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Biomedicines, Volume 10, Issue 6 (June 2022) – 247 articles

Cover Story (view full-size image): The deregulated DNA damage response (DDR) network is associated with cancer onset and progression. DDR defects in peripheral blood mononuclear cells (PBMCs) from lung cancer patients showed higher levels of endogenous DNA damage and higher levels of oxidative stress and apurinic/apyrimidinic sites than the healthy controls. Moreover, lower nucleotide excision repair and double-strand break repair capacities were also found in these patients, followed by reduced apoptotic markers. Together, oxidative stress and DDR-related aberrations contribute to the accumulation of endogenous DNA damage in PBMCs from lung cancer patients and can potentially be exploited for the identification of novel therapeutic targets and non-invasive biomarkers (The figure was created with BioRender.com). View this paper
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Article
Thrombin Activity in Rodent and Human Skin: Modified by Inflammation and Correlates with Innervation
Biomedicines 2022, 10(6), 1461; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061461 - 20 Jun 2022
Viewed by 320
Abstract
Thrombin is present in peripheral nerves and is involved in the pathogenesis of neuropathy. We evaluated thrombin activity in skin punch biopsies taken from the paws of male mice and rats and from the legs of patients with suspected small-fiber neuropathy (SFN). In [...] Read more.
Thrombin is present in peripheral nerves and is involved in the pathogenesis of neuropathy. We evaluated thrombin activity in skin punch biopsies taken from the paws of male mice and rats and from the legs of patients with suspected small-fiber neuropathy (SFN). In mice, inflammation was induced focally by subcutaneous adjuvant injection to one paw and systemically by intraperitoneal lipopolysaccharides (LPS) administration. One day following injection, thrombin activity increased in the skin of the injected compared with the contralateral and non-injected control paws (p = 0.0009). One week following injection, thrombin increased in both injected and contralateral paws compared with the controls (p = 0.026), coupled with increased heat-sensitivity (p = 0.009). Thrombin activity in the footpad skin was significantly increased one week after systemic administration of LPS compared with the controls (p = 0.023). This was not accompanied by increased heat sensitivity. In human skin, a correlation was found between nerve fiber density and thrombin activity. In addition, a lower thrombin activity was measured in patients with evidence of systemic inflammation compared with the controls (p = 0.0035). These results support the modification of skin thrombin activity by regional and systemic inflammation as well as a correlation with nerve fiber density. Skin thrombin activity measurments may aid in the diagnosis and treatment of SFN. Full article
(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Biomarkers in Pain)
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Article
Clinical and Molecular Spectrum of Sporadic Vascular Malformations: A Single-Center Study
Biomedicines 2022, 10(6), 1460; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061460 - 20 Jun 2022
Viewed by 334
Abstract
Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes—mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had [...] Read more.
Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes—mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent GNAQ somatic mutation p.Arg183Gln, while two had PIK3CA mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known PIK3CA mutations, and the remaining 3 had pathogenic GNA11 variants. Recurrent PIK3CA mutations were identified in the patients with megalencephaly–CM–polymicrogyria (MCAP), CLOVES, and Klippel–Trenaunay syndrome. Interestingly, PIK3CA somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic TEK mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an RASA1 mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic KRAS somatic variants, showing the variability of phenotypic features associated with KRAS mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies. Full article
(This article belongs to the Special Issue Somatic Mosaicism in Skin Disorders)
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Review
Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management
Biomedicines 2022, 10(6), 1459; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061459 - 20 Jun 2022
Viewed by 529
Abstract
Pancreatic cancer (PC) begins within the organ of the pancreas, which produces digestive enzymes, and is one of the formidable cancers for which appropriate treatment strategies are urgently needed. Autophagy occurs in the many chambers of PC tissue, including cancer cells, cancer-related fibroblasts, [...] Read more.
Pancreatic cancer (PC) begins within the organ of the pancreas, which produces digestive enzymes, and is one of the formidable cancers for which appropriate treatment strategies are urgently needed. Autophagy occurs in the many chambers of PC tissue, including cancer cells, cancer-related fibroblasts, and immune cells, and can be fine-tuned by various promotive and suppressive signals. Consequently, the impacts of autophagy on pancreatic carcinogenesis and progression depend greatly on its stage and conditions. Autophagy inhibits the progress of preneoplastic damage during the initial phase. However, autophagy encourages tumor formation during the development phase. Several studies have reported that both a tumor-promoting and a tumor-suppressing function of autophagy in cancer that is likely cell-type dependent. However, autophagy is dispensable for pancreatic ductal adenocarcinoma (PDAC) growth, and clinical trials with autophagy inhibitors, either alone or in combination with other therapies, have had limited success. Autophagy’s dual mode of action makes it therapeutically challenging despite autophagy inhibitors providing increased longevity in medical studies, highlighting the need for a more rigorous review of current findings and more precise targeting strategies. Indeed, the role of autophagy in PC is complicated, and numerous factors must be considered when transitioning from bench to bedside. In this review, we summarize the evidence for the tumorigenic and protective role of autophagy in PC tumorigenesis and describe recent advances in the understanding of how autophagy may be regulated and controlled in PDAC. Full article
(This article belongs to the Collection Autophagy in Cancer and Metastasis)
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Review
Self-Organization of the Retina during Eye Development, Retinal Regeneration In Vivo, and in Retinal 3D Organoids In Vitro
Biomedicines 2022, 10(6), 1458; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061458 - 20 Jun 2022
Viewed by 361
Abstract
Self-organization is a process that ensures histogenesis of the eye retina. This highly intricate phenomenon is not sufficiently studied due to its biological complexity and genetic heterogeneity. The review aims to summarize the existing central theories and ideas for a better understanding of [...] Read more.
Self-organization is a process that ensures histogenesis of the eye retina. This highly intricate phenomenon is not sufficiently studied due to its biological complexity and genetic heterogeneity. The review aims to summarize the existing central theories and ideas for a better understanding of retinal self-organization, as well as to address various practical problems of retinal biomedicine. The phenomenon of self-organization is discussed in the spatiotemporal context and illustrated by key findings during vertebrate retina development in vivo and retinal regeneration in amphibians in situ. Described also are histotypic 3D structures obtained from the disaggregated retinal progenitor cells of birds and retinal 3D organoids derived from the mouse and human pluripotent stem cells. The review highlights integral parts of retinal development in these conditions. On the cellular level, these include competence, differentiation, proliferation, apoptosis, cooperative movements, and migration. On the physical level, the focus is on the mechanical properties of cell- and cell layer-derived forces and on the molecular level on factors responsible for gene regulation, such as transcription factors, signaling molecules, and epigenetic changes. Finally, the self-organization phenomenon is discussed as a basis for the production of retinal organoids, a promising model for a wide range of basic scientific and medical applications. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Article
A Comparative Feasibility Study for Transcranial Extracorporeal Shock Wave Therapy
Biomedicines 2022, 10(6), 1457; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061457 - 20 Jun 2022
Viewed by 266
Abstract
The potential beneficial regenerative and stimulatory extracorporeal shock wave therapy (ESWT) applications to the central nervous system have garnered interest in recent years. Treatment zones for these indications are acoustically shielded by bones, which heavily impact generated sound fields. We present the results [...] Read more.
The potential beneficial regenerative and stimulatory extracorporeal shock wave therapy (ESWT) applications to the central nervous system have garnered interest in recent years. Treatment zones for these indications are acoustically shielded by bones, which heavily impact generated sound fields. We present the results of high-resolution tissue-realistic simulations, comparing the viability of different ESWT applicators in their use for transcranial applications. The performances of electrohydraulic, electromagnetic, and piezoelectric transducers for key reflector geometries are compared. Based on density information obtained from CT imaging of the head, we utilized the non-linear wave propagation toolset Matlab k-Wave to obtain spatial therapeutic sound field geometries and waveforms. In order to understand the reliability of results on the appropriate modeling of the skull, three different bone attenuation models were compared. We find that all currently clinically ESWT applicator technologies show significant retention of peak pressures and energies past the bone barrier. Electromagnetic transducers maintain a significantly higher energy flux density compared to other technologies while low focusing strength piezoelectric applicators have the weakest transmissions. Attenuation estimates provide insights into sound field degradation and energy losses, indicating that effective transcranial therapies can readily be attained with current applicators. Furthermore, the presented approach will allow for future targeted in silico development and the design of applicators and therapy plans to ultimately improve therapeutic outcomes. Full article
(This article belongs to the Special Issue Translational Research in Shock Wave Medicine)
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Review
Mitochondrial Phenotype as a Driver of the Racial Dichotomy in Obesity and Insulin Resistance
Biomedicines 2022, 10(6), 1456; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061456 - 20 Jun 2022
Viewed by 352
Abstract
African Americans (AA) are disproportionately burdened by metabolic diseases. While largely unexplored between Caucasian (C) and AA, differences in mitochondrial bioenergetics may provide crucial insight to mechanisms for increased susceptibility to metabolic diseases. AA display lower total energy expenditure and resting metabolic rate [...] Read more.
African Americans (AA) are disproportionately burdened by metabolic diseases. While largely unexplored between Caucasian (C) and AA, differences in mitochondrial bioenergetics may provide crucial insight to mechanisms for increased susceptibility to metabolic diseases. AA display lower total energy expenditure and resting metabolic rate compared to C, but paradoxically have a higher amount of skeletal muscle mass, suggestive of inherent energetic efficiency differences between these races. Such adaptations would increase the chances of overnutrition in AA; however, these disparities would not explain the racial difference in insulin resistance (IR) in healthy subjects. Hallmarks associated with insulin resistance (IR), such as reduced mitochondrial oxidative capacity and metabolic inflexibility are present even in healthy AA without a metabolic disease. These adaptations might be influential of mitochondrial “substrate preference” and could play a role in disproportionate IR rates among races. A higher glycolytic flux and provision of shuttles transferring electrons from cytosol to mitochondrial matrix could be a contributing factor in development of IR via heightened reactive oxygen species (ROS) production. This review highlights the above concepts and provides suggestions for future studies that could help delineate molecular premises behind potential impairments in insulin signaling and metabolic disease susceptibility in AA. Full article
(This article belongs to the Special Issue Emerging Paradigms in Insulin Resistance 2.0)
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Systematic Review
Prospective Risk of Type 2 Diabetes in Normal Weight Women with Polycystic Ovary Syndrome
Biomedicines 2022, 10(6), 1455; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061455 - 20 Jun 2022
Viewed by 319
Abstract
Background: Polycystic ovary syndrome (PCOS) is associated with obesity and increased risk for type 2 diabetes (T2D). However, the prospective risk of T2D in normal weight women with PCOS is debated, together with the relevant prospective screening programs for T2D in normal weight [...] Read more.
Background: Polycystic ovary syndrome (PCOS) is associated with obesity and increased risk for type 2 diabetes (T2D). However, the prospective risk of T2D in normal weight women with PCOS is debated, together with the relevant prospective screening programs for T2D in normal weight women with PCOS. Aim: To review and discuss prospective risk of T2D in normal weight women with PCOS, and to give recommendations regarding prospective screening for T2D in normal weight women with PCOS. Methods: Systematic review. Results: A systematic literature search resulted in 15 published prospective studies (10 controlled studies and 5 uncontrolled studies) regarding risk of T2D in study cohorts of PCOS, where data from normal weight women with PCOS were presented separately. In controlled studies, higher risk of T2D in normal weight women with PCOS compared to controls was reported in 4/10 studies, which included one study where T2D diagnosis was based on glucose measurement, two register-based studies, and one study where diagnosis of T2D was self-reported. Six of the 10 controlled studies reported no increased risk of T2D in normal weight women with PCOS. Four of these studies based the diagnosis of T2D on biochemical measurements, which supported the risk of surveillance bias in PCOS. In uncontrolled studies, 2/5 reported a higher risk of T2D in lean women with PCOS compared to the general population. We discuss the evidence for insulin resistance and β-cell dysfunction in normal weight women with PCOS, and aggravation in the hyperandrogenic phenotype, ageing women, and women with Asian ethnicity. Impaired glucose tolerance could be an important metabolic and vascular risk marker in PCOS. Conclusions: The risk of T2D may be increased in some normal weight women with PCOS. Individual risk markers such as hyperandrogenism, age >40 years, Asian ethnicity, and weight gain should determine prospective screening programs in normal weight women with PCOS. Full article
(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS))
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Article
Klebsiella pneumoniae Susceptibility to Carbapenem/Relebactam Combinations: Influence of Inoculum Density and Carbapenem-to-Inhibitor Concentration Ratio
Biomedicines 2022, 10(6), 1454; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061454 - 20 Jun 2022
Viewed by 321
Abstract
The inoculum effect (IE) is a well-known phenomenon with beta-lactams. At the same time, the IE has not been extensively studied with carbapenem/carbapenemase inhibitor combinations. The antibiotic-to-inhibitor concentration ratio used in susceptibility testing can influence the in vitro activity of the combination. To [...] Read more.
The inoculum effect (IE) is a well-known phenomenon with beta-lactams. At the same time, the IE has not been extensively studied with carbapenem/carbapenemase inhibitor combinations. The antibiotic-to-inhibitor concentration ratio used in susceptibility testing can influence the in vitro activity of the combination. To explore the role of these factors, imipenem/relebactam and doripenem/relebactam MICs were estimated against six Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae strains at standard inocula (SI) and high inocula (HI) by two methods: with a fixed relebactam concentration and with a fixed, pharmacokinetic-based carbapenem-to-relebactam concentration ratio. The combination MICs at HI, compared to SI, increased with most of the tested strains. However, the IE occurred with only two K. pneumoniae strains regardless of the MIC testing method. The relationship between the MICs at SI and the respective inoculum-induced MIC changes was observed when the MICs were estimated at pharmacokinetic-based carbapenem-to-relebactam concentration ratios. Thus, (1) IE was observed with both carbapenem/relebactam combinations regardless of the MIC testing method; however, IE was not observed frequently among tested K. pneumoniae strains. (2) At HI, carbapenem/relebactam combination MICs increased to levels associated with carbapenem resistance. (3) Combination MICs determined at pharmacokinetic-based carbapenem-to-inhibitor concentration ratios predict susceptibility elevations at HI in KPC-producing K. pneumoniae. Full article
(This article belongs to the Special Issue Drug Discovery for Infectious Diseases)
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Article
Cytotoxicity, Epidermal Barrier Function and Cytokine Evaluation after Antiseptic Treatment in Bioengineered Autologous Skin Substitute
Biomedicines 2022, 10(6), 1453; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061453 - 19 Jun 2022
Viewed by 376
Abstract
Bioengineered autologous skin substitutes (BASS) technology is an emerging field for skin burn therapy. However, further studies on BASS characterization, viability against standard procedures for wound healing, and protocol optimization are necessary for the improvement of BASS technology for clinical use. The aim [...] Read more.
Bioengineered autologous skin substitutes (BASS) technology is an emerging field for skin burn therapy. However, further studies on BASS characterization, viability against standard procedures for wound healing, and protocol optimization are necessary for the improvement of BASS technology for clinical use. The aim of this study is to evaluate the effect of common antiseptics for clinical use in BASS, focusing on cell viability, inflammatory cytokine pattern, and epithelium and skin barrier integrity, in order to establish the most adequate treatment for wound care after BASS grafting. Human keratinocytes (hKT) and dermal fibroblasts (hDF) were isolated from foreskin samples and integrated into hyaluronic acid-based BASS. The following antiseptics were applied every 48 h: ethanol (70%), chlorhexidine digluconate (1%), sodium hypochlorite (0.02%), povidone iodine (100 mg/mL), and polyhexanide (0.1%), during a follow-up of 16 days. Sodium hypochlorite was the only treatment that showed a high cell viability percentage throughout the evaluation time compared to other antiseptic treatments, as well as a similar cytokine secretion pattern as control BASS. No significant differences were found regarding epidermal barrier function. These findings point towards sodium hypochlorite being the least aggressive antiseptic treatment for BASS post-transplantation wound care. Full article
(This article belongs to the Special Issue Clinical Application for Tissue Engineering)
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Article
The Mediating Effect of Cytokines on the Association between Fungal Sensitization and Poor Clinical Outcome in Asthma
Biomedicines 2022, 10(6), 1452; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061452 - 19 Jun 2022
Viewed by 355
Abstract
Sensitization to fungal allergens is one of the proposed phenotypes in asthma. An association between fungal sensitization and worse clinical outcomes is apparent. Moreover, fungal sensitization in asthma that is associated with different type of immunological mechanism has been reported. How the role [...] Read more.
Sensitization to fungal allergens is one of the proposed phenotypes in asthma. An association between fungal sensitization and worse clinical outcomes is apparent. Moreover, fungal sensitization in asthma that is associated with different type of immunological mechanism has been reported. How the role of cytokines mediates the association between fungal sensitization and poorer asthmatic outcomes remains unclear. We aimed to determine role of cytokines in the relationship between fungal sensitization and worse clinical outcomes in asthma. Method: We conducted a prospective study to recruit adult patients with asthma. Data including age, sex, height, weight, smoking history, medication, emergency visit and admission, pulmonary function testing result, and Asthma Control Test (ACT) scores were collected. We used the automated BioIC method to measure fungal allergen sIgE in sera. Serum levels of Interleukin (IL) -4, IL-13, IL-6, IL-9, IL-10, IL-17 A, IL-22, Interferon (IFN) -γ, Immunoglobulin E (IgE), Tumor necrosis factor-α (TNF-α), and Transforming growth factor-β (TGF-β) were measured using ELISA. Result: IL-6 and IL-17A had a significant positive correlation between sensitization and most fungi species compared to IgE. Sensitization to Candida albicans had strongly positive association both with IL-6 and IL-17A. However, only IL-17A had significant relationship with ED visit times. The mediation analysis result indicates that IL-17A had a significant positively mediating effect (ME) on the association between Candida albicans and ED visit times. Conclusion: IL-17A is a potential mediator to link Candida albicans sensitization and ED visits for asthma. We suggest that patients with fungal sensitization, such as Candida albicans, have poorer outcomes associated with Th17-mediated immune response rather than Th2. Full article
(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)
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Article
The Impact of Inflammatory Stimuli on Xylosyltransferase-I Regulation in Primary Human Dermal Fibroblasts
Biomedicines 2022, 10(6), 1451; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061451 - 19 Jun 2022
Viewed by 339
Abstract
Inflammation plays a vital role in regulating fibrotic processes. Beside their classical role in extracellular matrix synthesis and remodeling, fibroblasts act as immune sentinel cells participating in regulating immune responses. The human xylosyltransferase-I (XT-I) catalyzes the initial step in proteoglycan biosynthesis and was [...] Read more.
Inflammation plays a vital role in regulating fibrotic processes. Beside their classical role in extracellular matrix synthesis and remodeling, fibroblasts act as immune sentinel cells participating in regulating immune responses. The human xylosyltransferase-I (XT-I) catalyzes the initial step in proteoglycan biosynthesis and was shown to be upregulated in normal human dermal fibroblasts (NHDF) under fibrotic conditions. Regarding inflammation, the regulation of XT-I remains elusive. This study aims to investigate the effect of lipopolysaccharide (LPS), a prototypical pathogen-associated molecular pattern, and the damage-associated molecular pattern adenosine triphosphate (ATP) on the expression of XYLT1 and XT-I activity of NHDF. We used an in vitro cell culture model and mimicked the inflammatory tissue environment by exogenous LPS and ATP supplementation. Combining gene expression analyses, enzyme activity assays, and targeted gene silencing, we found a hitherto unknown mechanism involving the inflammasome pathway components cathepsin B (CTSB) and caspase-1 in XT-I regulation. The suppressive role of CTSB on the expression of XYLT1 was further validated by the quantification of CTSB expression in fibroblasts from patients with the inflammation-associated disease Pseudoxanthoma elasticum. Altogether, this study further improves the mechanistic understanding of inflammatory XT-I regulation and provides evidence for fibroblast-targeted therapies in inflammatory diseases. Full article
(This article belongs to the Special Issue Fibroblasts: Key Mediators of Regeneration, Inflammation and Fibrosis)
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Article
Reprogrammed CD8+ T-Lymphocytes Isolated from Bone Marrow Have Anticancer Potential in Lung Cancer
Biomedicines 2022, 10(6), 1450; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061450 - 19 Jun 2022
Viewed by 414
Abstract
CD8+ T-lymphocytes play a key role in antitumor immune response. Patients with lung cancer often suffer from T-lymphocyte dysfunction and low T-cell counts. The exhaustion of effector T-lymphocytes largely limits the effectiveness of therapy. In this study, reprogrammed T-lymphocytes used MEK inhibitors [...] Read more.
CD8+ T-lymphocytes play a key role in antitumor immune response. Patients with lung cancer often suffer from T-lymphocyte dysfunction and low T-cell counts. The exhaustion of effector T-lymphocytes largely limits the effectiveness of therapy. In this study, reprogrammed T-lymphocytes used MEK inhibitors and PD-1 blockers to increase their antitumor activity. Antitumor effects of reprogrammed T-lymphocytes were shown in vitro and in vivo in the Lewis lung carcinoma model. The population of T- lymphocytes with persistent expression of CCR7 was formed as a result of reprogramming. Reprogrammed T-lymphocytes were resistant to apoptosis and characterized by high cytotoxicity against Lewis lung carcinoma (LLC) cells in vitro. Administration of reprogrammed T-lymphocytes to C57BL/6 mice with LLC reduced the number of lung metastases. The antitumor effect resulted from the elimination of tumor cells and cancer stem cells, and the effect of therapy on cytotoxic T-lymphocyte counts. Thus, reprogramming of T-lymphocytes using MEK inhibitors is a promising approach for targeted therapy of lung cancer. Full article
(This article belongs to the Section Gene and Cell Therapy)
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Article
Bromelain Protects Critically Perfused Musculocutaneous Flap Tissue from Necrosis
Biomedicines 2022, 10(6), 1449; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061449 - 19 Jun 2022
Viewed by 294
Abstract
Bromelain has previously been shown to prevent ischemia-induced necrosis in different types of tissues. In the present study, we, therefore, evaluated for the first time, the tissue-protective effects of bromelain in musculocutaneous flaps in mice. Adult C57BL/6N mice were randomly assigned to a [...] Read more.
Bromelain has previously been shown to prevent ischemia-induced necrosis in different types of tissues. In the present study, we, therefore, evaluated for the first time, the tissue-protective effects of bromelain in musculocutaneous flaps in mice. Adult C57BL/6N mice were randomly assigned to a bromelain treatment group and a control group. The animals were treated daily with intraperitoneal injections of 20 mg/kg bromelain or saline (control), starting 1 h before the flap elevation throughout a 10-day observation period. The random-pattern musculocutaneous flaps were raised on the backs of the animals and mounted into a dorsal skinfold chamber. Angiogenesis, nutritive blood perfusion and flap necrosis were quantitatively analyzed by means of repeated intravital fluorescence microscopy over 10 days after surgery. After the last microscopy, the flaps were harvested for additional histological and immunohistochemical analyses. Bromelain reduced necrosis of the critically perfused flap tissue by ~25%. The bromelain-treated flaps also exhibited a significantly higher functional microvessel density and an elevated formation of newly developed microvessels in the transition zone between the vital and necrotic tissues when compared to the controls. Immunohistochemical analyses demonstrated a markedly lower invasion of the myeloperoxidase-positive neutrophilic granulocytes and a significantly reduced number of cleaved caspase 3-positive apoptotic cells in the transition zone of bromelain-treated musculocutaneous flaps. These findings indicate that bromelain prevents flap necrosis by maintaining nutritive tissue perfusion and by suppressing ischemia-induced inflammation and apoptosis. Hence, bromelain may represent a promising compound to prevent ischemia-induced flap necrosis in clinical practice. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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Article
Discovering the Effects of Fisetin on NF-κB/NLRP-3/NRF-2 Molecular Pathways in a Mouse Model of Vascular Dementia Induced by Repeated Bilateral Carotid Occlusion
Biomedicines 2022, 10(6), 1448; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061448 - 19 Jun 2022
Viewed by 329
Abstract
Vascular dementia (VaD) is the second leading cause of dementia. The majority of VaD patients have cognitive abnormalities, which are caused by cerebral hypoperfusion-induced ischemia, endothelial dysfunction, oxidative stress, and neuroinflammation. Natural products are receiving increasing attention for the treatment of neuroinflammatory diseases. [...] Read more.
Vascular dementia (VaD) is the second leading cause of dementia. The majority of VaD patients have cognitive abnormalities, which are caused by cerebral hypoperfusion-induced ischemia, endothelial dysfunction, oxidative stress, and neuroinflammation. Natural products are receiving increasing attention for the treatment of neuroinflammatory diseases. The aim of this study was to investigate the molecular pathways underlying the protective effects of fisetin, a flavonoid present in many fruits and vegetables, in a mouse model of VaD induced by repeated ischemia-reperfusion (IR) of the total bilateral carotid artery. Here, we found that VaD caused brain injury, lipid peroxidation, and neuronal death in the hippocampus, as well as astrocyte and microglial activation, and reduced BDNF neurotrophic factor expression together with behavioral alterations. In addition, VaD induced the activation of inflammasome components (NLRP-3, ASC, and caspase 1), and their downstream products (IL-1β and IL-18) release and promote activation of apoptotic cell death. Fisetin attenuated histological injury, malondialdehyde levels, inflammasome pathway activation, apoptosis, as well as increased BDNF expression, reduced astrocyte, microglial activation, and cognitive deficits. In conclusion, the protective effects of fisetin could be due to the inhibition of the ROS-induced activation of NF-κB/NLRP3 inflammasome together with the activation of antioxidant Nrf2/HO-1, suggesting a possible crosstalk between these molecular pathways. Full article
(This article belongs to the Special Issue Molecular Pathology and Biomarkers of Neurodegenerative Diseases)
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Article
Traumatic and Diabetic Schwann Cell Demyelination Is Triggered by a Transient Mitochondrial Calcium Release through Voltage Dependent Anion Channel 1
Biomedicines 2022, 10(6), 1447; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061447 - 19 Jun 2022
Viewed by 415
Abstract
A large number of peripheral neuropathies, among which are traumatic and diabetic peripheral neuropathies, result from the degeneration of the myelin sheath, a process called demyelination. Demyelination does not result from Schwann cell death but from Schwann cell dedifferentiation, which includes reprograming and [...] Read more.
A large number of peripheral neuropathies, among which are traumatic and diabetic peripheral neuropathies, result from the degeneration of the myelin sheath, a process called demyelination. Demyelination does not result from Schwann cell death but from Schwann cell dedifferentiation, which includes reprograming and several catabolic and anabolic events. Starting around 4 h after nerve injury, activation of MAPK/cJun pathways is the earliest characterized step of this dedifferentiation program. Here we show, using real-time in vivo imaging, that Schwann cell mitochondrial pH, motility and calcium content are altered as soon as one hour after nerve injury. Mitochondrial calcium release occurred through the VDAC outer membrane channel and mPTP inner membrane channel. This calcium influx in the cytoplasm induced Schwann-cell demyelination via MAPK/c-Jun activation. Blocking calcium release through VDAC silencing or VDAC inhibitor TRO19622 prevented demyelination. We found that the kinetics of mitochondrial calcium release upon nerve injury were altered in the Schwann cells of diabetic mice suggesting a permanent leak of mitochondrial calcium in the cytoplasm. TRO19622 treatment alleviated peripheral nerve defects and motor deficit in diabetic mice. Together, these data indicate that mitochondrial calcium homeostasis is instrumental in the Schwann cell demyelination program and that blocking VDAC constitutes a molecular basis for developing anti-demyelinating drugs for diabetic peripheral neuropathy. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism in Health and Disease)
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Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model
Biomedicines 2022, 10(6), 1446; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061446 - 19 Jun 2022
Viewed by 471
Abstract
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential [...] Read more.
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [18F] DOPA or [18F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [18F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies. Full article
(This article belongs to the Special Issue New Techniques and Materials for Biomedical Applications)
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Review
Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury
Biomedicines 2022, 10(6), 1445; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061445 - 18 Jun 2022
Viewed by 317
Abstract
Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing [...] Read more.
Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia. Full article
(This article belongs to the Special Issue Connexins and Pannexins in Embryonic and Fetal Development)
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Review
The Emerging Role of Branched-Chain Amino Acids in Liver Diseases
Biomedicines 2022, 10(6), 1444; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061444 - 18 Jun 2022
Viewed by 434
Abstract
Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of [...] Read more.
Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs’ distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs’ possible contribution to liver health. Full article
(This article belongs to the Special Issue Cellular and Molecular Pathogenesis of Hepatobiliary Diseases)
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Article
Spontaneous Myocarditis in Mice Predisposed to Autoimmune Disease: Including Vaccination-Induced Onset
Biomedicines 2022, 10(6), 1443; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061443 - 18 Jun 2022
Viewed by 352
Abstract
Nonobese diabetic (NOD)/ShiLtJ mice, such as biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with moderate [...] Read more.
Nonobese diabetic (NOD)/ShiLtJ mice, such as biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with moderate glycosuria and nonfasting hyperglycemia. Previously, in NOD/ShiLtJ mice spontaneously developing type 1 diabetes, the possible involvement of decreased expression of nuclear factor-kappa B1 (NF-κB1) (also known as p50) in the development of type 1 diabetes was investigated. In response to these arguments, NOD mice with inconsistent NF-κB1 expression were established. Surprisingly, the majority of NOD Nfκb1 homozygote mice were found to die by the eighth week of life because of severe myocarditis. The incidence of spontaneous myocarditis in mice was slightly higher in males than in females. Furthermore, insulitis was observed in all NOD Nfκb1 heterozygote mice as early as 4 months of age. Additionally, in NOD Nfκb1 heterozygote mice, myocarditis with an increase in cTnT levels due to influenza or hepatitis B virus vaccination was observed with no significant gender difference. However, myocarditis was not observed with the two types of human papillomavirus vaccination. The results of immunological assays and histopathological examinations indicated that vaccination could induce myocarditis in genetically modified mice. In this study, we report that NOD Nfκb1 heterozygote mice can be used for investigating the risk of myocarditis development after vaccination. Full article
(This article belongs to the Topic Animal Model in Biomedical Research, 2nd Volume)
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Systematic Review
Embolization for Type Ia Endoleak after EVAR for Abdominal Aortic Aneurysms: A Systematic Review of the Literature
Biomedicines 2022, 10(6), 1442; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061442 - 18 Jun 2022
Viewed by 312
Abstract
(1) Successful endovascular repair for abdominal aortic aneurysms is based on the complete exclusion of the aneurysm sac from the systemic circulation. Type Ia endoleak (ELIA) is defined as the persistent perfusion of the aneurysm sac due to incomplete proximal sealing between aorta [...] Read more.
(1) Successful endovascular repair for abdominal aortic aneurysms is based on the complete exclusion of the aneurysm sac from the systemic circulation. Type Ia endoleak (ELIA) is defined as the persistent perfusion of the aneurysm sac due to incomplete proximal sealing between aorta and endograft, with a consequent risk of rupture and death. Endoleak embolization has been sporadically reported as a viable treatment for ELIA. (2) A systematic literature search in PubMed of all publications in English about ELIA embolization was performed until February 2022. Research methods and reporting were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data regarding patient numbers, technical success (endoleak absence at control angiography), reinterventions, clinical and imaging follow-up, and outcomes were collected and examined by two independent authors. (3) Twenty-one papers (12 original articles, 9 case reports) reported on 126 patients (age range 58–96 years) undergoing ELIA embolization 0–139 months after the index procedure. Indication for embolization was most often founded on unfavorable anatomy and patient comorbidities. Embolic agents used include liquid embolic agents, coils, plugs and combinations thereof. Technical success in this highly selected cohort ranged from 67–100%; the postprocedural complication rate within 30 days was 0–24%. ELIA recurrence was reported as 0–42.8%, with a secondary ELIA-embolization-intervention success rate of 50–100%. At a follow-up at 0–68 months, freedom from sac enlargement amounted to 76–100%, freedom from ELIA to 66.7–100%. (4) Specific literature about ELIA embolization is scant. ELIA embolization is a valuable bailout strategy for no-option patients; the immediate technical success rate is high and midterm and long-term outcomes are acceptable. Full article
(This article belongs to the Special Issue Vascular Embolization: Present and Future)
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Review
Virus-Based Immuno-Oncology Models
Biomedicines 2022, 10(6), 1441; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061441 - 18 Jun 2022
Viewed by 534
Abstract
Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of [...] Read more.
Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses’ mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations. Full article
(This article belongs to the Special Issue Innate Immune Memory in Health and Disease)
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Review
Harnessing the Potential of Enzymes as Inhaled Therapeutics in Respiratory Tract Diseases: A Review of the Literature
Biomedicines 2022, 10(6), 1440; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061440 - 17 Jun 2022
Viewed by 346
Abstract
Respiratory tract diseases (RTDs) are a global cause of mortality and affect patient well-being and quality of life. Specifically, there is a high unmet need concerning respiratory tract infections (RTIs) due to limitations of vaccines and increased antibiotic resistance. Enzyme therapeutics, and in [...] Read more.
Respiratory tract diseases (RTDs) are a global cause of mortality and affect patient well-being and quality of life. Specifically, there is a high unmet need concerning respiratory tract infections (RTIs) due to limitations of vaccines and increased antibiotic resistance. Enzyme therapeutics, and in particular plant-based enzymes, represent an underutilised resource in drug development warranting further attention. This literature review aims to summarise the current state of enzyme therapeutics in medical applications, with a focus on their potential to improve outcomes in RTDs, including RTIs. We used a narrative review approach, searching PubMed and clinicaltrials.gov with search terms including: enzyme therapeutics, enzyme therapy, inhaled therapeutics, botanical enzyme therapeutics, plant enzymes, and herbal extracts. Here, we discuss the advantages and challenges of enzyme therapeutics in the setting of RTDs and identify and describe several enzyme therapeutics currently used in the respiratory field. In addition, the review includes recent developments concerning enzyme therapies and plant enzymes in (pre-)clinical stages. The global coronavirus disease 2019 (COVID-19) pandemic has sparked development of several promising new enzyme therapeutics for use in the respiratory setting, and therefore, it is timely to provide a summary of recent developments, particularly as these therapeutics may also prove beneficial in other RTDs. Full article
(This article belongs to the Section Drug Discovery)
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Review
Clinical Application for Tissue Engineering Focused on Materials
Biomedicines 2022, 10(6), 1439; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061439 - 17 Jun 2022
Viewed by 385
Abstract
Cardiovascular-related medical conditions remain a significant cause of death worldwide despite the advent of tissue engineering research more than half a century ago. Although autologous tissue is still the preferred treatment, donor tissue is limited, and there remains a need for tissue-engineered vascular [...] Read more.
Cardiovascular-related medical conditions remain a significant cause of death worldwide despite the advent of tissue engineering research more than half a century ago. Although autologous tissue is still the preferred treatment, donor tissue is limited, and there remains a need for tissue-engineered vascular grafts (TEVGs). The production of extensive vascular tissue (>1 cm3) in vitro meets the clinical needs of tissue grafts and biological research applications. The use of TEVGs in human patients remains limited due to issues related to thrombogenesis and stenosis. In addition to the advancement of simple manufacturing methods, the shift of attention to the combination of synthetic polymers and bio-derived materials and cell sources has enabled synergistic combinations of vascular tissue development. This review details the selection of biomaterials, cell sources and relevant clinical trials related to large diameter vascular grafts. Finally, we will discuss the remaining challenges in the tissue engineering field resulting from complex requirements by covering both basic and clinical research from the perspective of material design. Full article
(This article belongs to the Special Issue Clinical Application for Tissue Engineering)
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Article
Phthalate Exposure and Oxidative/Nitrosative Stress in Childhood Asthma: A Nested Case-Control Study with Propensity Score Matching
Biomedicines 2022, 10(6), 1438; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061438 - 17 Jun 2022
Viewed by 325
Abstract
Whether low-dose phthalate exposure triggers asthma among children, and its underlying mechanisms, remain debatable. Here, we evaluated the individual and mixed effects of low-dose phthalate exposure on children with asthma and five (oxidative/nitrosative stress/lipid peroxidation) mechanistic biomarkers—8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 4-hydroxy-2-nonenal-mercapturic [...] Read more.
Whether low-dose phthalate exposure triggers asthma among children, and its underlying mechanisms, remain debatable. Here, we evaluated the individual and mixed effects of low-dose phthalate exposure on children with asthma and five (oxidative/nitrosative stress/lipid peroxidation) mechanistic biomarkers—8-hydroxy-2′-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), 8-isoprostaglandin F2α (8-isoPF2α), and malondialdehyde (MDA)—using a propensity score-matched case-control study (case vs. control = 41 vs. 111). The median monobenzyl phthalate (MBzP) concentrations in the case group were significantly higher than those in the control group (3.94 vs. 2.52 ng/mL, p = 0.02), indicating that dust could be an important source. After adjustment for confounders, the associations of high monomethyl phthalate (MMP) (75th percentile) with 8-NO2Gua (adjusted odds ratio (aOR): 2.66, 95% confidence interval (CI): 1.03–6.92) and 8-isoPF2α (aOR: 4.04, 95% CI: 1.51–10.8) and the associations of mono-iso-butyl phthalate (MiBP) with 8-isoPF2α (aOR: 2.96, 95% CI: 1.13–7.79) were observed. Weighted quantile sum regression revealed that MBzP contributed more than half of the association (56.8%), followed by MiBP (26.6%) and mono-iso-nonyl phthalate (MiNP) (8.77%). Our findings supported the adjuvant effect of phthalates in enhancing the immune system response. Full article
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Article
Sulfonamide-Derived Dithiocarbamate Gold(I) Complexes Induce the Apoptosis of Colon Cancer Cells by the Activation of Caspase 3 and Redox Imbalance
Biomedicines 2022, 10(6), 1437; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061437 - 17 Jun 2022
Viewed by 326
Abstract
Two new families of dithiocarbamate gold(I) complexes derived from benzenesulfonamide with phosphine or carbene as ancillary ligands have been synthesized and characterized. In the screening of their in vitro activity on human colon carcinoma cells (Caco-2), we found that the more lipophilic complexes—those [...] Read more.
Two new families of dithiocarbamate gold(I) complexes derived from benzenesulfonamide with phosphine or carbene as ancillary ligands have been synthesized and characterized. In the screening of their in vitro activity on human colon carcinoma cells (Caco-2), we found that the more lipophilic complexes—those with the phosphine PPh3—exhibited the highest anticancer activity whilst also displaying significant cancer cell selectivity. [Au(S2CNHSO2C6H5)(PPh3)] (1) and [Au(S2CNHSO2-p-Me-C6H4)(IMePropargyl)] (8) produce cell death, probably by intrinsic apoptosis (mitochondrial membrane potential modification) and caspase 3 activation, causing cell cycle arrest in the G1 phase with p53 activation. Besides this, both complexes might act as multi-target anticancer drugs, as they inhibit the activity of the enzymes thioredoxin reductase (TrxR) and carbonic anhydrase (CA IX) with the alteration of the redox balance, and show a pro-oxidant effect. Full article
(This article belongs to the Special Issue Gold and Silver Complexes in the Treatment of Diseases)
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Review
Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men
Biomedicines 2022, 10(6), 1436; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061436 - 17 Jun 2022
Viewed by 470
Abstract
Aberrant cell death can cause inflammation and inflammation-related diseases. While the link between cell death and inflammation has been widely established in mouse models, evidence supporting a role for cell death in the onset of inflammatory and autoimmune diseases in patients is still [...] Read more.
Aberrant cell death can cause inflammation and inflammation-related diseases. While the link between cell death and inflammation has been widely established in mouse models, evidence supporting a role for cell death in the onset of inflammatory and autoimmune diseases in patients is still missing. In this review, we discuss how the lessons learnt from mouse models can help shed new light on the initiating or contributing events leading to immune-mediated disorders. In addition, we discuss how multiomic approaches can provide new insight on the soluble factors released by dying cells that might contribute to the development of such diseases. Full article
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Article
Gene Expression-Based Functional Differences between the Bladder Body and Trigonal Urothelium in Adolescent Female Patients with Micturition Dysfunction
Biomedicines 2022, 10(6), 1435; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061435 - 17 Jun 2022
Viewed by 312
Abstract
The aim of this study is to determine the molecular differences between the urothelial transcriptomes of the bladder body and trigone. The transcriptomes of the bladder body and trigonal epithelia were analyzed by massive sequencing of total epithelial RNA. The profiles of urothelial [...] Read more.
The aim of this study is to determine the molecular differences between the urothelial transcriptomes of the bladder body and trigone. The transcriptomes of the bladder body and trigonal epithelia were analyzed by massive sequencing of total epithelial RNA. The profiles of urothelial and urinal microbiomes were assessed by amplicon sequencing of bacterial 16S rRNA genes in 17 adolescent females with pain and micturition dysfunction and control female subjects. The RNA sequencing identified 10,261 differentially expressed genes (DEGs) in the urothelia of the bladder body and trigone, with the top 1000 DEGs at these locations annotated to 36 and 77 of the Reactome-related pathways in the bladder body and trigone, respectively. These pathways represented 11 categories enriched in the bladder body urothelium, including extracellular matrix organization, the neuronal system, and 15 categories enriched in the trigonal epithelium, including RHO GTPase effectors, cornified envelope formation, and neutrophil degranulation. Five bacterial taxa in urine differed significantly in patients and healthy adolescent controls. The evaluation of their transcriptomes indicated that the bladder body and trigonal urothelia were functionally different tissues. The molecular differences between the body and trigonal urothelia responsible for clinical symptoms in adolescents with bladder pain syndrome/interstitial cystitis remain unclear. Full article
(This article belongs to the Section Gene and Cell Therapy)
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Article
Urinary MicroRNA Sensing Using Electrochemical Biosensor to Evaluate Colorectal Cancer Progression
Biomedicines 2022, 10(6), 1434; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061434 - 17 Jun 2022
Viewed by 254
Abstract
Research in cancer diagnostics has recently established its footing and significance in the biosensor sphere, emphasizing the idea of a unique probe design used as a sensor and actuator, to identify the presence of protein, DNA, RNA, or miRNA. The fluorescein isothiocyanate (FITC) [...] Read more.
Research in cancer diagnostics has recently established its footing and significance in the biosensor sphere, emphasizing the idea of a unique probe design used as a sensor and actuator, to identify the presence of protein, DNA, RNA, or miRNA. The fluorescein isothiocyanate (FITC) probe and biotinylated probe are designed for a two-pronged approach to the detection of the urinary miR-21 and miR-141, both of which have demonstrated significance in the development and progression of colorectal cancer, a leading cause of mortality and morbidity. The remainder of the apparatus is composed of a modified screen-printed carbon electrode (SPCE), to which the probes adhere, that transduces signals via the redox reaction between H2O2 and HRP, measured with chronoamperometry and cyclic voltammetry. The precise nature of our ultra-non-invasive biosensor makes for a highly sensitive and practical cancer detector, concluded by the significance when establishing disease presence (miR-21 p-value = 0.0176, miR-141 p-value = 0.0032), disease follow-up (miR-21 p-value = 0.00154, miR141 p-value < 0.0005), and even disease severity. This article hopes to emphasize the potential of an additional clinical tool for the management of colorectal cancer. Full article
(This article belongs to the Special Issue Nucleic Acid Based Sensing for Biomedical Applications)
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Article
Temporal Characterization of Behavioral and Hippocampal Dysfunction in the YAC128 Mouse Model of Huntington’s Disease
Biomedicines 2022, 10(6), 1433; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061433 - 17 Jun 2022
Viewed by 369
Abstract
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal [...] Read more.
Huntington’s disease (HD) is a genetic neurodegenerative disease characterized by motor, psychiatric, and cognitive symptoms. Emerging evidence suggests that emotional and cognitive deficits seen in HD may be related to hippocampal dysfunction. We used the YAC128 HD mouse model to perform a temporal characterization of the behavioral and hippocampal dysfunctions. Early and late symptomatic YAC128 mice exhibited depressive-like behavior, as demonstrated by increased immobility times in the Tail Suspension Test. In addition, YAC128 mice exhibited cognitive deficits in the Swimming T-maze Test during the late symptomatic stage. Except for a reduction in basal mitochondrial respiration, no significant deficits in the mitochondrial respiratory rates were observed in the hippocampus of late symptomatic YAC128 mice. In agreement, YAC128 animals did not present robust alterations in mitochondrial ultrastructural morphology. However, light and electron microscopy analysis revealed the presence of dark neurons characterized by the intense staining of granule cell bodies and shrunken nuclei and cytoplasm in the hippocampal dentate gyrus (DG) of late symptomatic YAC128 mice. Furthermore, structural alterations in the rough endoplasmic reticulum and Golgi apparatus were detected in the hippocampal DG of YAC128 mice by electron microscopy. These results clearly show a degenerative process in the hippocampal DG in late symptomatic YAC128 animals. Full article
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Review
Molecular Pathophysiological Mechanisms in Huntington’s Disease
Biomedicines 2022, 10(6), 1432; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061432 - 17 Jun 2022
Viewed by 377
Abstract
Huntington’s disease is an inherited neurodegenerative disease described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 4. In the following almost 30 [...] Read more.
Huntington’s disease is an inherited neurodegenerative disease described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 4. In the following almost 30 years, a considerable amount of research, using mainly animal models or in vitro experiments, has tried to unravel the complex molecular cascades through which the transcription of the mutant protein leads to neuronal loss, especially in the medium spiny neurons of the striatum, and identified excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking and reduced availability of trophic factors to be crucial contributors. This review discusses the pathogenic cascades described in the literature through which mutant huntingtin leads to neuronal demise. However, due to the ubiquitous presence of huntingtin, astrocytes are also dysfunctional, and neuroinflammation may additionally contribute to Huntington’s disease pathology. The quest for therapies to delay the onset and reduce the rate of Huntington’s disease progression is ongoing, but is based on findings from basic research. Full article
(This article belongs to the Special Issue Molecular Basis of Neurodegenerative Diseases)
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