the formation of colonic tumors. In addition, tussilagone treatment markedly reduced the inflammatory mediators and increased heme oxygease-1 in protein and mRNA levels in colon tissues. Meanwhile, nuclear NF-κB-positive cells were elevated and nuclear Nrf2-positive cells were demised by tussilagone treatment in colon tissues. Tussilagone also reduced cell proliferation, induced apoptosis and decreased the β-catenin expression. Conclusions: Tussilagone administration decreases the inflammation and proliferation induced by AOM/DSS and induced apoptosis in colon tissue. Overall, this study indicates the potential value of tussilagone in suppressing colon tumorigenesis. Full article

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

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11 pages, 1865 KiB

Open AccessArticle

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

by Domenico De Rasmo, Anna Ferretta, Silvia Russo, Maddalena Ruggieri, Piergiorgio Lasorella, Damiano Paolicelli, Maria Trojano and Anna Signorile

Biomedicines 2020, 8(4), 85; https://doi.org/10.3390/biomedicines8040085 - 11 Apr 2020

Cited by 17 | Viewed by 3205

Abstract

Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by [...] Read more.

Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by several mechanisms and proteins. Among others, optic atrophy 1 (OPA1) protein plays a key role in the regulating mitochondrial dynamics, cristae architecture and release of pro-apoptotic factors. Very interesting, mutations in OPA1 gene, have been associated with multiple sclerosis-like disorder. We have analyzed OPA1 and some factors involved in its regulation. Fifteen patients with MS and fifteen healthy control subjects (HC) were enrolled into the study and peripheral blood mononuclear cells (PBMCs) were isolated. H₂O₂ level was measured spectrofluorimetrically, OPA1, PHB2, SIRT3, and OMA1 were analyzed by western blotting. Statistical analysis was performed using Student’s t-test. The results showed that PBMC of MS patients were characterized by a deregulation of OPA1 processing associated with increased H₂O₂ production, inactivation of OMA1 and increase of PHB2 protein level. The presented data suggest that the alteration of PHB2, OMA1, and OPA1 processing could be involved in resistance towards apoptosis. These molecular parameters could also be useful to assess disease activity. Full article

(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)

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10 pages, 2632 KiB

Open AccessArticle

Epigallocatechin-3-Gallate Induces Apoptosis as a TRAIL Sensitizer via Activation of Caspase 8 and Death Receptor 5 in Human Colon Cancer Cells

by Oh Sung Kwon, Ji Hoon Jung, Eun Ah Shin, Ji Eon Park, Woon Yi Park and Sung-Hoon Kim

Biomedicines 2020, 8(4), 84; https://doi.org/10.3390/biomedicines8040084 - 09 Apr 2020

Cited by 9 | Viewed by 2641

Abstract

Though epigallocatechin-3-gallate (EGCG), a major compound of green tea, has anti-diabetes, anti-obesity, anti-inflammatory, and antitumor effects, the underlying antitumor molecular mechanism of EGCG was not fully understood so far. Here the sensitizing effect of EGCG to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was examined in [...] Read more.

Though epigallocatechin-3-gallate (EGCG), a major compound of green tea, has anti-diabetes, anti-obesity, anti-inflammatory, and antitumor effects, the underlying antitumor molecular mechanism of EGCG was not fully understood so far. Here the sensitizing effect of EGCG to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was examined in colorectal cancers. Cotreatment of EGCG and TRAIL synergistically enhanced cytotoxicity and sub G1 accumulation, increased the number of terminal deoxynucleotidyl transferase-dT-mediated dUTP nick end labelling (TUNEL)-positive cells in SW480 and HCT116 cells. Furthermore, this cotreatment promoted the cleavages of poly (adenosine diphosphate-ribose) polymerase (PARP) and induced caspase 8 activation compared to TRAIL or EGCG alone in SW480 and HCT116 cells. Of note, cotreatment of EGCG and TRAIL increased the expression of death receptor 5 (DR5) at protein and mRNA levels and also DR5 cell surface level in colon cancer cells. Conversely, depletion of DR5 reduced the apoptotic activity of cotreatment of EGCG and TRAIL to increase cytotoxicity, sub-G1 population and PARP cleavages in colon cancer cells. Overall, our findings provide evidence that EGCG can be a sensitizer of TRAIL via DR5 and caspase 8 mediated apoptosis in colorectal cancer cells. Full article

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

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8 pages, 687 KiB

Open AccessArticle

Fecal Recovery of Probiotics Administered as a Multi-Strain Formulation during Antibiotic Treatment

by Sofia D. Forssten, Nicolas Yeung and Arthur C. Ouwehand

Biomedicines 2020, 8(4), 83; https://doi.org/10.3390/biomedicines8040083 - 09 Apr 2020

Cited by 1 | Viewed by 3044

Abstract

The present study aimed to investigate whether probiotic recovery is affected when consumed together with antibiotics. Fecal samples were collected from an earlier antibiotic associated diarrhea, randomized, placebo-controlled study with a product consisting of a combination of Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, [...] Read more.

The present study aimed to investigate whether probiotic recovery is affected when consumed together with antibiotics. Fecal samples were collected from an earlier antibiotic associated diarrhea, randomized, placebo-controlled study with a product consisting of a combination of Lactobacillus acidophilus NCFM, Lactobacillus paracasei Lpc-37, and Bifidobacterium lactis Bi-07, B. lactis Bl-04 at equal numbers and at a total dose of 10¹⁰ CFU. Fecal samples were collected during the screening visit (T0), i.e., at the time of antibiotic prescription, and then on the last day of the antibiotic treatment (T1) as well as seven days after the subject had stopped taking the antibiotic treatment (T2) and at two weeks after completing antibiotic treatment and one week after probiotic/placebo consumption stopped (T3). Samples were analyzed for the presence of the four administered strains. The study was registered at clinicaltrials.gov as NCT01596829. Detection levels of all four strains were significantly increased from T0 to T1 and returned to baseline level from T2 to T3. There were also significantly more subjects with detectable levels of L. paracasei Lpc-37, B. lactis Bi-07, and B. lactis Bl-04 at T1 and T2 compared to T0 and T3, and compared to placebo. Each of the four strains could be detected in the feces of patients apparently unaffected by the simultaneous consumption of antibiotics. Full article

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

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24 pages, 1946 KiB

Open AccessReview

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

by János Szebeni and Raj Bawa

Biomedicines 2020, 8(4), 82; https://doi.org/10.3390/biomedicines8040082 - 08 Apr 2020

Cited by 21 | Viewed by 4080

Abstract

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was [...] Read more.

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the “global response” of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the “global response” claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model’s demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine “complement activation-related pseudoallergy” (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs. Full article

(This article belongs to the Special Issue Impact of Nanobiotechnology (Nanomedicine) on the Future of Medicine: The Road toward Precision Medicine)

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17 pages, 810 KiB

Open AccessArticle

A Protocol for the Multi-Omic Integration of Cervical Microbiota and Urine Metabolomics to Understand Human Papillomavirus (HPV)-Driven Dysbiosis

by Nataliya Chorna and Filipa Godoy-Vitorino

Biomedicines 2020, 8(4), 81; https://doi.org/10.3390/biomedicines8040081 - 08 Apr 2020

Cited by 4 | Viewed by 3816

Abstract

The multi-omic integration of microbiota data with metabolomics has gained popularity. This protocol is based on a human multi-omics study, integrating cervicovaginal microbiota, HPV status and neoplasia, with urinary metabolites. Indeed, to understand the biology of the infections and to develop adequate interventions [...] Read more.

The multi-omic integration of microbiota data with metabolomics has gained popularity. This protocol is based on a human multi-omics study, integrating cervicovaginal microbiota, HPV status and neoplasia, with urinary metabolites. Indeed, to understand the biology of the infections and to develop adequate interventions for cervical cancer prevention, studies are needed to characterize in detail the cervical microbiota and understand the systemic metabolome. This article is a detailed protocol for the multi-omic integration of cervical microbiota and urine metabolome to shed light on the systemic effects of cervical dysbioses associated with Human Papillomavirus (HPV) infections. This methods article suggests detailed sample collection and laboratory processes of metabolomics, DNA extraction for microbiota, HPV typing, and the bioinformatic analyses of the data, both to characterize the metabolome, the microbiota, and joint multi-omic analyses, useful for the development of new point-of-care diagnostic tests based on these approaches. Full article

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

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20 pages, 3474 KiB

Open AccessArticle

Factors Influencing the Prevalence of Resistance-Associated Substitutions in NS5A Protein in Treatment-Naive Patients with Chronic Hepatitis C

by Karen K. Kyuregyan, Vera S. Kichatova, Anastasiya A. Karlsen, Olga V. Isaeva, Sergei A. Solonin, Stefan Petkov, Morten Nielsen, Maria G. Isaguliants and Mikhail I. Mikhailov

Biomedicines 2020, 8(4), 80; https://doi.org/10.3390/biomedicines8040080 - 07 Apr 2020

Cited by 2 | Viewed by 2410

Abstract

Direct-acting antivirals (DAAs) revolutionized treatment of hepatitis C virus (HCV) infection. Resistance-associated substitutions (RASs) present at the baseline impair response to DAA due to rapid selection of resistant HCV strains. NS5A is indispensable target of the current DAA treatment regimens. We evaluated prevalence [...] Read more.

Direct-acting antivirals (DAAs) revolutionized treatment of hepatitis C virus (HCV) infection. Resistance-associated substitutions (RASs) present at the baseline impair response to DAA due to rapid selection of resistant HCV strains. NS5A is indispensable target of the current DAA treatment regimens. We evaluated prevalence of RASs in NS5A in DAA-naïve patients infected with HCV 1a (n = 19), 1b (n = 93), and 3a (n = 90) before systematic DAA application in the territory of the Russian Federation. Total proportion of strains carrying at least one RAS constituted 35.1% (71/202). In HCV 1a we detected only M28V (57.9%) attributed to a founder effect. Common RASs in HCV 1b were R30Q (7.5%), L31M (5.4%), P58S (4.4%), and Y93H (5.4%); in HCV 3a, A30S (31.0%), A30K (5.7%), S62L (8.9%), and Y93H (2.2%). Prevalence of RASs in NS5A of HCV 1b and 3a was similar to that worldwide, including countries practicing massive DAA application, i.e., it was not related to treatment. NS5A with and without RASs exhibited different co-variance networks, which could be attributed to the necessity to preserve viral fitness. Majority of RASs were localized in polymorphic regions subjected to immune pressure, with selected substitutions allowing immune escape. Altogether, this explains high prevalence of RAS in NS5A and low barrier for their appearance in DAA-inexperienced population. Full article

(This article belongs to the Section Virology, Vaccines and Viral Vectors)

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10 pages, 1688 KiB

Open AccessArticle

Characterization of the Antinociceptive Activity from Stevia serrata Cav

by Millena S. Cordeiro, Daniel L. R. Simas, Juan F. Pérez-Sabino, Max S. Mérida-Reyes, Manuel A. Muñoz-Wug, Bessie E. Oliva-Hernández, Antônio J. R. da Silva, Patricia D. Fernandes and Thais B. S. Giorno

Biomedicines 2020, 8(4), 79; https://doi.org/10.3390/biomedicines8040079 - 07 Apr 2020

Cited by 8 | Viewed by 2813

Abstract

Background: Stevia serrata Cav. (Asteraceae), widely found in Guatemala, is used to treat gastrointestinal problems. The aim of this study was to demonstrate the antinociceptive and anti-inflammatory effects of the essential oil (EO) and the mechanism of action. Methods: EO was tested in [...] Read more.

Background: Stevia serrata Cav. (Asteraceae), widely found in Guatemala, is used to treat gastrointestinal problems. The aim of this study was to demonstrate the antinociceptive and anti-inflammatory effects of the essential oil (EO) and the mechanism of action. Methods: EO was tested in chemical (capsaicin- and glutamate-induced licking response) or thermal (hot plate) models of nociception at 10, 30 or 100 mg/kg doses. The mechanism of action was evaluated using two receptor antagonists (naloxone, atropine) and an enzyme inhibitor (L-NAME). The anti-hyperalgesic effect was evaluated using carrageenan-induced nociception and evaluated in the hot plate. Results: All three doses of EO reduced licking response induced by glutamate, and higher doses reduced capsaicin-induced licking. EO also increased area under the curve, similar to the morphine-treated group. The antinociceptive effect induced by EO was reversed by pretreatment of mice with naloxone (1 mg/kg, ip), atropine (1 mg/kg, ip) or L-NAME (3 mg/kg, ip). EO also demonstrated an anti-hyperalgesic effect. The 100 mg/kg dose increased the latency time, even at 1 h after oral administration and this effect has been maintained until the 96th hour, post-administration. Conclusions: Our data suggest that essential oil of S. serrata presents an antinociceptive effect mediated, at least in part, through activation of opioid, cholinergic and nitrergic pathways. Full article

(This article belongs to the Special Issue Natural Medicine in Therapy)

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11 pages, 2014 KiB

Open AccessArticle

Atropine Differentially Modulates ECM Production by Ocular Fibroblasts, and Its Ocular Surface Toxicity Is Blunted by Colostrum

by Martina Cristaldi, Melania Olivieri, Salvatore Pezzino, Giorgia Spampinato, Gabriella Lupo, Carmelina Daniela Anfuso and Dario Rusciano

Biomedicines 2020, 8(4), 78; https://doi.org/10.3390/biomedicines8040078 - 05 Apr 2020

Cited by 16 | Viewed by 3322

Abstract

Background: The etiology and the mechanism behind atropine treatment of progressive myopia are still poorly understood. Our study addressed the role of scleral and choroidal fibroblasts in myopia development and atropine function. Methods: Fibroblasts treated in vitro with atropine or 7-methylxanthine were tested [...] Read more.

Background: The etiology and the mechanism behind atropine treatment of progressive myopia are still poorly understood. Our study addressed the role of scleral and choroidal fibroblasts in myopia development and atropine function. Methods: Fibroblasts treated in vitro with atropine or 7-methylxanthine were tested for ECM production by Western blotting. Corneal epithelial cells were treated with atropine in the presence or absence of colostrum or fucosyl-lactose, and cell survival was evaluated by the MTT metabolic test. Results: Atropine and 7-methyl-xanthine stimulated collagen I and fibronectin production in scleral fibroblasts, while they inhibited their production in choroidal fibroblasts. Four days of treatment with atropine of corneal epithelial cells significantly decreased cell viability, which could be prevented by the presence of colostrum or fucosyl-lactose. Conclusions: Our results show that atropine may function in different ways in different eye districts, strengthening the scleral ECM and increasing permeability in the choroid. The finding that colostrum or fucosyl-lactose attenuate the corneal epithelial toxicity after long-term atropine treatment suggests the possibility that both compounds can efficiently blunt its toxicity in children subjected to chronic atropine treatment. Full article

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

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9 pages, 242 KiB

Open AccessArticle

Persistently Worsened Tear Break-up Time and Keratitis in Unilateral Pseudophakic Eyes after a Long Postoperative Period

by Akiko Hanyuda, Kazuno Negishi, Kazuo Tsubota and Masahiko Ayaki

Biomedicines 2020, 8(4), 77; https://doi.org/10.3390/biomedicines8040077 - 05 Apr 2020

Cited by 7 | Viewed by 2060

Abstract

Dry eye disease may develop and persist after cataract surgery; however, unilateral cases have not been fully documented. This cross-sectional, observational study was conducted in five eye clinics in Japan. A total of 1023 outpatients were initially enrolled, and 89 unilateral pseudophakic subjects [...] Read more.

Dry eye disease may develop and persist after cataract surgery; however, unilateral cases have not been fully documented. This cross-sectional, observational study was conducted in five eye clinics in Japan. A total of 1023 outpatients were initially enrolled, and 89 unilateral pseudophakic subjects with 1+ year of follow-up after uncomplicated cataract surgery were included. The tear break-up times (TBUTs) and keratoconjunctival staining results were compared between phakic and pseudophakic eyes. The mean age of the patients was 69.3 ± 10.4 years (32 men, 36.0%), and the mean postoperative period was 4.6 ± 4.4 (1–20) years. For the ophthalmic parameters, the TBUTs were 4.4 ± 1.9 and 3.8 ± 1.9 s (p < 0.001), the keratoconjunctival staining scores were 0.11 ± 0.38 and 0.22 ± 0.56 (p = 0.02), the spherical equivalents were −1.27 ± 2.51 and −0.99 ± 1.45 D (p = 0.21), the astigmatic errors were 0.79 ± 0.66 and 0.78 ± 0.58 D (p = 0.80), and the intraocular pressures were 13.6 ± 2.9 and 13.5 ± 2.6 mmHg (p = 0.62) for the phakic and pseudophakic eyes, respectively. The corneal status was significantly worse in the pseudophakic eyes than in the contralateral phakic eyes, even after more than one year after implant surgery. The present results suggested that long-term ocular surface problems should be examined further since they may not originate only from surgery or postoperative ocular surface diseases. Full article

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

16 pages, 2337 KiB

Open AccessArticle

Polymerized Selenium Nanoparticles for Folate-Receptor-Targeted Delivery of Anti-Luc-siRNA: Potential for Gene Silencing

by Fiona Maiyo and Moganavelli Singh

Biomedicines 2020, 8(4), 76; https://doi.org/10.3390/biomedicines8040076 - 05 Apr 2020

Cited by 31 | Viewed by 4068

Abstract

The development of a biocompatible and nontoxic gene delivery vehicle remains a challenging task. Selenium nanoparticles (SeNPs) have the potential to increase delivery efficiency, to reduce side effects, and to improve therapeutic outcomes. In this study, chitosan (Ch) functionalized folate (FA)-targeted SeNPs were [...] Read more.

The development of a biocompatible and nontoxic gene delivery vehicle remains a challenging task. Selenium nanoparticles (SeNPs) have the potential to increase delivery efficiency, to reduce side effects, and to improve therapeutic outcomes. In this study, chitosan (Ch) functionalized folate (FA)-targeted SeNPs were synthesized, characterized, and evaluated for their potential to bind, protect, and safely deliver Fluc-siRNA in vitro. SeNPs of less than 100 nm were successfully synthesised and further confirmed using UV-vis and Fourier transform infrared spectroscopy, transmission electron microscopy, and nanoparticle tracking analysis. Cell viability studies were conducted in vitro in selected cancer and non-cancer cell lines. Folate receptor (FOLR1) targeted and nontargeted luciferase gene silencing studies were assessed in the transformed Hela-tat-Luc cell line expressing the luciferase gene. Targeted and nontargeted SeNP nanocomplexes showed minimal toxicity in all cell lines at selected w/w ratios. Maximum gene silencing was achieved at optimum w/w ratios for both nanocomplexes, with Selenium-chitosan-folic acid (SeChFA) nanocomplexes showing slightly better transgene silencing, as supported by results from docking studies showing that SeChFA nanocomplexes interacted strongly with the folate receptor (FOLR1) with high binding energy of −4.4 kcal mol⁻¹. Full article

(This article belongs to the Section Gene and Cell Therapy)

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11 pages, 288 KiB

Open AccessArticle

Dietary Supplementation with Chestnut (Castanea sativa) Reduces Abdominal Adiposity in FVB/n Mice: A Preliminary Study

by Pedro Rodrigues, Tiago Ferreira, Elisabete Nascimento-Gonçalves, Fernanda Seixas, Rui Miguel Gil da Costa, Tânia Martins, Maria João Neuparth, Maria João Pires, Germano Lanzarin, Luís Félix, Carlos Venâncio, Isabel C.F.R. Ferreira, Margarida M.S.M. Bastos, Rui Medeiros, Isabel Gaivão, Eduardo Rosa and Paula A. Oliveira

Biomedicines 2020, 8(4), 75; https://doi.org/10.3390/biomedicines8040075 - 04 Apr 2020

Cited by 16 | Viewed by 3639

Abstract

The production of chestnut (Castanea sativa Miller) is mostly concentrated in Europe. Chestnut is recognized by its high content of antioxidants and phytosterols. This work aimed to evaluate the effects of dietary chestnut consumption over physiological variables of FVB/n mice. Eighteen FVB/n [...] Read more.

The production of chestnut (Castanea sativa Miller) is mostly concentrated in Europe. Chestnut is recognized by its high content of antioxidants and phytosterols. This work aimed to evaluate the effects of dietary chestnut consumption over physiological variables of FVB/n mice. Eighteen FVB/n male 7-month-old mice were randomly divided into three experimental groups (n = 6): 1 (control group) fed a standard diet; 2 fed a diet supplemented with 0.55% (w/w) chestnut; and 3 supplemented with 1.1% (w/w) chestnut. Body weight, water, and food intake were recorded weekly. Following 35 days of supplementation, the mice were sacrificed for the collection of biological samples. Chestnut supplementation at 1.1% reduced abdominal adipose tissue. Lower serum cholesterol was also observed in animals supplemented with chestnut. There were no significant differences concerning the incidence of histological lesions nor in biochemical markers of hepatic damage and oxidative stress. These results suggest that chestnut supplementation may contribute to regulate adipose tissue deposition. Full article

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

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11 pages, 432 KiB

Open AccessArticle

Effectiveness of Glecaprevir/Pibrentasvir for Hepatitis C: Real-World Experience and Clinical Features of Retreatment Cases

by Ayumi Sugiura, Satoru Joshita, Yuki Yamashita, Tomoo Yamazaki, Naoyuki Fujimori, Takefumi Kimura, Akihiro Matsumoto, Shuichi Wada, Hiromitsu Mori, Soichiro Shibata, Kaname Yoshizawa, Susumu Morita, Kiyoshi Furuta, Atsushi Kamijo, Akihiro Iijima, Satoko Kako, Atsushi Maruyama, Masakazu Kobayashi, Michiharu Komatsu, Makiko Matsumura, Chiharu Miyabayashi, Tetsuya Ichijo, Aki Takeuchi, Yuriko Koike, Yukio Gibo, Toshihisa Tsukadaira, Hiroyuki Inada, Yoshiyuki Nakano, Seiichi Usuda, Kendo Kiyosawa, Eiji Tanaka and Takeji Umemura Show full author list Hide full author list

Biomedicines 2020, 8(4), 74; https://doi.org/10.3390/biomedicines8040074 - 03 Apr 2020

Cited by 14 | Viewed by 3020

Abstract

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n [...] Read more.

Glecaprevir/pibrentasvir (G/P) are direct-acting antivirals (DAAs) that achieve a high sustained virological response (SVR) rate for hepatitis C virus (HCV) infection. We investigated G/P effectiveness for HCV patients based on real-world experience and the clinical features of retreatment cases. HCV patients (n = 182) were compared for clinical features and outcomes between first treatment (n = 159) and retreatment (n = 23) G/P groups. Overall, 77 patients (42.3%) were male, the median age was 68 years, and 86/66/1/4 cases had genotype 1/2/1 + 2/3, respectively. An SVR was achieved in 97.8% (178/182) of cases by intention-to-treat analysis and 99.4% (178/179) of cases by per-protocol analysis. There were no remarkable differences between the first treatment and retreatment groups for male (42.8% vs. 39.1%, p = 0.70), median age (68 vs. 68 years, p = 0.36), prior hepatocellular carcinoma (5.8% vs. 8.7%, p = 0.59), or the fibrosis markers AST-to-platelet ratio index (APRI) (0.5 vs. 0.5, p = 0.80) and fibrosis-4 (FIB-4) index (2.2 vs. 2.6, p = 0.59). The retreatment group had a significantly more frequent history of interferon treatment (12.3% vs. 52.2%, p < 0.01) and the Y93H mutation (25.0% vs. 64.7%, p = 0.02). The number of retreatment patients who had experienced 3, 2, and 1 DAA treatment failures was 1, 3, and 19, respectively, all of whom ultimately achieved an SVR by G/P treatment. In conclusion, G/P was effective and safe for both HCV first treatment and retreatment cases despite the retreatment group having specific resistance mutations for other prior DAAs. As G/P treatment failure has been reported for P32 deletions, clinicians should consider resistance mutations during DAA selection. Full article

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

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16 pages, 3949 KiB

Open AccessArticle

Progesterone-Calcitriol Combination Enhanced Cytotoxicity of Cisplatin in Ovarian and Endometrial Cancer Cells In Vitro

by Ana Paucarmayta, Hannah Taitz, Latoya McGlorthan, Yovanni Casablanca, G. Larry Maxwell, Kathleen M. Darcy and Viqar Syed

Biomedicines 2020, 8(4), 73; https://doi.org/10.3390/biomedicines8040073 - 31 Mar 2020

Cited by 5 | Viewed by 2828

Abstract

Initially, patients that respond to cisplatin (DDP) treatment later relapse and develop chemoresistance. Agents that enhance DDP effectiveness will have a significant impact on cancer treatment. We have shown pronounced inhibitory effects of the progesterone-calcitriol combination on endometrial and ovarian cancer cell growth. [...] Read more.

Initially, patients that respond to cisplatin (DDP) treatment later relapse and develop chemoresistance. Agents that enhance DDP effectiveness will have a significant impact on cancer treatment. We have shown pronounced inhibitory effects of the progesterone-calcitriol combination on endometrial and ovarian cancer cell growth. Here, we examined whether and how progesterone-calcitriol combination potentiates DDP anti-tumor effects in cancer cells. Ovarian and endometrial cancer cells treated with various concentrations of DDP showed a concentration-dependent decrease in cell proliferation. Concurrent treatment of cells with DDP and progesterone-calcitriol ombination potentiated anticancer effects of DDP compared to DDP-calcitriol, or DDP-progesterone treated groups. The anticancer effects were mediated by increased caspase-3, BAX, and decreased BCL2 and PARP-1 expression in DDP and progesterone-calcitriol combination-treated cells. Stimulation of the PI3K/AKT and MAPK/ERK pathways seen in cancer cells was reduced in DDP-progesterone-calcitriol treated cells. Pretreatment of cells with specific inhibitors further diminished AKT and ERK expression. Furthermore, progesterone-calcitriol potentiated the anti-growth effects of DDP on cancer cells by attenuating the expression of SMAD2/3, multidrug resistance protein- 1 (MDR-1), and ABC transporters (ABCG1, and ABCG2), thereby impeding the efflux of chemo drugs from cancer cells. These results suggest a potential clinical benefit of progesterone-calcitriol combination therapy when used in combination with DDP. Full article

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

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15 pages, 1652 KiB

Open AccessArticle

Immunosuppression with Calcineurin Inhibitor after Renal Transplant Failure Inhibits Allosensitization

by Covadonga López del Moral Cuesta, Sandra Guiral Foz, David Gómez Pereda, José Luis Pérez Canga, Marina de Cos Gómez, Jaime Mazón Ruiz, Ana García Santiago, José Iñigo Romón Alonso, Rosalía Valero San Cecilio, Emilio Rodrigo Calabia, David San Segundo Arribas, Marcos López Hoyos and Juan Carlos Ruiz San Millán

Biomedicines 2020, 8(4), 72; https://doi.org/10.3390/biomedicines8040072 - 28 Mar 2020

Cited by 6 | Viewed by 2614

Abstract

Immunosuppression withdrawal after graft failure seems to favor sensitization. A high percentage of calculated panel-reactive antibody (cPRA) and the development of de novo donor specific antibodies (dnDSA) indicate human leukocyte antigen (HLA) sensitization and may hinder the option of retransplantation. There are no [...] Read more.

Immunosuppression withdrawal after graft failure seems to favor sensitization. A high percentage of calculated panel-reactive antibody (cPRA) and the development of de novo donor specific antibodies (dnDSA) indicate human leukocyte antigen (HLA) sensitization and may hinder the option of retransplantation. There are no established protocols on the immunosuppressive treatment that should be maintained after transplant failure. A retrospective analysis including 77 patients who lost their first renal graft between 1 January 2006–31 December 2015 was performed. Two sera were selected per patient, one immediately prior to graft loss and another one after graft failure. cPRA was calculated by Single Antigen in all patients. It was possible to analyze the development of dnDSA in 73 patients. By multivariate logistic regression analysis, the absence of calcineurin inhibitor (CNI) at 6 months after graft failure was related to cPRA > 75% (OR 4.8, CI 95% 1.5–15.0, p = 0.006). The absence of calcineurin inhibitor (CNI) at 6 months after graft loss was significantly associated with dnDSA development (OR 23.2, CI 95% 5.3–100.6, p < 0.001). Our results suggest that the absence of CNI at the sixth month after graft loss is a risk factor for sensitization. Therefore, maintenance of an immunosuppressive regimen based on CNI after transplant failure should be considered when a new transplant is planned, since it seems to prevent HLA allosensitization. Full article

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

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14 pages, 223 KiB

Open AccessReview

Current Advances in Pediatric Onset Multiple Sclerosis

by Kristen S. Fisher, Fernando X. Cuascut, Victor M. Rivera and George J. Hutton

Biomedicines 2020, 8(4), 71; https://doi.org/10.3390/biomedicines8040071 - 28 Mar 2020

Cited by 27 | Viewed by 4485

Abstract

Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more [...] Read more.

Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more about pediatric MS, there has been a development of improved diagnostic criteria leading to earlier diagnosis, earlier initiation of disease-modifying therapies (DMT), and an increasing number of DMT used in the treatment of pediatric MS. Over time, treatment with DMT has trended towards the initiation of higher efficacy treatment at time of diagnosis to help prevent further disease progression and accrual of disability over time, and there is evidence in current literature that supports this change in treatment patterns. In this review, we discuss the current knowledge in diagnosis, treatment, and clinical outcomes in pediatric MS. Full article

(This article belongs to the Special Issue Multiple Sclerosis: Diagnosis and Treatment II)

9 pages, 881 KiB

Open AccessArticle

The Lymphoscintigraphic Study of Unpredictable Head and Neck Cutaneous Melanoma Lymphatic Drainage

by Valentina Lavelli, Cristina Ferrari, Giulia Santo, Corinna Altini, Andrea Ballini, Angela Sardaro, Margherita Fanelli, Antonio Rosario Pisani, Anna Giulia Nappi, Giuseppe Giudice and Giuseppe Rubini

Biomedicines 2020, 8(4), 70; https://doi.org/10.3390/biomedicines8040070 - 27 Mar 2020

Cited by 11 | Viewed by 2615

Abstract

Head and neck cutaneous melanoma (HNCM) does not always follow standard lymphatic drainage; typical expected lymphatic pathways are associated with unexpected ones. The aim of this study was to investigate the relation between the primary HNCM sites and all possible lymphatic drainage pathways [...] Read more.

Head and neck cutaneous melanoma (HNCM) does not always follow standard lymphatic drainage; typical expected lymphatic pathways are associated with unexpected ones. The aim of this study was to investigate the relation between the primary HNCM sites and all possible lymphatic drainage pathways by lymphoscintigraphy with a special focus on the unexpected sentinel lymph node (SLNs) detection. We retrospectively analyzed 67 patients (46 M, 21 F; mean age 63 years) who underwent lymphoscintigraphy from January 2004 to November 2018. 99mTc-serum albumin was injected intra-dermally at the dose of 18–37 MBq in 0.2–0.4 mL. All patients underwent dynamic and static image acquisition. For all patients, the relation between the expected and unexpected SLNs was performed using the “Sidney Melanoma Unit Database” as our reference. The relation was performed also according to the primary HNCM localization. Cohens’ kappa was calculated. In 61/67 (91%) of patients, SLNs were detected only in predictable sites, while in six/67 (9%), unexpected SLNs were revealed. In all patients, the agreement proportion was 91% (95% confidence interval CI 0.8–0.96) and Cohen’s K was 0.11 (95% CI 0–0.43). Regarding the primary melanoma sites, the nasolabial field HNCM showed the highest rate of concordance (K = 0.60; 95%, CI 0.32–0.89) while the preauricular region HNCM revealed the highest rate of discordance with the clinically predictable drainage. The HNCM lymphatic drainage is extremely variable in regard to both the sites and the number of involved SLNs. The lymphoscintigraphic study is highly recommended to identify all possible SLNs in order to perform an accurate staging for all patients and to avoid missing unexpected SLNs. Full article

(This article belongs to the Special Issue Malignant and Potentially Malignant Disorders of the Oral Cavity: Updates from Pathogenesis to Therapy)

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18 pages, 5731 KiB

Open AccessArticle

Two-Step Size-Exclusion Nanofiltration of Prothrombin Complex Concentrate Using Nanocellulose-Based Filter Paper

by Levon Manukyan, Athanasios Mantas, Mikhail Razumikhin, Andrey Katalevsky, Eugen Golubev and Albert Mihranyan

Biomedicines 2020, 8(4), 69; https://doi.org/10.3390/biomedicines8040069 - 26 Mar 2020

Cited by 6 | Viewed by 4507

Abstract

Coagulation Factor IX-rich protrhombin complex concentrate (FIX-PCC) is a therapeutic biologic product that consists of a mixture of several human plasma-derived proteins, useful for treating hemophilia B. Due to its complex composition, FIX-PCC is very challenging to bioprocess through virus removing nanofilters in [...] Read more.

Coagulation Factor IX-rich protrhombin complex concentrate (FIX-PCC) is a therapeutic biologic product that consists of a mixture of several human plasma-derived proteins, useful for treating hemophilia B. Due to its complex composition, FIX-PCC is very challenging to bioprocess through virus removing nanofilters in order to ensure its biosafety. This article describes a two-step filtration process of FIX-PCC using a nanocellulose-based filter paper with tailored porosity. The filters were characterized with scanning electron microscopy (SEM), cryoporometry with differential scanning calorimetry, and nitrogen gas sorption. Furthermore, in order to probe the filter’s cut-off size rejection threshold, removal of small- and large-size model viruses, i.e., ΦX174 (28 nm) and PR772 (70 nm), was evaluated. The feed, pre-filtrate, and permeate solutions were characterized with mass-spectrometric proteomic analysis, dynamic light scattering (DLS), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and analytical size-exclusion high-performance liquid chromatography (SEHPLC). By sequential filtration through 11 μm pre-filter and 33 μm virus removal filter paper, it was possible to achieve high product throughput and high virus removal capacity. The presented approach could potentially be applied for bioprocessing other protein-based drugs. Full article

(This article belongs to the Section Biomedical Materials and Nanomedicine)

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15 pages, 3687 KiB

Open AccessArticle

Comparative Study of Piper sylvaticum Roxb. Leaves and Stems for Anxiolytic and Antioxidant Properties Through In Vivo, In Vitro, and In Silico Approaches

by Md. Adnan, Md. Nazim Uddin Chy, A.T.M. Mostafa Kamal, Md Obyedul Kalam Azad, Kazi Asfak Ahmed Chowdhury, Mohammad Shah Hafez Kabir, Shaibal Das Gupta, Md. Ashiqur Rahman Chowdhury, Young Seok Lim and Dong Ha Cho

Biomedicines 2020, 8(4), 68; https://doi.org/10.3390/biomedicines8040068 - 25 Mar 2020

Cited by 14 | Viewed by 5318

Abstract

Piper sylvaticum Roxb. is traditionally used by the indigenous people of tropical and subtropical countries like Bangladesh, India, and China for relieving the common cold or a variety of chronic diseases, such as asthma, chronic coughing, piles, rheumatic pain, headaches, wounds, tuberculosis, indigestion, [...] Read more.

Piper sylvaticum Roxb. is traditionally used by the indigenous people of tropical and subtropical countries like Bangladesh, India, and China for relieving the common cold or a variety of chronic diseases, such as asthma, chronic coughing, piles, rheumatic pain, headaches, wounds, tuberculosis, indigestion, and dyspepsia. This study tested anxiolytic and antioxidant activities by in vivo, in vitro, and in silico experiments for the metabolites extracted (methanol) from the leaves and stems of P. sylvaticum (MEPSL and MEPSS). During the anxiolytic evaluation analyzed by elevated plus maze and hole board tests, MEPSL and MEPSS (200 and 400 mg/kg, body weight) exhibited a significant and dose-dependent reduction of anxiety-like behavior in mice. Similarly, mice treated with MEPSL and MEPSS demonstrated dose-dependent increases in locomotion and CNS simulative effects in open field test. In addition, both extracts (MEPSL and MEPSS) also showed moderate antioxidant activities in DPPH scavenging and ferric reducing power assays compared to the standard, ascorbic acid. In parallel, previously isolated bioactive compounds from this plant were documented and subjected to a molecular docking study to correlate them with the pharmacological outcomes. The selected four major phytocompounds displayed favorable binding affinities to potassium channel and xanthine oxidoreductase enzyme targets in molecular docking experiments. Overall, P. sylvaticum is bioactive, as is evident through experimental and computational analysis. Further experiments are necessary to evaluate purified novel compounds for the clinical evaluation. Full article

(This article belongs to the Special Issue Natural Medicine in Therapy)

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Biomedicines, Volume 8, Issue 4 (April 2020) – 28 articles

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