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Biomedicines, Volume 9, Issue 1 (January 2021) – 95 articles

Cover Story (view full-size image): Endothelial cell-specific CRIF1 deletion decreased SIRT1 expression, resulting in mitochondrial dysfunction, reduced nitric oxide production, inflammation, excessive oxidative stress, and decreased zona occludens-1 in cardiac tissues. However, intraperitoneal injection of SRT1720 ameliorated cardiac dysfunction by activating endothelial nitric oxide synthase, inhibiting inflammation, reducing oxidative stress, and increasing zona occludens-1 in endothelial cell-specific CRIF1-deleted mice. View this paper.
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Article
Human VAMP3 Suppresses or Negatively Regulates Bax Induced Apoptosis in Yeast
Biomedicines 2021, 9(1), 95; https://doi.org/10.3390/biomedicines9010095 - 19 Jan 2021
Cited by 2 | Viewed by 1964
Abstract
Apoptosis is an essential process that is regulated genetically and could lead to a serious disease condition if not well controlled. Bax is one of the main proapoptotic proteins and actively involved in programmed cell death. It has been suggested that Bax induced [...] Read more.
Apoptosis is an essential process that is regulated genetically and could lead to a serious disease condition if not well controlled. Bax is one of the main proapoptotic proteins and actively involved in programmed cell death. It has been suggested that Bax induced apoptosis in yeast could be obstructed by enhancing vesicular membrane trafficking. Plasma membrane proteins and lipid oxidation were reduced by a vesicle-associated membrane protein (VAMP) when expressed in yeast, suggesting its potential role in repairing membranes. Membrane integrity is crucial, as the loss of membrane integrity will result in the leakage of ions from mitochondria, and ultimately cell death due to overproduction of reactive oxygen species (ROS). Expression of Arabidopsis’ VAMP has been linked to antiapoptosis activity. Since plant VAMP has been associated with antiapoptotic activities, this study investigates the possible participation of human VAMP3 in blocking human Bax mediated apoptosis. Some novel genes were identified to rescue Bax’s proapoptotic effects, in a yeast-based human hippocampal cDNA library screen. VAMP3 (a gene code for proteins involved in protein secretion) gene was chosen for further study to confirm its role in inhibiting apoptosis. VAMP3 was coexpressed with a chromosomally integrated Bax gene expression cassette driven by the GAL1 promoter. The antiapoptotic proteins of the Bcl-2 family (Bcl xL) were known to negate the proapoptotic properties of Bax. However, the new gene (VAMP3) results show that novel antiapoptotic proteins can be identified using a yeast-based assay. The findings presented here show that human VAMP3 protein has antiapoptotic property and could abrogate Bax induced apoptosis (cell death). Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Article
Clinical Significance of Preoperative Inflammatory Markers in Prediction of Prognosis in Node-Negative Colon Cancer: Correlation between Neutrophil-to-Lymphocyte Ratio and Poorly Differentiated Clusters
Biomedicines 2021, 9(1), 94; https://doi.org/10.3390/biomedicines9010094 - 19 Jan 2021
Cited by 6 | Viewed by 1613
Abstract
Although stage I and II colon cancers (CC) generally show a very good prognosis, a small proportion of these patients dies from recurrent disease. The identification of high-risk patients, who may benefit from adjuvant chemotherapy, becomes therefore essential. We retrospectively evaluated 107 cases [...] Read more.
Although stage I and II colon cancers (CC) generally show a very good prognosis, a small proportion of these patients dies from recurrent disease. The identification of high-risk patients, who may benefit from adjuvant chemotherapy, becomes therefore essential. We retrospectively evaluated 107 cases of stage I (n = 28, 26.2%) and II (n = 79, 73.8%) CC for correlations among preoperative inflammatory markers, histopathological factors and long-term prognosis. A neutrophil-to-lymphocyte ratio greater than 3 (H-NLR) and a platelet-to-lymphocyte ratio greater than 150 (H-PLR) were significantly associated with the presence of poorly differentiated clusters (PDC) (p = 0.007 and p = 0.039, respectively). In addition, H-NLR and PDC proved to be significant and independent survival prognosticators for overall survival (OS; p = 0.007 and p < 0.001, respectively), while PDC was the only significant prognostic factor for cancer-specific survival (CSS; p < 0.001,). Finally, the combination of H-NLR and PDC allowed an optimal stratification of OS and CSS in our cohort, suggesting a potential role in clinical practice for the identification of high-risk patients with stage I and II CC. Full article
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Review
Extracellular Vesicles as Drivers of Non-Alcoholic Fatty Liver Disease: Small Particles with Big Impact
Biomedicines 2021, 9(1), 93; https://doi.org/10.3390/biomedicines9010093 - 19 Jan 2021
Cited by 9 | Viewed by 2315
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading chronic liver disease, negatively affecting the lives of millions of patients worldwide. The complex pathogenesis involves crosstalk between multiple cellular networks, but how the intricate communication between these cells drives disease progression remains to [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is becoming the leading chronic liver disease, negatively affecting the lives of millions of patients worldwide. The complex pathogenesis involves crosstalk between multiple cellular networks, but how the intricate communication between these cells drives disease progression remains to be further elucidated. Furthermore, the disease is not limited to the liver and includes the reprogramming of distant cell populations in different organs. Extracellular vesicles (EVs) have gained increased attention as mediators of cellular communication. EVs carry specific cargos that can act as disease-specific signals both locally and systemically. Focusing on NAFLD advancing to steatohepatitis (NASH), this review provides an update on current experimental and clinical findings of the potential role of EVs in hepatic inflammation and fibrosis, the main contributors to progressive NASH. Particular attention is placed on the characteristics of EV cargos and potential specificity to disease stages, with putative value as disease markers and treatment targets for future investigations. Full article
(This article belongs to the Special Issue NASH and Systemic Complications: From Basic to Clinical Research)
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Article
Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines
Biomedicines 2021, 9(1), 92; https://doi.org/10.3390/biomedicines9010092 - 19 Jan 2021
Cited by 32 | Viewed by 2772
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central [...] Read more.
Signal transducer and activator of transcription 3 (STAT3) is a transcriptional regulator of a number of biological processes including cell differentiation, proliferation, survival, and angiogenesis, while cyclin-dependent kinases (CDKs) are a critical regulator of cell cycle progression. These proteins appear to play central roles in angiogenesis and cell survival and are widely implicated in tumor progression. In this study, we used the well-characterized US National Cancer Institute 60 (NCI60) human tumor cell lines to screen the in vitro anti-cancer activities of our novel small molecule derivatives (NSC765690 and NSC765599) of salicylanilide. Furthermore, we used the DTP-COMPARE algorithm and in silico drug target prediction to identify the potential molecular targets, and finally, we used molecular docking to assess the interaction between the compounds and prominent potential targets. We found that NSC765690 and NSC765599 exhibited an anti-proliferative effect against the 60 panels of NCI human cancer cell lines, and dose-dependent cytotoxic preference for NSCLC, melanoma, renal, and breast cancer cell lines. Protein–ligand interactions studies revealed that NSC765690 and NSC765599 were favored ligands for STAT3/CDK2/4/6. Moreover, cyclization of the salicylanilide core scaffold of NSC765690 mediated its higher anti-cancer activities and had greater potential to interact with STAT3/CDK2/4/6 than did NSC765599 with an open-ring structure. NSC765690 and NSC765599 met the required safety and criteria of a good drug candidate, and are thus worthy of further in-vitro and in-vivo investigations in tumor-bearing mice to assess their full therapeutic efficacy. Full article
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Article
Anti-Adipogenic Polyacetylene Glycosides from the Florets of Safflower (Carthamus tinctorius)
Biomedicines 2021, 9(1), 91; https://doi.org/10.3390/biomedicines9010091 - 19 Jan 2021
Cited by 5 | Viewed by 2396
Abstract
Safflower (Carthamus tinctorius) is an annual herb belonging to the Compositae family; it has a history of use as a food colorant, dye, and medicine in oriental countries. LC-MS-UV-based chemical analysis of extract of the florets of C. tinctorius led to [...] Read more.
Safflower (Carthamus tinctorius) is an annual herb belonging to the Compositae family; it has a history of use as a food colorant, dye, and medicine in oriental countries. LC-MS-UV-based chemical analysis of extract of the florets of C. tinctorius led to the isolation of two new C10-polyacetylene glycosides, (8Z)-decaene-4,6-diyne-1,10-diol-1-O-β-d-glucopyranoside (1) and (8S)-deca-4,6-diyne-1,8-diol-1-O-β-d-glucopyranoside (2), together with five known analogs (37). The structures of the new compounds were determined by using 1D and 2D NMR spectroscopic data and HR-MS data, as well as chemical transformations. Of compounds 17, compounds 2, 3, and 4 inhibited the adipogenesis of 3T3-L1 preadipocytes, whereas compounds 1 and 6 promoted adipogenesis. Compounds 2, 3, and 4 also prevented lipid accumulation through the suppression of the expression of lipogenic genes and the increase of the expression of lipolytic genes. Moreover, compounds 3 and 4 activated AMPK, which is known to facilitate lipid metabolism. Our findings provide a mechanistic rationale for the use of safflower-derived polyacetylene glycosides as potential therapeutic agents against obesity. Full article
(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)
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Review
Circulating Long and Circular Noncoding RNA as Non-Invasive Diagnostic Tools of Hepatocellular Carcinoma
Biomedicines 2021, 9(1), 90; https://doi.org/10.3390/biomedicines9010090 - 19 Jan 2021
Cited by 20 | Viewed by 2521
Abstract
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, partially due to late diagnosis of the disease. Growing evidence in the field of biomarker discovery has shown the promising use of nucleic acid in the early detection of [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, partially due to late diagnosis of the disease. Growing evidence in the field of biomarker discovery has shown the promising use of nucleic acid in the early detection of many cancers, including HCC. Here, we review data on how various long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) could be used as a diagnostic tool for HCC being differentially expressed in HCC compared to non-HCC patients. These non-coding RNAs (ncRNAs) showed high stability in the blood being present as free-circulating molecules or encapsulated into exosomes. This review reports some recent evidence on the use of lncRNAs and circRNAs as possible diagnostic biomarkers for HCC. Further, their pathophysiological mechanism in liver carcinogenesis was also described, elucidating the complex regulatory networks making these ncRNAs of particular relevance for the study of liver malignancy cancer. Full article
(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)
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Review
The Biology of Vasopressin
Biomedicines 2021, 9(1), 89; https://doi.org/10.3390/biomedicines9010089 - 18 Jan 2021
Cited by 14 | Viewed by 8439
Abstract
Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin [...] Read more.
Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists. Full article
(This article belongs to the Special Issue Peptide-Based Drug Development)
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Article
Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses
Biomedicines 2021, 9(1), 88; https://doi.org/10.3390/biomedicines9010088 - 18 Jan 2021
Cited by 6 | Viewed by 2191
Abstract
Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We [...] Read more.
Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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Article
Immunogenicity of Viral Vaccines in the Italian Military
Biomedicines 2021, 9(1), 87; https://doi.org/10.3390/biomedicines9010087 - 17 Jan 2021
Cited by 4 | Viewed by 1729
Abstract
Military personnel of all armed forces receive multiple vaccinations and have been doing so since long ago, but relatively few studies have investigated the possible negative or positive interference of simultaneous vaccinations. As a contribution to fill this gap, we analyzed the response [...] Read more.
Military personnel of all armed forces receive multiple vaccinations and have been doing so since long ago, but relatively few studies have investigated the possible negative or positive interference of simultaneous vaccinations. As a contribution to fill this gap, we analyzed the response to the live trivalent measles/mumps/rubella (MMR), the inactivated hepatitis A virus (HAV), the inactivated trivalent polio, and the trivalent subunits influenza vaccines in two cohorts of Italian military personnel. The first cohort was represented by 108 students from military schools and the second by 72 soldiers engaged in a nine-month mission abroad. MMR and HAV vaccines had never been administered before, whereas inactivated polio was administered to adults primed at infancy with a live trivalent oral polio vaccine. Accordingly, nearly all subjects had baseline antibodies to polio types 1 and 3, but unexpectedly, anti-measles/-mumps/-rubella antibodies were present in 82%, 82%, and 73.5% of subjects, respectively (43% for all of the antigens). Finally, anti-HAV antibodies were detectable in 14% and anti-influenza (H1/H3/B) in 18% of the study population. At mine months post-vaccination, 92% of subjects had protective antibody levels for all MMR antigens, 96% for HAV, 69% for the three influenza antigens, and 100% for polio types 1 and 3. An inverse relationship between baseline and post-vaccination antibody levels was noticed with all the vaccines. An excellent vaccine immunogenicity, a calculated long antibody persistence, and apparent lack of vaccine interference were observed. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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Review
Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme
Biomedicines 2021, 9(1), 86; https://doi.org/10.3390/biomedicines9010086 - 17 Jan 2021
Cited by 25 | Viewed by 3784
Abstract
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin [...] Read more.
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease. Full article
(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance)
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Review
Current Limitations and Recent Progress in Nanomedicine for Clinically Available Photodynamic Therapy
Biomedicines 2021, 9(1), 85; https://doi.org/10.3390/biomedicines9010085 - 16 Jan 2021
Cited by 26 | Viewed by 4245
Abstract
Photodynamic therapy (PDT) using oxygen, light, and photosensitizers has been receiving great attention, because it has potential for making up for the weakness of the existing therapies such as surgery, radiation therapy, and chemotherapy. It has been mainly used to treat cancer, and [...] Read more.
Photodynamic therapy (PDT) using oxygen, light, and photosensitizers has been receiving great attention, because it has potential for making up for the weakness of the existing therapies such as surgery, radiation therapy, and chemotherapy. It has been mainly used to treat cancer, and clinical tests for second-generation photosensitizers with improved physicochemical properties, pharmacokinetic profiles, or singlet oxygen quantum yield have been conducted. Progress is also being made in cancer theranostics by using fluorescent signals generated by photosensitizers. In order to obtain the effective cytotoxic effects on the target cells and prevent off-target side effects, photosensitizers need to be localized to the target tissue. The use of nanocarriers combined with photosensitizers can enhance accumulation of photosensitizers in the tumor site, owing to preferential extravasation of nanoparticles into the tumor vasculature by the enhanced permeability and retention effect. Self-assembly of amphiphilic polymers provide good loading efficiency and sustained release of hydrophobic photosensitizers. In addition, prodrug nanomedicines for PDT can be activated by stimuli in the tumor site. In this review, we introduce current limitations and recent progress in nanomedicine for PDT and discuss the expected future direction of research. Full article
(This article belongs to the Special Issue Advanced Nanomedicines for Optical Imaging and Phototherapy)
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Article
M2 Monocyte Polarization in Dialyzed Patients Is Associated with Increased Levels of M-CSF and Myeloperoxidase-Associated Oxidative Stress: Preliminary Results
Biomedicines 2021, 9(1), 84; https://doi.org/10.3390/biomedicines9010084 - 16 Jan 2021
Cited by 4 | Viewed by 1404
Abstract
Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized [...] Read more.
Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized LDLs. Monocytes-macrophages are classified into subsets of polarized cells, with M1 and M2 macrophages considered, respectively, as pro- and anti-inflammatory. (1) Methods: The monocyte subsets and phenotypes were analyzed by flow cytometry. These data were completed by the quantification of plasma M-CSF, IL-8, CRP, Mox-LDLs, Apo-B, Apo-AI, chloro-tyrosine, and homocitrulline concentrations. The statistical differences and associations between two continuous variables were assessed using the Mann–Whitney U test and Spearman’s correlation coefficient, respectively. (2) Results: Hemodialyzed patients showed a significant increase in their concentrations of CRP, M-CSF, and IL-8 (inflammation biomarkers), as well as chloro-tyrosine and homocitrulline (myeloperoxidase-associated oxidative stress biomarkers). Moreover, we observed a higher percentage of M2 monocytes in the plasma of hemodialysis patients as compared to the controls. (3) Conclusions: Our data suggest that oxidative stress and an inflammatory environment, which is amplified in hemodialysis patients, seems to favor an increase in the concentration of circulating M-CSF, therefore leading to an increase in M2 polarization among circulating monocytes. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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Review
Therapeutic Targeting of Autoreactive B Cells: Why, How, and When?
Biomedicines 2021, 9(1), 83; https://doi.org/10.3390/biomedicines9010083 - 16 Jan 2021
Cited by 6 | Viewed by 2402
Abstract
B lymphocytes play critical roles in the development of autoimmunity, acting as autoantibody manufacturers, antigen-presenting cells, and producers of cytokines. Pan-B cell depletion has demonstrated efficacy in treatment of many autoimmune disorders, but carries with it an unfavorable safety profile due to global [...] Read more.
B lymphocytes play critical roles in the development of autoimmunity, acting as autoantibody manufacturers, antigen-presenting cells, and producers of cytokines. Pan-B cell depletion has demonstrated efficacy in treatment of many autoimmune disorders, but carries with it an unfavorable safety profile due to global immune suppression. Hence, attention has turned to the potential of autoantigen-specific B cell targeted therapies, which would deplete or silence pathogenic self-antigen-reactive cells while sparing B cells needed for immune defense. Here, we discuss the antigen-specific B cell-targeted approaches that are under development or are under consideration, that could be employed to allow for more precise therapy in the treatment of autoimmunity. Lastly, we discuss some of the challenges associated with antigen-specific B cell targeting that may impact their clinical applicability. Full article
(This article belongs to the Special Issue Antigen-Specific Immunotherapies for Autoimmune Disease)
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Review
Crosstalk between Depression and Dementia with Resting-State fMRI Studies and Its Relationship with Cognitive Functioning
Biomedicines 2021, 9(1), 82; https://doi.org/10.3390/biomedicines9010082 - 16 Jan 2021
Cited by 19 | Viewed by 3610
Abstract
Alzheimer’s disease (AD) is the most common type of dementia, and depression is a risk factor for developing AD. Epidemiological studies provide a clinical correlation between late-life depression (LLD) and AD. Depression patients generally remit with no residual symptoms, but LLD patients demonstrate [...] Read more.
Alzheimer’s disease (AD) is the most common type of dementia, and depression is a risk factor for developing AD. Epidemiological studies provide a clinical correlation between late-life depression (LLD) and AD. Depression patients generally remit with no residual symptoms, but LLD patients demonstrate residual cognitive impairment. Due to the lack of effective treatments, understanding how risk factors affect the course of AD is essential to manage AD. Advances in neuroimaging, including resting-state functional MRI (fMRI), have been used to address neural systems that contribute to clinical symptoms and functional changes across various psychiatric disorders. Resting-state fMRI studies have contributed to understanding each of the two diseases, but the link between LLD and AD has not been fully elucidated. This review focuses on three crucial and well-established networks in AD and LLD and discusses the impacts on cognitive decline, clinical symptoms, and prognosis. Three networks are the (1) default mode network, (2) executive control network, and (3) salience network. The multiple properties emphasized here, relevant for the hypothesis of the linkage between LLD and AD, will be further developed by ongoing future studies. Full article
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Article
Covalently Labeled Fluorescent Exosomes for In Vitro and In Vivo Applications
Biomedicines 2021, 9(1), 81; https://doi.org/10.3390/biomedicines9010081 - 16 Jan 2021
Cited by 8 | Viewed by 3301
Abstract
The vertiginous increase in the use of extracellular vesicles and especially exosomes for therapeutic applications highlights the necessity of advanced techniques for gaining a deeper knowledge of their pharmacological properties. Herein, we report a novel chemical approach for the robust attachment of commercial [...] Read more.
The vertiginous increase in the use of extracellular vesicles and especially exosomes for therapeutic applications highlights the necessity of advanced techniques for gaining a deeper knowledge of their pharmacological properties. Herein, we report a novel chemical approach for the robust attachment of commercial fluorescent dyes to the exosome surface with covalent binding. The applicability of the methodology was tested on milk and cancer cell-derived exosomes (from U87 and B16F10 cancer cells). We demonstrated that fluorescent labeling did not modify the original physicochemical properties of exosomes. We tested this nanoprobe in cell cultures and healthy mice to validate its use for in vitro and in vivo applications. We confirmed that these fluorescently labeled exosomes could be successfully visualized with optical imaging. Full article
(This article belongs to the Special Issue Optical Nanoparticles for Biomedicine)
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Review
Recent Trends in Photoacoustic Imaging Techniques for 2D Nanomaterial-Based Phototherapy
Biomedicines 2021, 9(1), 80; https://doi.org/10.3390/biomedicines9010080 - 15 Jan 2021
Cited by 15 | Viewed by 2414
Abstract
A variety of 2D materials have been developed for therapeutic biomedical studies. Because of their excellent physicochemical properties, 2D materials can be used as carriers for delivering therapeutic agents into a lesion, leading to phototherapy. Various optical imaging techniques have been used for [...] Read more.
A variety of 2D materials have been developed for therapeutic biomedical studies. Because of their excellent physicochemical properties, 2D materials can be used as carriers for delivering therapeutic agents into a lesion, leading to phototherapy. Various optical imaging techniques have been used for the monitoring of the treatment process. Among these, photoacoustic imaging has unique advantages including relatively deep imaging depth and large field of view with high spatial resolution. In this review article, we summarize the types of photoacoustic imaging systems used for phototherapy monitoring, then we explore contrast-enhanced photoacoustic images using 2D materials. Finally, photoacoustic image-guided phototherapies are discussed. We conclude that 2D material-based phototherapy can be efficiently monitored by photoacoustic imaging techniques. Full article
(This article belongs to the Special Issue Advanced Nanomedicines for Optical Imaging and Phototherapy)
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Article
Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals
Biomedicines 2021, 9(1), 79; https://doi.org/10.3390/biomedicines9010079 - 15 Jan 2021
Cited by 8 | Viewed by 2177
Abstract
The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The [...] Read more.
The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines—that potentially facilitate melanoma growth—than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance. Full article
(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)
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An In-Vitro Analysis of Peri-Implant Mucosal Seal Following Photofunctionalization of Zirconia Abutment Materials
Biomedicines 2021, 9(1), 78; https://doi.org/10.3390/biomedicines9010078 - 15 Jan 2021
Cited by 5 | Viewed by 1512
Abstract
The presence of epithelial and connective tissue attachment at the peri-implant–soft tissue region has been demonstrated to provide a biological barrier of the alveolar bone from the oral environment. This barrier can be improved via surface modification of implant abutment materials. The effect [...] Read more.
The presence of epithelial and connective tissue attachment at the peri-implant–soft tissue region has been demonstrated to provide a biological barrier of the alveolar bone from the oral environment. This barrier can be improved via surface modification of implant abutment materials. The effect of photofunctionalization on creating a bioactive surface for the enhancement of the epithelial and connective tissue attachment of zirconia implant abutment’s peri-implant mucosal interface using organotypic model has not been investigated. Therefore, this study aimed to evaluate the soft tissue seal around peri-implant mucosa and to understand the effect of photofunctionalization on the abutment materials. Three types of abutment materials were used in this study; yttria-stabilized zirconia (YSZ), alumina-toughened zirconia, and grade 2 commercially pure titanium (CPTi) which were divided into nontreated (N-Tx) and photofunctionalized group (UV-Tx). The three-dimensional peri-implant mucosal model was constructed using primary human gingival keratinocytes and fibroblasts co-cultured on the acellular dermal membrane. The biological seal was determined through the concentration of tritiated water permeating the material–soft tissue interface. The biological seal formed by the soft tissue in the N-Tx group was significantly reduced compared to the UV-treated group (p < 0.001), with YSZ exhibiting the lowest permeability among all materials. Photofunctionalization of implant abutment materials improved the biological seal of the surrounding soft tissue peri-implant interface. Full article
(This article belongs to the Special Issue Bioengineered In Vitro Models for Biomedical Applications)
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Article
Changes in Prefrontal Cortex–Thalamic Circuitry after Acoustic Trauma
Biomedicines 2021, 9(1), 77; https://doi.org/10.3390/biomedicines9010077 - 14 Jan 2021
Cited by 1 | Viewed by 1332
Abstract
In the adult auditory system, loss of input resulting from peripheral deafferentation is well known to lead to plasticity in the central nervous system, manifested as reorganization of cortical maps and altered activity throughout the central auditory pathways. The auditory system also has [...] Read more.
In the adult auditory system, loss of input resulting from peripheral deafferentation is well known to lead to plasticity in the central nervous system, manifested as reorganization of cortical maps and altered activity throughout the central auditory pathways. The auditory system also has strong afferent and efferent connections with cortico-limbic circuitry including the prefrontal cortex and the question arises whether this circuitry is also affected by loss of peripheral input. Recent studies in our laboratory showed that PFC activation can modulate activity of the auditory thalamus or medial geniculate nucleus (MGN) in normal hearing rats. In addition, we have shown in rats that cochlear trauma resulted in altered spontaneous burst firing in MGN. However, whether the PFC influence on MGN is changed after cochlear trauma is unknown. We investigated the effects of electrical stimulation of PFC on single neuron activity in the MGN in anaesthetized Wistar rats 2 weeks after acoustic trauma or sham surgery. Electrical stimulation of PFC showed a variety of effects in MGN neurons both in sham and acoustic trauma groups but inhibitory responses were significantly larger in the acoustic trauma animals. These results suggest an alteration in functional connectivity between PFC and MGN after cochlear trauma. This change may be a compensatory mechanism increasing sensory gating after the development of altered spontaneous activity in MGN, to prevent altered activity reaching the cortex and conscious perception. Full article
(This article belongs to the Section Neurobiology and Neurologic Disease)
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Case Report
Denosumab-Induced Immune Hepatitis
Biomedicines 2021, 9(1), 76; https://doi.org/10.3390/biomedicines9010076 - 14 Jan 2021
Cited by 2 | Viewed by 1842
Abstract
Denosumab–Prolia®, Xgeva® (Amgen) is a fully human antibody to the receptor activator of the nuclear factor-K ligand (RANKL). Hepatotoxicity is extremely rare, with only one reported case of immune origin. We present a second case of hepatotoxicity resulting from an immune reaction to [...] Read more.
Denosumab–Prolia®, Xgeva® (Amgen) is a fully human antibody to the receptor activator of the nuclear factor-K ligand (RANKL). Hepatotoxicity is extremely rare, with only one reported case of immune origin. We present a second case of hepatotoxicity resulting from an immune reaction to denosumab. A 43-year-old female was referred to the Endocrinology, Diabetes & Metabolism Department for treatment of low bone mineral density (BMD) following endocrine therapy with letrozole and lucrin because of breast cancer. She developed premature menopause at the age of 36 years when she underwent a left lumpectomy due to an infiltrating duct carcinoma of the breast (T1 NO MO) and was subsequently started on endocrine therapy. Denosumab was started to prevent osteoporosis. On the third year after starting on denosumab and one month after she received the last injection, she became ill. The routine biochemical analysis showed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) rose appreciatively to 10 times the upper limit of normal (ULN). The gamma-glutamyl transferase (GGT) level was elevated slightly to 67 U/L (0–38 U/L). The serum gamma-globulin level was elevated to 1.72 g/dL (0.7–1.6 gr/dl), while the total bilirubin (TB) and serum albumin levels were normal. A liver biopsy revealed a moderate to severe chronic inflammatory infiltrate containing MUM-1 positive plasma cells. In addition, numerous CD-3 positive small T lymphocytes and few CD-20 positive B lymphocytes and eosinophils were seen in the portal tracts. Moderate to severe interface hepatitis, bile duct proliferation and mild portal fibrosis were also identified. The results could be consistent with the diagnosis of drug-induced liver injury (DILI). Full article
(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)
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Article
Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel
Biomedicines 2021, 9(1), 75; https://doi.org/10.3390/biomedicines9010075 - 14 Jan 2021
Cited by 2 | Viewed by 1692
Abstract
The KCNA1 gene encodes the α subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by [...] Read more.
The KCNA1 gene encodes the α subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation. Full article
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Article
Rational Design of Albumin Theranostic Conjugates for Gold Nanoparticles Anticancer Drugs: Where the Seed Meets the Soil?
Biomedicines 2021, 9(1), 74; https://doi.org/10.3390/biomedicines9010074 - 13 Jan 2021
Cited by 6 | Viewed by 2224
Abstract
Multifunctional gold nanoparticles (AuNPs) may serve as a scaffold to integrate diagnostic and therapeutic functions into one theranostic system, thereby simultaneously facilitating diagnosis and therapy and monitoring therapeutic responses. Herein, albumin-AuNP theranostic agents have been obtained by conjugation of an anticancer nucleotide trifluorothymidine [...] Read more.
Multifunctional gold nanoparticles (AuNPs) may serve as a scaffold to integrate diagnostic and therapeutic functions into one theranostic system, thereby simultaneously facilitating diagnosis and therapy and monitoring therapeutic responses. Herein, albumin-AuNP theranostic agents have been obtained by conjugation of an anticancer nucleotide trifluorothymidine (TFT) or a boron-neutron capture therapy drug undecahydro-closo-dodecaborate (B12H12) to bimodal human serum albumin (HSA) followed by reacting of the albumin conjugates with AuNPs. In vitro studies have revealed a stronger cytotoxicity by the AuNPs decorated with the TFT-tagged bimodal HSA than by the boronated albumin conjugates. Despite long circulation time, lack of the significant accumulation in the tumor was observed for the AuNP theranostic conjugates. Our unique labelling strategy allows for monitoring of spatial distribution of the AuNPs theranostic in vivo in real time with high sensitivity, thus reducing the number of animals required for testing and optimizing new nanosystems as chemotherapeutic agents and boron-neutron capture therapy drug candidates. Full article
(This article belongs to the Special Issue Theranostic Drug Delivery: Prospects and Problems)
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Review
Development of Non-Porous Silica Nanoparticles towards Cancer Photo-Theranostics
Biomedicines 2021, 9(1), 73; https://doi.org/10.3390/biomedicines9010073 - 13 Jan 2021
Cited by 20 | Viewed by 3042
Abstract
Nanoparticles have demonstrated several advantages for biomedical applications, including for the development of multifunctional agents as innovative medicine. Silica nanoparticles hold a special position among the various types of functional nanoparticles, due to their unique structural and functional properties. The recent development of [...] Read more.
Nanoparticles have demonstrated several advantages for biomedical applications, including for the development of multifunctional agents as innovative medicine. Silica nanoparticles hold a special position among the various types of functional nanoparticles, due to their unique structural and functional properties. The recent development of silica nanoparticles has led to a new trend in light-based nanomedicines. The application of light provides many advantages for in vivo imaging and therapy of certain diseases, including cancer. Mesoporous and non-porous silica nanoparticles have high potential for light-based nanomedicine. Each silica nanoparticle has a unique structure, which incorporates various functions to utilize optical properties. Such advantages enable silica nanoparticles to perform powerful and advanced optical imaging, from the in vivo level to the nano and micro levels, using not only visible light but also near-infrared light. Furthermore, applications such as photodynamic therapy, in which a lesion site is specifically irradiated with light to treat it, have also been advancing. Silica nanoparticles have shown the potential to play important roles in the integration of light-based diagnostics and therapeutics, termed “photo-theranostics”. Here, we review the recent development and progress of non-porous silica nanoparticles toward cancer “photo-theranostics”. Full article
(This article belongs to the Special Issue Advanced Nanomedicines for Optical Imaging and Phototherapy)
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Article
High Monopolar Spindle 1 Is Associated with Short Survival of Cholangiocarcinoma Patients and Enhances the Progression Via AKT and STAT3 Signaling Pathways
Biomedicines 2021, 9(1), 68; https://doi.org/10.3390/biomedicines9010068 - 13 Jan 2021
Cited by 1 | Viewed by 1864
Abstract
Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium. The major problems of this cancer are late diagnosis and a high rate of metastasis. CCA patients in advanced stages have poor survival and cannot be cured with surgery. Therefore, targeting molecules involved [...] Read more.
Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium. The major problems of this cancer are late diagnosis and a high rate of metastasis. CCA patients in advanced stages have poor survival and cannot be cured with surgery. Therefore, targeting molecules involved in the metastatic process may be an effective CCA treatment. Monopolar spindle 1 (MPS1) is a kinase protein that controls the spindle assemble checkpoint in mitosis. It is overexpressed in proliferating cells and various cancers. The functional roles of MPS1 in CCA progression have not been investigated. The aims of this study were to examine the roles and molecular mechanisms of MPS1 in CCA progression. Immunohistochemistry results showed that MPS1 was up-regulated in carcinogenesis of CCA in a hamster model, and positive expression of MPS1 in human CCA tissues was correlated to short survival of CCA patients (n = 185). Small interfering RNA (siRNA)-induced knockdown of MPS1 expression reduced cell proliferation via G2/M arrest, colony formation, migration, and invasion. Moreover, MPS1 controlled epithelial to mesenchymal transition (EMT)-mediated migration via AKT and STAT3 signaling transductions. MPS1 was also involved in MMPs-dependent invasion of CCA cell lines. The current research highlights for the first time that MPS1 has an essential role in promoting the progression of CCA via AKT and STAT3 signaling pathways and could be an attractive target for metastatic CCA treatment. Full article
(This article belongs to the Section Cancer Biology and Therapeutics)
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Article
Comparison of Plasma Lipoprotein Composition and Function in Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Biomedicines 2021, 9(1), 72; https://doi.org/10.3390/biomedicines9010072 - 12 Jan 2021
Cited by 4 | Viewed by 2043
Abstract
Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aβ) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aβ can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer’s disease (AD). Our study aimed to determine whether [...] Read more.
Cerebral amyloid angiopathy (CAA) refers to beta-amyloid (Aβ) deposition in brain vessels and is clinically the main cause of lobar intracerebral hemorrhage (ICH). Aβ can also accumulate in brain parenchyma forming neuritic plaques in Alzheimer’s disease (AD). Our study aimed to determine whether the peripheral lipid profile and lipoprotein composition are associated with cerebral beta-amyloidosis pathology and may reflect biological differences in AD and CAA. For this purpose, lipid and apolipoproteins levels were analyzed in plasma from 51 ICH-CAA patients (collected during the chronic phase of the disease), 60 AD patients, and 60 control subjects. Lipoproteins (VLDL, LDL, and HDL) were isolated and their composition and pro/antioxidant ability were determined. We observed that alterations in the lipid profile and lipoprotein composition were remarkable in the ICH-CAA group compared to control subjects, whereas the AD group presented no specific alterations compared with controls. ICH-CAA patients presented an atheroprotective profile, which consisted of lower total and LDL cholesterol levels. Plasma from chronic ICH-CAA patients also showed a redistribution of ApoC-III from HDL to VLDL and a higher ApoE/ApoC-III ratio in HDL. Whether these alterations reflect a protective response or have a causative effect on the pathology requires further investigation. Full article
Article
Identification of Sclerostin as a Putative New Myokine Involved in the Muscle-to-Bone Crosstalk
Biomedicines 2021, 9(1), 71; https://doi.org/10.3390/biomedicines9010071 - 12 Jan 2021
Cited by 12 | Viewed by 2434
Abstract
Bone and muscle have been recognized as endocrine organs since they produce and secrete “hormone-like factors” that can mutually influence each other and other tissues, giving rise to a “bone–muscle crosstalk”. In our study, we made use of myogenic (C2C12 cells) and osteogenic [...] Read more.
Bone and muscle have been recognized as endocrine organs since they produce and secrete “hormone-like factors” that can mutually influence each other and other tissues, giving rise to a “bone–muscle crosstalk”. In our study, we made use of myogenic (C2C12 cells) and osteogenic (2T3 cells) cell lines to investigate the effects of muscle cell-produced factors on the maturation process of osteoblasts. We found that the myogenic medium has inhibitory effects on bone cell differentiation and we identified sclerostin as one of the myokines produced by muscle cells. Sclerostin is a secreted glycoprotein reportedly expressed by bone/cartilage cells and is considered a negative regulator of bone growth due to its role as an antagonist of the Wnt/β-catenin pathway. Given the inhibitory role of sclerostin in bone, we analyzed its expression by muscle cells and how it affects bone formation and homeostasis. Firstly, we characterized and quantified sclerostin synthesis by a myoblast cell line (C2C12) and by murine primary muscle cells by Western blotting, real-time PCR, immunofluorescence, and ELISA assay. Next, we investigated in vivo production of sclerostin in distinct muscle groups with different metabolic and mechanical loading characteristics. This analysis was done in mice of different ages (6 weeks, 5 and 18 months after birth) and revealed that sclerostin expression is dynamically modulated in a muscle-specific way during the lifespan. Finally, we transiently expressed sclerostin in the hind limb muscles of young mice (2 weeks of age) via in vivo electro-transfer of a plasmid containing the SOST gene in order to investigate the effects of muscle-specific overproduction of the protein. Our data disclosed an inhibitory role of the muscular sclerostin on the bones adjacent to the electroporated muscles. This observation suggests that sclerostin released by skeletal muscle might synergistically interact with osseous sclerostin and potentiate negative regulation of osteogenesis possibly by acting in a paracrine/local fashion. Our data point out a role for muscle as a new source of sclerostin. Full article
(This article belongs to the Special Issue Bone Tissue Regeneration: Biology and Strategies)
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Review
Mithramycin and Analogs for Overcoming Cisplatin Resistance in Ovarian Cancer
Biomedicines 2021, 9(1), 70; https://doi.org/10.3390/biomedicines9010070 - 12 Jan 2021
Cited by 3 | Viewed by 2296
Abstract
Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by [...] Read more.
Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, in the treatment of platinum-resistant ovarian cancer. Full article
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Review
Recent Advances in Photodynamic Therapy for Deep-Seated Tumors with the Aid of Nanomedicine
Biomedicines 2021, 9(1), 69; https://doi.org/10.3390/biomedicines9010069 - 12 Jan 2021
Cited by 24 | Viewed by 3897
Abstract
Photodynamic therapy (PDT) works through photoactivation of a specific photosensitizer (PS) in a tumor in the presence of oxygen. PDT is widely applied in oncology to treat various cancers as it has a minimally invasive procedure and high selectivity, does not interfere with [...] Read more.
Photodynamic therapy (PDT) works through photoactivation of a specific photosensitizer (PS) in a tumor in the presence of oxygen. PDT is widely applied in oncology to treat various cancers as it has a minimally invasive procedure and high selectivity, does not interfere with other treatments, and can be repeated as needed. A large amount of reactive oxygen species (ROS) and singlet oxygen is generated in a cancer cell during PDT, which destroys the tumor effectively. However, the efficacy of PDT in treating a deep-seated tumor is limited due to three main reasons: Limited light penetration depth, low oxygen concentration in the hypoxic core, and poor PS accumulation inside a tumor. Thus, PDT treatments are only approved for superficial and thin tumors. With the advancement of nanotechnology, PDT to treat deep-seated or thick tumors is becoming a reachable goal. In this review, we provide an update on the strategies for improving PDT with nanomedicine using different sophisticated-design nanoparticles, including two-photon excitation, X-ray activation, targeting tumor cells with surface modification, alteration of tumor cell metabolism pathways, release of therapeutic gases, improvement of tumor hypoxia, and stimulation of host immunity. We focus on the difficult-to-treat pancreatic cancer as a model to demonstrate the influence of advanced nanomedicine in PDT. A bright future of PDT application in the treatment of deep-seated tumors is expected. Full article
(This article belongs to the Special Issue Advanced Nanomedicines for Optical Imaging and Phototherapy)
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Article
Plumericin Protects against Experimental Inflammatory Bowel Disease by Restoring Intestinal Barrier Function and Reducing Apoptosis
Biomedicines 2021, 9(1), 67; https://doi.org/10.3390/biomedicines9010067 - 12 Jan 2021
Cited by 7 | Viewed by 2127
Abstract
Intestinal epithelial barrier impairment plays a key pathogenic role in inflammatory bowel diseases (IBDs). In particular, together with oxidative stress, intestinal epithelial barrier alteration is considered as upstream event in ulcerative colitis (UC). In order to identify new products of natural origin with [...] Read more.
Intestinal epithelial barrier impairment plays a key pathogenic role in inflammatory bowel diseases (IBDs). In particular, together with oxidative stress, intestinal epithelial barrier alteration is considered as upstream event in ulcerative colitis (UC). In order to identify new products of natural origin with a potential activity for UC treatment, this study evaluated the effects of plumericin, a spirolactone iridoid, present as one of the main bioactive components in the bark of Himatanthus sucuuba (Woodson). Plumericin was evaluated for its ability to improve barrier function and to reduce apoptotic parameters during inflammation, both in intestinal epithelial cells (IEC-6), and in an animal experimental model of 2, 4, 6-dinitrobenzene sulfonic acid (DNBS)-induced colitis. Our results indicated that plumericin increased the expression of adhesion molecules, enhanced IEC-6 cells actin cytoskeleton rearrangement, and promoted their motility. Moreover, plumericin reduced apoptotic parameters in IEC-6. These results were confirmed in vivo. Plumericin reduced the activity of myeloperoxidase, inhibited the expression of ICAM-1, P-selectin, and the formation of PAR, and reduced apoptosis parameters in mice colitis induced by DNBS. These results support a pharmacological potential of plumericin in the treatment of UC, due to its ability to improve the structural integrity of the intestinal epithelium and its barrier function. Full article
(This article belongs to the Special Issue Natural Medicine in Therapy)
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Article
Concurrent Prebiotic Intake Reverses Insulin Resistance Induced by Early-Life Pulsed Antibiotic in Rats
Biomedicines 2021, 9(1), 66; https://doi.org/10.3390/biomedicines9010066 - 12 Jan 2021
Cited by 3 | Viewed by 1992
Abstract
Pulsed antibiotic treatment (PAT) early in life increases risk of obesity. Prebiotics can reduce fat mass and improve metabolic health. We examined if co-administering prebiotic with PAT reduces obesity risk in rat pups weaned onto a high fat/sucrose diet. Pups were randomized to [...] Read more.
Pulsed antibiotic treatment (PAT) early in life increases risk of obesity. Prebiotics can reduce fat mass and improve metabolic health. We examined if co-administering prebiotic with PAT reduces obesity risk in rat pups weaned onto a high fat/sucrose diet. Pups were randomized to (1) control [CTR], (2) antibiotic [ABT] (azithromycin), (3) prebiotic [PRE] (10% oligofructose (OFS)), (4) antibiotic + prebiotic [ABT + PRE]. Pulses of antibiotics/prebiotics were administered at d19–21, d28–30 and d37–39. Male and female rats given antibiotics (ABT) had higher body weight than all other groups at 10 wk of age. The PAT phenotype was stronger in ABT males than females, where increased fat mass, hyperinsulinemia and insulin resistance were present and all reversible with prebiotics. Reduced hypothalamic and hepatic expression of insulin receptor substrates and ileal tight junction proteins was seen in males only, explaining their greater insulin resistance. In females, insulin resistance was improved with prebiotics and normalized to lean control. ABT reduced Lactobacillaceae and increased Bacteroidaceae in both sexes. Using a therapeutic dose of an antibiotic commonly used for acute infection in children, PAT increased body weight and impaired insulin production and insulin sensitivity. The effects were reversed with prebiotic co-administration in a sex-specific manner. Full article
(This article belongs to the Special Issue Nutraceuticals in Disease Prevention)
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