Current Issues in Molecular Biology

11 pages, 4404 KiB

Open AccessArticle

CD44 Sorted Cells Have an Augmented Potential for Proliferation, Epithelial-Mesenchymal Transition, Stemness, and a Predominantly Inflammatory Cytokine and Angiogenic Secretome

by Shankargouda Patil

Curr. Issues Mol. Biol. 2021, 43(1), 423-433; https://doi.org/10.3390/cimb43010034 - 21 Jun 2021

Cited by 4 | Viewed by 2808

Abstract

Cancer stem cells (CSCs) have garnered attention with their potential for early diagnosis and prognosis of oral squamous cell carcinoma (OSCC). It is still indistinct whether CSCs are recognized with a specific set of characteristics. The present study aimed to assess the association [...] Read more.

Cancer stem cells (CSCs) have garnered attention with their potential for early diagnosis and prognosis of oral squamous cell carcinoma (OSCC). It is still indistinct whether CSCs are recognized with a specific set of characteristics. The present study aimed to assess the association of CD44 with stemness-related, Epithelial Mesenchymal Transition EMT-related genes and the secretome of the CSCs. The single-cell suspension from primary OSCC tumors was prepared by enzymatic digestion and the cells were cultured in-vitro. The cancer stem cells were isolated by CD44+ selection using magnetic cell-sorting. The expression of CD44, proliferation rate, gene expression of EMT-related transcription factors, stemness markers, cytokine levels and angiogenic factors in both cell population was assessed. The sorted CD44+ cells showed significantly higher proliferation rate than heterogenous population. The CD44 expression was >90% in the sorted cells which was higher than the heterogenous cells. The CD44+ CSCs cells demonstrated significant increased levels of EMT-related genes TWIST1 and CDH2 (N-cadherin), CSC-related genes CD44 and CD133 (PROM1), stemness-related genes OCT4, SOX2, inflammatory cytokines IL-1ß, IL-12, IL-18 and TNF-α and angiogenic factors Angiopoietin-1, Angiopoietin-2, bFGF and VEGF while levels of epithelial gene CDH1 (E-cadherin) decreased in comparison to mixed cell population. The genetic and secretome profiling of the CD44+ CSCs could serve as diagnostic and prognostic tools in the treatment of oral cancers. Full article

(This article belongs to the Special Issue Advances of Molecular Sciences in Dental Diseases Detection and Treatment)

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18 pages, 3192 KiB

Open AccessArticle

Immature Persimmon Suppresses Amyloid Beta (Aβ) Mediated Cognitive Dysfunction via Tau Pathology in ICR Mice

by Seul-Ki Yoo, Jong-Min Kim, Uk Lee, Jin-Yong Kang, Seon-Kyeong Park, Hye-Ju Han, Hyo-Won Park, Hyun-Jin Kim, Chul-Woo Kim, Mahn-Jo Kim and Ho-Jin Heo

Curr. Issues Mol. Biol. 2021, 43(1), 405-422; https://doi.org/10.3390/cimb43010033 - 21 Jun 2021

Cited by 4 | Viewed by 2801

Abstract

This study confirmed the ameliorating effect of immature persimmon (Diospyros kaki) ethanolic extract (IPEE) on neuronal cytotoxicity in amyloid beta (Aβ)_1–42-induced ICR mice. The administration of IPEE ameliorated the cognitive dysfunction in Aβ_1–42-induced mice by improving the [...] Read more.

This study confirmed the ameliorating effect of immature persimmon (Diospyros kaki) ethanolic extract (IPEE) on neuronal cytotoxicity in amyloid beta (Aβ)_1–42-induced ICR mice. The administration of IPEE ameliorated the cognitive dysfunction in Aβ_1–42-induced mice by improving the spatial working memory, the short-term and long-term memory functions. IPEE protected the cerebral cholinergic system, such as the acetylcholine (ACh) level and acetylcholinesterase (AChE) activity, and antioxidant system, such as the superoxide dismutase (SOD), reduced glutathione (GSH) and malondialdehyde (MDA) contents. In addition, mitochondrial dysfunction against Aβ_1–42-induced toxicity was reduced by regulating the reactive oxygen species (ROS), mitochondrial membrane potential and ATP contents. In addition, IPEE regulated the expression levels of tau signaling, such as TNF-α, p-JNK, p-Akt, p-GSK3β, p-tau, p-NF-κB, BAX and caspase 3. Finally, gallic acid, ellagic acid and quercetin 3-O-(6″-acetyl-glucoside) were identified as the physiological compounds of IPEE using ultra-performance liquid chromatography ion mobility separation quadrupole time-of-flight/tandem mass spectrometry (UPLC IMS Q-TOF/MS²). Full article

(This article belongs to the Special Issue Involvement of Medicinal Plants and Food in the Molecular Mechanisms of Disease Prevention)

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16 pages, 1836 KiB

Open AccessArticle

Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort

by Hiroki Maruyama, Atsumi Taguchi, Mariko Mikame, Atsushi Izawa, Naoki Morito, Kazufumi Izaki, Toshiyuki Seto, Akifumi Onishi, Hitoshi Sugiyama, Norio Sakai, Kenji Yamabe, Yukio Yokoyama, Satoshi Yamashita, Hiroshi Satoh, Shigeru Toyoda, Michihiro Hosojima, Yumi Ito, Ryushi Tazawa and Satoshi Ishii

Curr. Issues Mol. Biol. 2021, 43(1), 389-404; https://doi.org/10.3390/cimb43010032 - 19 Jun 2021

Cited by 5 | Viewed by 3527

Abstract

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients [...] Read more.

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands. Full article

(This article belongs to the Section Molecular Medicine)

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5 pages, 231 KiB

Open AccessEditorial

Current Issues in Molecular Biology Journal Enters a New Era

by Rafael Franco

Curr. Issues Mol. Biol. 2021, 43(1), 384-388; https://doi.org/10.3390/cimb43010031 - 18 Jun 2021

Viewed by 2459

Abstract

Current Issues in Molecular Biology (CIMB) (https://www [...] Full article

19 pages, 3528 KiB

Open AccessArticle

Water Extract of Mixed Mushroom Mycelia Grown on a Solid Barley Medium Is Protective against Experimental Focal Cerebral Ischemia

by Ji Heun Jeong, Shin Hye Kim, Mi Na Park, Jong Yea Park, Hyun Young Park, Chan Eui Song, Ji Hyun Moon, Ah La Choi, Ki Duck Kim, Nam Seob Lee, Young Gil Jeong, Do Kyung Kim, Bong Ho Lee, Yung Choon Yoo and Seung Yun Han

Curr. Issues Mol. Biol. 2021, 43(1), 365-383; https://doi.org/10.3390/cimb43010030 - 15 Jun 2021

Cited by 5 | Viewed by 4241

Abstract

Although the individual consumption of medicinal mushrooms, including Phellinus linteus (PL), Ganoderma lucidum (GL), and Inonotus obliquus (IO), is known to be neuroprotective, the associated mechanisms underlying their therapeutic synergism on focal cerebral ischemia (fCI) have yet to be elucidated. This study aimed [...] Read more.

Although the individual consumption of medicinal mushrooms, including Phellinus linteus (PL), Ganoderma lucidum (GL), and Inonotus obliquus (IO), is known to be neuroprotective, the associated mechanisms underlying their therapeutic synergism on focal cerebral ischemia (fCI) have yet to be elucidated. This study aimed to demonstrate the neuroprotective effects of mixed mushroom mycelia (MMM) against experimental fCI. The water-fractions, ethanolic-fractions, and ethyl acetate-fractions of the MMM (PL, GL, and IO) grown in a barley medium using solid-state fermentation techniques were prepared and their protective effects against glutamate-induced excitotoxicity were compared in PC-12 cells. After the identification of the water extracts of MMM (wMMM) as the most suitable form, which possessed the lowest toxicity and highest efficacy, further analyses for evaluating the anti-apoptotic effects of wMMM, including Hoechst 33258-based nuclear staining, fluorescence-activated cell sorting, and reactive oxygen species (ROS) detection assays, were performed. Rats were subjected to a 90 min middle cerebral artery occlusion and reperfusion, after which a wMMM treatment resulted in significant dose-dependent improvements across a number of parameters. Furthermore, measurements of intracellular ROS and levels of antioxidant enzymes revealed a wMMM-mediated ROS attenuation and antioxidant enzyme upregulation. We suggest that wMMM is neuroprotective against fCI through its anti-apoptotic and anti-oxidative effects. Full article

(This article belongs to the Special Issue Involvement of Medicinal Plants and Food in the Molecular Mechanisms of Disease Prevention)

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12 pages, 1112 KiB

Open AccessArticle

Microbial Screening Reveals Oral Site-Specific Locations of the Periodontal Pathogen Selenomonas noxia

by Jaydene McDaniel, Steven McDaniel, Beanca Jhanine Samiano, Matthew Marrujo, Karl Kingsley and Katherine M. Howard

Curr. Issues Mol. Biol. 2021, 43(1), 353-364; https://doi.org/10.3390/cimb43010029 - 12 Jun 2021

Cited by 14 | Viewed by 3284

Abstract

Introduction: Selenomonas noxia (SN) is an important periodontal pathogen, associated with gingivitis and periodontitis. Many studies have found associations between SN and indicators of poor health outcomes, such as smoking, low socioeconomic status and obesity. However, less is known about the prevalence of [...] Read more.

Introduction: Selenomonas noxia (SN) is an important periodontal pathogen, associated with gingivitis and periodontitis. Many studies have found associations between SN and indicators of poor health outcomes, such as smoking, low socioeconomic status and obesity. However, less is known about the prevalence of this organism and more specifically about other oral site-specific locations that may harbor this organism. Methods: Using an existing patient repository (n = 47) of DNA isolated from saliva and other oral sites (n = 235), including the dorsum of the tongue, lower lingual incisor, upper buccal molar and gingival crevicular fluid (GCF), molecular screening for SN was performed. Screening results were analyzed for associations between demographic variables (age, sex, race/ethnicity) and clinical information (body mass index or BMI, presence of orthodontic brackets, primary/mixed/permanent dentition). Results: qPCR screening revealed a total of n = 62/235 sites or 26.3% harboring SN with saliva and GCF (either alone or in combination with one or more sites) most often observed (Saliva, n = 23/27 or 85.18%, GCF, n = 14/27 or 51%). Analysis of site-specific data revealed most positive results were found among saliva and GCF alone or in combination, with fewer positive results observed among the tongue (33.3%), lower lingual incisor (29.6%), and upper buccal molar (25.9%). No significant associations were found between demographic or clinical variables and presence of SN at any site. Conclusions: These results may be among the first to describe site-specific locations of S. noxia among various additional oral biofilm sites. These data may represent a significant advancement in our understanding of the sites and locations that harbor this organism, which may be important for our understanding of the prevalence and distribution of these organisms among patients of different ages undergoing different types of oral treatments, such as orthodontic treatment or therapy. Full article

(This article belongs to the Special Issue Advances in Research on Molecular Oral Microorganisms)

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18 pages, 5001 KiB

Open AccessArticle

Histological Evidence of Wound Healing Improvement in Rats Treated with Oral Administration of Hydroalcoholic Extract of Vitis labrusca

by Tarsizio S. Santos, Izabella D. D. dos Santos, Rose N. Pereira-Filho, Silvana V. F. Gomes, Isabel B. Lima-Verde, Maria N. Marques, Juliana C. Cardoso, Patricia Severino, Eliana B. Souto and Ricardo L. C. de Albuquerque-Júnior

Curr. Issues Mol. Biol. 2021, 43(1), 335-352; https://doi.org/10.3390/cimb43010028 - 11 Jun 2021

Cited by 31 | Viewed by 5855

Abstract

Plant extracts rich in phenolic compounds have been demonstrated to accelerate wound healing, but their use by oral route has been poorly studied. The leaves of Vitis labrusca are rich in phenolic acids and flavonoids. The goal of this study was to assess [...] Read more.

Plant extracts rich in phenolic compounds have been demonstrated to accelerate wound healing, but their use by oral route has been poorly studied. The leaves of Vitis labrusca are rich in phenolic acids and flavonoids. The goal of this study was to assess the healing properties of the oral administration of hydroalcoholic extract of V. labrusca leaves (HEVL) in a murine model. HEVL was obtained by Soxhlet and dynamic maceration, and their yield and phenolic acids and flavonoid contents were determined. For the wound healing assay, 8 mm wounds were performed on the back of 48 Wistar rats, assigned into four groups (n = 12): CTR (distilled water), HEVL100, HEVL200, and HEVL300 (HEVL at 100, 200, and 300 mg/kg, respectively). On days 7 and 14, wound closure rates were assessed, and the healing wounds were subjected to histological analysis. Soxhlet-obtained extract was selected for the wound healing assay because it provided a higher yield and phenolic acid and flavonoid contents. HEVL significantly reduced leukocytosis in the peripheral blood (p < 0.05), accelerated wound closure (p < 0.05), and improved collagenization (p < 0.05) on day 7, as well as enhanced the epidermal tissue thickness (p < 0.001) and elastic fiber deposition on day 14 (p < 0.01). Furthermore, HEVL promoted an increase in the histological grading of wound healing on both days 7 and 14 (p < 0.01). The doses of 200 and 300 mg/kg provided better results than 100 mg/Kg. Our data provide histological evidence that the oral administration of HEVL improves wound healing in rodents. Therefore, the extract can be a potential oral medicine for healing purposes. Full article

(This article belongs to the Special Issue Involvement of Medicinal Plants and Food in the Molecular Mechanisms of Disease Prevention)

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11 pages, 1124 KiB

Open AccessArticle

Adrenomedullin Is a Diagnostic and Prognostic Biomarker for Acute Intracerebral Hemorrhage

by Francisco J. Julián-Villaverde, Laura Ochoa-Callejero, Eva Siles, Esther Martínez-Lara and Alfredo Martínez

Curr. Issues Mol. Biol. 2021, 43(1), 324-334; https://doi.org/10.3390/cimb43010027 - 11 Jun 2021

Cited by 7 | Viewed by 2518

Abstract

Hemorrhagic stroke remains an important health challenge. Adrenomedullin (AM) is a vasoactive peptide with an important role in cardiovascular diseases, including stroke. Serum AM and nitrate–nitrite and S-nitroso compounds (NOx) levels were measured and compared between healthy volunteers (n = 50) and [...] Read more.

Hemorrhagic stroke remains an important health challenge. Adrenomedullin (AM) is a vasoactive peptide with an important role in cardiovascular diseases, including stroke. Serum AM and nitrate–nitrite and S-nitroso compounds (NOx) levels were measured and compared between healthy volunteers (n = 50) and acute hemorrhagic stroke patients (n = 64). Blood samples were taken at admission (d0), 24 h later (d1), and after 7 days or at the time of hospital discharge (d7). Neurological severity (NIHSS) and functional prognosis (mRankin) were measured as clinical outcomes. AM levels were higher in stroke patients at all times when compared with healthy controls (p < 0.0001). A receiving operating characteristic curve analysis identified that AM levels at admission > 69.0 pg/mL had a great value as a diagnostic biomarker (area under the curve = 0.89, sensitivity = 80.0%, specificity = 100%). Furthermore, patients with a favorable outcome (NIHSS ≤ 3; mRankin ≤ 2) experienced an increase in AM levels from d0 to d1, and a decrease from d1 to d7, whereas patients with unfavorable outcome had no significant changes over time. NOx levels were lower in patients at d0 (p = 0.04) and d1 (p < 0.001) than in healthy controls. In conclusion, AM levels may constitute a new diagnostic and prognostic biomarker for this disease, and identify AM as a positive mediator for hemorrhagic stroke resolution. Full article

(This article belongs to the Section Molecular Medicine)

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11 pages, 1665 KiB

Open AccessArticle

Three-Dimensional Reconstructed Bone Marrow Matrix Culture Improves the Viability of Primary Myeloma Cells In-Vitro via a STAT3-Dependent Mechanism

by Yung-Hsing Huang, Meaad Almowaled, Jing Li, Christopher Venner, Irwindeep Sandhu, Anthea Peters, Afsaneh Lavasanifar and Raymond Lai

Curr. Issues Mol. Biol. 2021, 43(1), 313-323; https://doi.org/10.3390/cimb43010026 - 8 Jun 2021

Cited by 3 | Viewed by 2860

Abstract

Primary myeloma (PM) cells are short-lived in conventional culture, which limited their usefulness as a study model. Here, we evaluated if three-dimensional (3D) culture can significantly prolong the longevity of PM cells in-vitro. We employed a previously established 3D model for culture of [...] Read more.

Primary myeloma (PM) cells are short-lived in conventional culture, which limited their usefulness as a study model. Here, we evaluated if three-dimensional (3D) culture can significantly prolong the longevity of PM cells in-vitro. We employed a previously established 3D model for culture of bone marrow mononuclear cells isolated from 15 patients. We assessed the proportion of PM cells, viability and proliferation using CD38 staining, trypan blue exclusion assays and carboxy fluorescein succinimidyl ester (CFSE) staining, respectively. We observed significantly more CD38+ viable cells in 3D than in conventional culture (65% vs. 25%, p = 0.006) on day 3. CFSE staining showed no significant difference in cell proliferation between the two culture systems. Moreover, we found that PM cells in 3D culture are more STAT3 active by measure of pSTAT3 staining (66% vs. 10%, p = 0.008). Treatment of IL6, a STAT3 activator significantly increased CD38+ cell viability (41% to 68%, p = 0.021). In comparison, inhibition of STAT3 with Stattic significantly decreased PM cell viability in 3D culture (38% to 17% p = 0.010). Neither IL6 nor Stattic affected the PM cell viability in conventional culture. This study suggests that 3D culture can significantly improve the longevity of PM cells in-vitro, and STAT3 activation can further improve their viability. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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12 pages, 5308 KiB

Open AccessArticle

Poly(ADP-Ribose) Polymerase Inhibitor PJ34 Reduces Brain Damage after Stroke in the Neonatal Mouse Brain

by Philippe Bonnin, Tania Vitalis, Leslie Schwendimann, Alexandre Boutigny, Nassim Mohamedi, Valérie C Besson and Christiane Charriaut-Marlangue

Curr. Issues Mol. Biol. 2021, 43(1), 301-312; https://doi.org/10.3390/cimb43010025 - 7 Jun 2021

Cited by 6 | Viewed by 2743

Abstract

The poly(ADP-ribose) polymerase inhibitor PJ34 has recently been reported to increase cerebral blood flow, via the endothelial NO synthase, in the naive mouse brain throughout life. We addressed here the benefits of PJ34 after neonatal ischemia on hemodynamics and components of the neurovascular [...] Read more.

The poly(ADP-ribose) polymerase inhibitor PJ34 has recently been reported to increase cerebral blood flow, via the endothelial NO synthase, in the naive mouse brain throughout life. We addressed here the benefits of PJ34 after neonatal ischemia on hemodynamics and components of the neurovascular unit including the blood-brain barrier (BBB), microglia, and astrocytes. Nine-day-old mice were subjected to permanent MCA occlusion (pMCAo), and treated with either PBS or PJ34 (10 mg/kg). Mean blood-flow velocities (mBFV) were measured in both internal carotid arteries (ICA) and basilar trunk (BT) using Doppler-ultrasonography. BBB opening was assessed through somatostatin-receptor type-2 internalization and immunohistochemistry at 24 and 48 h. Lesion areas were measured 8 days after ischemia. In PBS-treated mice, pMCAo involved a drop in mBFV in the left ICA (p < 0.001 vs. basal), whereas mBFV remained stable in both right ICA and BT. PJ34 prevented this drop in the left ICA (NS vs. basal) and increased mBFV in the right ICA (p = 0.0038 vs. basal). No modification was observed in the BT. In contrast to PBS, BBB disruption extent and astrocyte demise were reduced in PJ34 mice only in the rostral brain at 48 h and 8 days post-pMCAo, respectively. Accordingly, 8 days after pMCAo, affected areas were reduced in the rostral brain (Bregma +0.86 and +0.14 mm), whereas total tissue loss was not reduced after PJ34 (4.0 ± 3.1%) vs. PBS (5.8 ± 3.4%). These results show that PJ34 reduced BBB permeability, astrocyte demise, and tissue loss (particularly in the rostral territories), suggesting that collateral supply mainly proceeds from the anterior ICA’s branches in the ischemic neonatal mouse brain. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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15 pages, 2564 KiB

Open AccessArticle

Differentially Expressed Extracellular Vesicle-Contained microRNAs before and after Transurethral Resection of Bladder Tumors

by Olaf Strømme, Kathleen A. Heck, Gaute Brede, Håvard T. Lindholm, Marit Otterlei and Carl-Jørgen Arum

Curr. Issues Mol. Biol. 2021, 43(1), 286-300; https://doi.org/10.3390/cimb43010024 - 4 Jun 2021

Cited by 9 | Viewed by 3948

Abstract

Bladder cancer (BC) is currently diagnosed and monitored by cystoscopy, a costly and invasive procedure. Potential biomarkers in urine, blood, and, more recently, extracellular vesicles (EVs), have been explored as non-invasive alternatives for diagnosis and surveillance of BC. EVs are nanovesicles secreted by [...] Read more.

Bladder cancer (BC) is currently diagnosed and monitored by cystoscopy, a costly and invasive procedure. Potential biomarkers in urine, blood, and, more recently, extracellular vesicles (EVs), have been explored as non-invasive alternatives for diagnosis and surveillance of BC. EVs are nanovesicles secreted by most cell types containing diverse molecular cargo, including different types of small RNAs, such as microRNA (miRNA). In this study, we performed next-generation sequencing of EV-contained miRNA isolated from urine and serum of 41 patients with non-muscle invasive BC (27 stage Ta, 14 stage T1) and 15 non-cancer patients (NCP) with benign cystoscopy findings. MiRNA sequencing was also performed on serum supernatant samples for T1 patients. To identify potential BC-specific biomarkers, expression levels of miRNA in presurgery samples were compared to those at postsurgery check-ups, and to NCPs. Results showed that two miRNAs, urinary EV-contained miR-451a and miR-486-5p, were significantly upregulated in presurgery samples from T1 patients compared to postsurgery check-up samples. This was confirmed in a replica EV/RNA isolation and sequencing run of 10 T1 patients from the primary run; however, analyses revealed no differential expression of miRNAs in serum EVs, serum supernatant, or when comparing BC patients to NCPs. This is the first study to investigate EV-containing miRNA sequencing in pre- and postsurgery BC patient samples and our findings suggest that urinary EV-contained miR-451a and miR-486-5p may be potential biomarkers for recurrence-free survival of BC patients with stage T1 disease. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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10 pages, 1249 KiB

Open AccessArticle

Influence of TGFBR2, TGFB3, DNMT1, and DNMT3A Knockdowns on CTGF, TGFBR2, and DNMT3A in Neonatal and Adult Human Dermal Fibroblasts Cell Lines

by Katarzyna Tomela, Justyna A. Karolak, Barbara Ginter-Matuszewska, Michal Kabza and Marzena Gajecka

Curr. Issues Mol. Biol. 2021, 43(1), 276-285; https://doi.org/10.3390/cimb43010023 - 3 Jun 2021

Cited by 2 | Viewed by 3149

Abstract

Dermal fibroblasts are responsible for the production of the extracellular matrix that undergoes significant changes during the skin aging process. These changes are partially controlled by the TGF-β signaling, which regulates tissue homeostasis dependently on several genes, including CTGF and DNA methyltransferases. To [...] Read more.

Dermal fibroblasts are responsible for the production of the extracellular matrix that undergoes significant changes during the skin aging process. These changes are partially controlled by the TGF-β signaling, which regulates tissue homeostasis dependently on several genes, including CTGF and DNA methyltransferases. To investigate the potential differences in the regulation of the TGF-β signaling and related molecular pathways at distinct developmental stages, we silenced the expression of TGFB1, TGFB3, TGFBR2, CTGF, DNMT1, and DNMT3A in the neonatal (HDF-N) and adult (HDF-A) human dermal fibroblasts using the RNAi method. Through Western blot, we analyzed the effects of the knockdowns of these genes on the level of the CTGF, TGFBR2, and DNMT3A proteins in both cell lines. In the in vitro assays, we observed that CTGF level was decreased after knockdown of DNMT1 in HDF-N but not in HDF-A. Similarly, the level of DNMT3A was decreased only in HDF-N after silencing of TGFBR2, TGFB3, or DNMT1. TGFBR2 level was lower in HDF-N after knockdown of TGFB3, DNMT1, or DNMT3A, but it was higher in HDF-A after TGFB1 silencing. The reduction of TGFBR2 after silencing of DNMT3A and vice versa in neonatal cells only suggests the developmental stage-specific interactions between these two genes. However, additional studies are needed to explain the dependencies between analyzed proteins. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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12 pages, 3649 KiB

Open AccessArticle

Sevoflurane Modulates AKT Isoforms in Triple Negative Breast Cancer Cells. An Experimental Study

by Crina E. Tiron, Emilia Patrașcanu, Paula A. Postu, Irina C. Vacarean Trandafir, Adrian Tiron and Ioana Grigoras

Curr. Issues Mol. Biol. 2021, 43(1), 264-275; https://doi.org/10.3390/cimb43010022 - 2 Jun 2021

Cited by 7 | Viewed by 3509

Abstract

(1) Background: Triple negative breast cancer (TNBC) is a highly aggressive tumor, associated with high rates of early distant recurrence and short survival times, and treatment may require surgery, and thus anesthesia. The effects of anesthetic drugs on cancer progression are under scrutiny, [...] Read more.

(1) Background: Triple negative breast cancer (TNBC) is a highly aggressive tumor, associated with high rates of early distant recurrence and short survival times, and treatment may require surgery, and thus anesthesia. The effects of anesthetic drugs on cancer progression are under scrutiny, but published data are controversial, and the involved mechanisms unclear. Anesthetic agents have been shown to modulate several molecular cascades, including PI3K/AKT/mTOR. AKT isoforms are frequently amplified in various malignant tumors and associated with malignant cell survival, proliferation and invasion. Their activation is often observed in human cancers and is associated with decreased survival rate. Certain anesthetics are known to affect hypoxia cell signaling mechanisms by upregulating hypoxia-inducible factors (HIFs). (2) Methods: MCF-10A and MDA-MB 231 cells were cultivated and CellTiter-Blue^® Cell Viability assay, 2D and 3D matrigel assay, immunofluorescence assays and gene expressions assay were performed after exposure to different sevoflurane concentrations. (3) Results: Sevoflurane exposure of TNBC cells results in morphological and behavioral changes. Sevoflurane differently influences the AKT isoforms expression in a time-dependent manner, with an important early AKT3 upregulation. The most significant effects occur at 72 h after 2 mM sevoflurane treatment and consist in increased viability, proliferation and aggressiveness and increased vimentin and HIF expression. (4) Conclusions: Sevoflurane exposure during surgery may contribute to cancer recurrence via AKT3 induced epithelial–mesenchymal transition (EMT) and by all three AKT isoforms enhanced cancer cell survival and proliferation. Full article

(This article belongs to the Section Molecular Medicine)

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13 pages, 2050 KiB

Open AccessArticle

DNA-DAPI Interaction-Based Method for Cell Proliferation Rate Evaluation in 3D Structures

by Egidijus Šimoliūnas, Paulius Kantakevičius, Miglė Kalvaitytė, Lina Bagdzevičiūtė, Milda Alksnė and Daiva Baltriukienė

Curr. Issues Mol. Biol. 2021, 43(1), 251-263; https://doi.org/10.3390/cimb43010021 - 30 May 2021

Cited by 5 | Viewed by 4242

Abstract

Effective cell number monitoring throughout the three-dimensional (3D) scaffold is a key factor in tissue engineering. There are many methods developed to evaluate cell number in 2D environments; however, they often encounter limitations in 3D. Therefore, there is a demand for reliable methods [...] Read more.

Effective cell number monitoring throughout the three-dimensional (3D) scaffold is a key factor in tissue engineering. There are many methods developed to evaluate cell number in 2D environments; however, they often encounter limitations in 3D. Therefore, there is a demand for reliable methods to measure cell proliferation in 3D surroundings. Here, we report a novel technique for the DNA content-based evaluation of cell proliferation using DNA-binding dye DAPI. We demonstrated the method’s compatibility with four different cell cultures: cancer lines MCF-7 and MH-22a, embryonic fibroblast cell line Swiss 3T3, and primary mesenchymal stem cell culture isolated from rat’s incisors. The DAPI based method was able to successfully evaluate cell proliferation in 2D, 2.5D, and 3D environments. Even though the proposed method does not discriminate between viable and dead cells, it might give a convenient snapshot of the cell number at a given time point. This should help to more reliably evaluate various processes proceeding in 2.5D and 3D cultures. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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11 pages, 2534 KiB

Open AccessArticle

Pancreatic Islets Exhibit Dysregulated Adaptation of Insulin Secretion after Chronic Epinephrine Exposure

by Rui Li, Huichai Huang, Sean W. Limesand and Xiaochuan Chen

Curr. Issues Mol. Biol. 2021, 43(1), 240-250; https://doi.org/10.3390/cimb43010020 - 28 May 2021

Cited by 6 | Viewed by 2965

Abstract

Chronic adrenergic stimulation is the dominant factor in impairment of the β-cell function. Sustained adrenergic exposure generates dysregulated insulin secretion in fetal sheep. Similar results have been shown in Min6 under the elevated epinephrine condition, but impairments after adrenergic removal are still unknown [...] Read more.

Chronic adrenergic stimulation is the dominant factor in impairment of the β-cell function. Sustained adrenergic exposure generates dysregulated insulin secretion in fetal sheep. Similar results have been shown in Min6 under the elevated epinephrine condition, but impairments after adrenergic removal are still unknown and a high rate of proliferation in Min6 has been ignored. Therefore, we incubated primary rats’ islets with half maximal inhibitory concentrations of epinephrine for three days, then determined their insulin secretion responsiveness and related signals two days after removal of adrenaline via radioimmunoassay and qPCR. Insulin secretion was not different between the exposure group (1.07 ± 0.04 ng/islet/h) and control (1.23 ± 0.17 ng/islet/h), but total islet insulin content after treatment (5.46 ± 0.87 ng/islet/h) was higher than control (3.17 ± 0.22 ng/islet/h, p < 0.05), and the fractional insulin release was 36% (p < 0.05) lower after the treatment. Meanwhile, the mRNA expression of Gαs, Gαz and Gβ1-2 decreased by 42.8% 19.4% and 24.8%, respectively (p < 0.05). Uncoupling protein 2 (Ucp2), sulphonylurea receptor 1 (Sur1) and superoxide dismutase 2 (Sod2) were significantly reduced (38.5%, 23.8% and 53.8%, p < 0.05). Chronic adrenergic exposure could impair insulin responsiveness in primary pancreatic islets. Decreased G proteins and Sur1 expression affect the regulation of insulin secretion. In conclusion, the sustained under-expression of Ucp2 and Sod2 may further change the function of β-cell, which helps to understand the long-term adrenergic adaptation of pancreatic β-cell. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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14 pages, 4129 KiB

Open AccessArticle

Renal Cell Carcinoma-Infiltrating CD3^low Vγ9Vδ1 T Cells Represent Potentially Novel Anti-Tumor Immune Players

by Hye Won Lee, Chanho Park, Je-Gun Joung, Minyong Kang, Yun Shin Chung, Won Joon Oh, Seon-Yong Yeom, Woong-Yang Park, Tae Jin Kim and Seong Il Seo

Curr. Issues Mol. Biol. 2021, 43(1), 226-239; https://doi.org/10.3390/cimb43010019 - 27 May 2021

Cited by 6 | Viewed by 4475

Abstract

Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of [...] Read more.

Due to the highly immunogenic nature of renal cell carcinoma (RCC), the tumor microenvironment (TME) is enriched with various innate and adaptive immune subsets. In particular, gamma-delta (γδ) T cells can act as potent attractive mediators of adoptive cell transfer immunotherapy because of their unique properties such as non-reliance on major histocompatibility complex expression, their ability to infiltrate human tumors and recognize tumor antigens, relative insensitivity to immune checkpoint molecules, and broad tumor cytotoxicity. Therefore, it is now critical to better characterize human γδ T-cell subsets and their mechanisms in RCCs, especially the stage of differentiation. In this study, we aimed to identify γδ T cells that might have adaptive responses against RCC progression. We characterized γδ T cells in peripheral blood and tumor-infiltrating lymphocytes (TILs) in freshly resected tumor specimens from 20 RCC patients. Furthermore, we performed a gene set enrichment analysis on RNA-sequencing data from The Cancer Genome Atlas (TCGA) derived from normal kidneys and RCC tumors to ascertain the association between γδ T-cell infiltration and anti-cancer immune activity. Notably, RCC-infiltrating CD3^low Vγ9Vδ1 T cells with a terminally differentiated effector memory phenotype with up-regulated activation/exhaustion molecules were newly detected as predominant TILs, and the cytotoxic activity of these cells against RCC was confirmed in vitro. In an additional analysis of the TCGA RCC dataset, γδ T-cell enrichment scores correlated strongly with those for CTLs, Th1 cells, “exhausted” T cells, and M1 macrophages, suggesting active involvement of γδ T cells in anti-tumor rather than pro-tumor activity, and Vδ1 cells were more abundant than Vδ2 or Vδ3 cells in RCC tumor samples. Thus, we posit that Vγ9Vδ1 T cells may represent an excellent candidate for adoptive immunotherapy in RCC patients with a high risk of relapse after surgery. Full article

(This article belongs to the Section Molecular Medicine)

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11 pages, 1488 KiB

Open AccessArticle

Isoform-Specific Effects of Apolipoprotein E on Markers of Inflammation and Toxicity in Brain Glia and Neuronal Cells In Vitro

by Jaclyn Iannucci, Abhik Sen and Paula Grammas

Curr. Issues Mol. Biol. 2021, 43(1), 215-225; https://doi.org/10.3390/cimb43010018 - 27 May 2021

Cited by 25 | Viewed by 4379

Abstract

Mutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the e4 allele representing an increased risk and the rare e2 allele having a reduced [...] Read more.

Mutations to the cholesterol transport protein apolipoprotein E (ApoE) have been identified as a major risk factor for the development of sporadic or late-onset Alzheimer’s disease (AD), with the e4 allele representing an increased risk and the rare e2 allele having a reduced risk compared to the primary e3 form. The reasons behind the change in risk are not entirely understood, though ApoE4 has been connected to inflammation and toxicity in both the brain and the periphery. The goal of this study was to better understand how the ApoE isoforms (ApoE2/3/4) confer differential AD-related risk by assessing cell-specific ApoE-related neuroinflammatory and neurotoxic effects. We compared the effects of ApoE isoforms in vitro on human astrocytes, a human immortalized microglia cell line (HMC3), and the human neuroblastoma cell line SH-SY5Y. Cells were treated for 24 h with or without recombinant ApoE2, ApoE3, or ApoE4 (20 nM) and inflammation and toxicity markers assessed. Our results indicated the expression of inflammatory cytokines IL-1β, TNFα, and IL-6 in human astrocytes was increased in response to all ApoE isoforms, with ApoE4 evoking the highest level of cytokine expression. In response to ApoE2 or ApoE3, microglial cells showed reduced levels of microglial activation markers TREM2 and Clec7a, while ApoE4 induced increased levels of both markers. ApoE2 promoted neuron survival through increased BDNF release from astrocytes. In addition, ApoE2 promoted, while ApoE4 reduced, neuronal viability. Overall, these results suggest that ApoE4 acts on cells in the brain to promote inflammation and neuronal injury and that the deleterious effects of ApoE4 on these cells may, in part, contribute to its role as a risk factor for AD. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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18 pages, 2119 KiB

Open AccessArticle

The Moringin/α-CD Pretreatment Induces Neuroprotection in an In Vitro Model of Alzheimer’s Disease: A Transcriptomic Study

by Serena Silvestro, Luigi Chiricosta, Agnese Gugliandolo, Renato Iori, Patrick Rollin, Daniele Perenzoni, Fulvio Mattivi, Placido Bramanti and Emanuela Mazzon

Curr. Issues Mol. Biol. 2021, 43(1), 197-214; https://doi.org/10.3390/cimb43010017 - 26 May 2021

Cited by 18 | Viewed by 4667

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and represents the most common form of senile dementia. Autophagy and mitophagy are cellular processes that play a key role in the aggregation of β-amyloid (Aβ) and tau phosphorylation. As a consequence, impairment of these [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and represents the most common form of senile dementia. Autophagy and mitophagy are cellular processes that play a key role in the aggregation of β-amyloid (Aβ) and tau phosphorylation. As a consequence, impairment of these processes leads to the progression of AD. Thus, interest is growing in the search for new natural compounds, such as Moringin (MOR), with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties that could be used for AD prevention. However, MOR appears to be poorly soluble and stable in water. To increase its solubility MOR was conjugated with α-cyclodextrin (MOR/α-CD). In this work, it was evaluated if MOR/α-CD pretreatment was able to exert neuroprotective effects in an AD in vitro model through the evaluation of the transcriptional profile by next-generation sequencing (NGS). To induce the AD model, retinoic acid-differentiated SH-SY5Y cells were exposed to Aβ_1-42. The MOR/α-CD pretreatment reduced the expression of the genes which encode proteins involved in senescence, autophagy, and mitophagy processes. Additionally, MOR/α-CD was able to induce neuronal remodeling modulating the axon guidance, principally downregulating the Slit/Robo signaling pathway. Noteworthy, MOR/α-CD, modulating these important pathways, may induce neuronal protection against Aβ_1-42 toxicity as demonstrated also by the reduction of cleaved caspase 3. These data indicated that MOR/α-CD could attenuate the progression of the disease and promote neuronal repair. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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10 pages, 1992 KiB

Open AccessArticle

Allicin Could Potentially Alleviate Oral Cancer Pain by Inhibiting “Pain Mediators” TNF-alpha, IL-8, and Endothelin

by Abdulwahab H. Alamir and Shankargouda Patil

Curr. Issues Mol. Biol. 2021, 43(1), 187-196; https://doi.org/10.3390/cimb43010016 - 23 May 2021

Cited by 16 | Viewed by 3419

Abstract

To evaluate the effects of allicin on mediators of pain secreted by oral cancer cells in vitro, single-cell suspensions were prepared by enzymatic method from oral squamous cell carcinoma (OSCC). Cancer stem cells were isolated by the CD133+ selection method with magnetic cell [...] Read more.

To evaluate the effects of allicin on mediators of pain secreted by oral cancer cells in vitro, single-cell suspensions were prepared by enzymatic method from oral squamous cell carcinoma (OSCC). Cancer stem cells were isolated by the CD133+ selection method with magnetic cell sorting. Stemness markers were checked in both cancer cells and cancer stem cells by RT-PCR. Comparative analysis of pain mediators TNF-alpha, IL-8, and endothelin at both RNA and protein levels for normal epithelial cells, cancer cells, and cancer stem cells was carried out with and without allicin treatment. CD133 and CD44 expression levels were checked in cancer cells and cancer stem cells flow cytometrically. Allicin inhibited both gene and protein expression of TNF-alpha, IL-8, and endothelin in both cancer cells and cancer stem cells. Allicin is more likely to be a promising treatment in alleviating the levels of pain and inflammation in OSCCs. Full article

(This article belongs to the Special Issue Advances of Molecular Sciences in Dental Diseases Detection and Treatment)

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11 pages, 1312 KiB

Open AccessArticle

Mitochondrial Respiration in Drosophila Ovaries after a Full Cycle of Oogenesis under Simulated Microgravity

by Irina V. Ogneva and Maria A. Usik

Curr. Issues Mol. Biol. 2021, 43(1), 176-186; https://doi.org/10.3390/cimb43010015 - 22 May 2021

Cited by 10 | Viewed by 2463

Abstract

Studies of the function of the female reproductive system in zero gravity are urgent for the future exploration of deep space. Female reproductive cells, oocytes, are rich in mitochondria, which allow oocytes to produce embryos. The rate of cellular respiration was determined to [...] Read more.

Studies of the function of the female reproductive system in zero gravity are urgent for the future exploration of deep space. Female reproductive cells, oocytes, are rich in mitochondria, which allow oocytes to produce embryos. The rate of cellular respiration was determined to assess the functional state of the mitochondrial apparatus in Drosophila melanogaster ovaries in which the full cycle of oogenesis took place under simulated microgravity. Since cellular respiration depends on the state of the cytoskeleton, the contents of the main cytoskeletal proteins were determined by Western blotting. To modulate the structure of the cytoskeleton, essential phospholipids were administered per os at a dosage of 500 mg/kg in medium. The results of this study show that after a full cycle of oogenesis under simulated microgravity, the rate of cellular respiration in the fruit fly ovaries increases, apparently due to complex II of the respiratory chain. At the same time, we did not find any changes in the area of oocytes or in the content of proteins in the respiratory chain. However, changes were found in the relative contents of proteins of the actin cytoskeleton. There were no changes of essential phospholipids and no increase in the rate of cellular respiration of the ovaries after exposure to simulated microgravity. However, in the control, the administration of essential phospholipids led to a decrease in the efficiency of oxygen consumption in the flies’ ovaries due to complexes IV–V. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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13 pages, 2170 KiB

Open AccessArticle

A Comparison of Doxorubicin-Resistant Colon Cancer LoVo and Leukemia HL60 Cells: Common Features, Different Underlying Mechanisms

by Laura Locatelli, Alessandra Cazzaniga, Giorgia Fedele, Monica Zocchi, Roberta Scrimieri, Claudia Moscheni, Sara Castiglioni and Jeanette A. Maier

Curr. Issues Mol. Biol. 2021, 43(1), 163-175; https://doi.org/10.3390/cimb43010014 - 22 May 2021

Cited by 5 | Viewed by 3304

Abstract

Chemoresistance causes cancer relapse and metastasis, thus remaining the major obstacle to cancer therapy. While some light has been shed on the underlying mechanisms, it is clear that chemoresistance is a multifaceted problem strictly interconnected with the high heterogeneity of neoplastic cells. We [...] Read more.

Chemoresistance causes cancer relapse and metastasis, thus remaining the major obstacle to cancer therapy. While some light has been shed on the underlying mechanisms, it is clear that chemoresistance is a multifaceted problem strictly interconnected with the high heterogeneity of neoplastic cells. We utilized two different human cell lines, i.e., LoVo colon cancer and promyelocytic leukemia HL60 cells sensitive and resistant to doxorubicin (DXR), largely used as a chemotherapeutic and frequently leading to chemoresistance. LoVo and HL60 resistant cells accumulate less reactive oxygen species by differently modulating the levels of some pro- and antioxidant proteins. Moreover, the content of intracellular magnesium, known to contribute to protect cells from oxidative stress, is increased in DXR-resistant LoVo through the upregulation of MagT1 and in DXR-resistant HL60 because of the overexpression of TRPM7. In addition, while no major differences in mitochondrial mass are observed in resistant HL60 and LoVo cells, fragmented mitochondria due to increased fission and decreased fusion are detected only in resistant LoVo cells. We conclude that DXR-resistant cells evolve adaptive mechanisms to survive DXR cytotoxicity by activating different molecular pathways. Full article

(This article belongs to the Section Molecular Medicine)

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10 pages, 2590 KiB

Open AccessArticle

KPNB1 Inhibitor Importazole Reduces Ionizing Radiation-Increased Cell Surface PD-L1 Expression by Modulating Expression and Nuclear Import of IRF1

by Hironori Yoshino, Yoshiaki Sato and Manabu Nakano

Curr. Issues Mol. Biol. 2021, 43(1), 153-162; https://doi.org/10.3390/cimb43010013 - 19 May 2021

Cited by 6 | Viewed by 4021

Abstract

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that negatively regulates anti-tumor immunity. Recent reports indicate that anti-cancer treatments, such as radiation therapy, increase PD-L1 expression on the surface of tumor cells. We previously reported that the nuclear transport receptor karyopherin-β1 (KPNB1) [...] Read more.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that negatively regulates anti-tumor immunity. Recent reports indicate that anti-cancer treatments, such as radiation therapy, increase PD-L1 expression on the surface of tumor cells. We previously reported that the nuclear transport receptor karyopherin-β1 (KPNB1) is involved in radiation-increased PD-L1 expression on head-and-neck squamous cell carcinoma cells. However, the mechanisms underlying KPNB1-mediated, radiation-increased PD-L1 expression remain unknown. Thus, the mechanisms of radiation-increased, KPNB1-mediated PD-L1 expression were investigated by focusing on the transcription factor interferon regulatory factor 1 (IRF1), which is reported to regulate PD-L1 expression. Western blot analysis showed that radiation increased IRF1 expression. In addition, flow cytometry showed that IRF1 knockdown decreased cell surface PD-L1 expression of irradiated cells but had a limited effect on non-irradiated cells. These findings suggest that the upregulation of IRF1 after irradiation is required for radiation-increased PD-L1 expression. Notably, immunofluorescence and western blot analyses revealed that KPNB1 inhibitor importazole not only diffused nuclear localization of IRF1 but also decreased IRF1 upregulation by irradiation, which attenuated radiation-increased PD-L1 expression. Taken together, these findings suggest that KPNB1 mediates radiation-increased cell surface PD-L1 expression through both upregulation and nuclear import of IRF1. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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11 pages, 505 KiB

Open AccessArticle

Association between Proton Pump Inhibitors and Hearing Impairment: A Nested Case-Control Study

by So Young Kim, Chang Ho Lee, Chanyang Min, Dae Myoung Yoo and Hyo Geun Choi

Curr. Issues Mol. Biol. 2021, 43(1), 142-152; https://doi.org/10.3390/cimb43010012 - 18 May 2021

Cited by 3 | Viewed by 3049

Abstract

This study investigated the association of previous use of proton pump inhibitors (PPIs) with the rate of hearing impairment. The ≥40-year-old population in the Korean National Health Insurance Service-Health Screening Cohort was enrolled. The 6626 registered hearing-impaired patients were matched with 508,240 control [...] Read more.

This study investigated the association of previous use of proton pump inhibitors (PPIs) with the rate of hearing impairment. The ≥40-year-old population in the Korean National Health Insurance Service-Health Screening Cohort was enrolled. The 6626 registered hearing-impaired patients were matched with 508,240 control participants for age, sex, income, region of residence, and index date (date of hearing impairment diagnosis). The prescription histories of PPIs were collected for 2 years before the index date. The odds ratios of the duration of PPI use for hearing impairment were analyzed using conditional logistic regression. Subgroups of age/sex and severity of hearing impairments were additionally analyzed for the relation of PPI use with hearing impairment. PPI use for 30–365 days was associated with a 1.65-times higher odds of hearing impairment (95% confidence interval (CI) = 1.47–1.86 for 30–365 days of PPI medication). PPI use for ≥365 days was also related to 1.52-times higher odds of hearing impairment (95% CI = 1.35–1.72, p < 0.001). All age and sex subgroups demonstrated a positive association between PPI use and hearing impairment. Severe hearing impairment showed consistently higher odds of a relation with PPI use. PPI use was associated with an increased rate of hearing impairment. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 2029 KiB

Open AccessReview

Molecular Changes Underlying Genistein Treatment of Wound Healing: A Review

by Matúš Čoma, Veronika Lachová, Petra Mitrengová and Peter Gál

Curr. Issues Mol. Biol. 2021, 43(1), 127-141; https://doi.org/10.3390/cimb43010011 - 17 May 2021

Cited by 16 | Viewed by 3623

Abstract

Estrogen deprivation is one of the major factors responsible for many age-related processes including poor wound healing in postmenopausal women. However, the reported side-effects of estrogen replacement therapy (ERT) have precluded broad clinical administration. Therefore, selective estrogen receptor modulators (SERMs) have been developed [...] Read more.

Estrogen deprivation is one of the major factors responsible for many age-related processes including poor wound healing in postmenopausal women. However, the reported side-effects of estrogen replacement therapy (ERT) have precluded broad clinical administration. Therefore, selective estrogen receptor modulators (SERMs) have been developed to overcome the detrimental side effects of ERT on breast and/or uterine tissues. The use of natural products isolated from plants (e.g., soy) may represent a promising source of biologically active compounds (e.g., genistein) as efficient alternatives to conventional treatment. Genistein as natural SERM has the unique ability to selectively act as agonist or antagonist in a tissue-specific manner, i.e., it improves skin repair and simultaneously exerts anti-cancer and chemopreventive properties. Hence, we present here a wound healing phases-based review of the most studied naturally occurring SERM. Full article

(This article belongs to the Special Issue Involvement of Medicinal Plants and Food in the Molecular Mechanisms of Disease Prevention)

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11 pages, 834 KiB

Open AccessReview

Immunomodulatory Expression of Cathelicidins Peptides in Pulp Inflammation and Regeneration: An Update

by Nireeksha, Sudhir Rama Varma, Marah Damdoum, Mohammed Amjed Alsaegh, Mithra N. Hegde, Suchetha N. Kumari, Srinivasan Ramamurthy, Jayaraj Narayanan, Eisha Imran, Juzer Shabbir and Zohaib Khurshid

Curr. Issues Mol. Biol. 2021, 43(1), 116-126; https://doi.org/10.3390/cimb43010010 - 13 May 2021

Cited by 8 | Viewed by 3742

Abstract

The role of inflammatory mediators in dental pulp is unique. The local environment of pulp responds to any changes in the physiology that are highly fundamental, like odontoblast cell differentiation and other secretory activity. The aim of this review is to assess the [...] Read more.

The role of inflammatory mediators in dental pulp is unique. The local environment of pulp responds to any changes in the physiology that are highly fundamental, like odontoblast cell differentiation and other secretory activity. The aim of this review is to assess the role of cathelicidins based on their capacity to heal wounds, their immunomodulatory potential, and their ability to stimulate cytokine production and stimulate immune-inflammatory response in pulp and periapex. Accessible electronic databases were searched to find studies reporting the role of cathelicidins in pulpal inflammation and regeneration published between September 2010 and September 2020. The search was performed using the following databases: Medline, Scopus, Web of Science, SciELO and PubMed. The electronic search was performed using the combination of keywords “cathelicidins” and “dental pulp inflammation”. On the basis of previous studies, it can be inferred that LL-37 plays an important role in odontoblastic cell differentiation and stimulation of antimicrobial peptides. Furthermore, based on these outcomes, it can be concluded that LL-37 plays an important role in reparative dentin formation and provides signaling for defense by activating the innate immune system. Full article

(This article belongs to the Section Molecular Medicine)

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9 pages, 251 KiB

Open AccessArticle

Critical Amino Acid Variants in HLA-DRB1 and -DQB1 Allotypes in the Development of Classical Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Japanese Population

by Masahito Katahira, Taku Tsunekawa, Akira Mizoguchi, Mariko Yamaguchi, Kahori Tsuru, Hiromi Takashima and Ryoma Terada

Curr. Issues Mol. Biol. 2021, 43(1), 107-115; https://doi.org/10.3390/cimb43010009 - 9 May 2021

Cited by 4 | Viewed by 2567

Abstract

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 [...] Read more.

The effects of amino acid variants encoded by the human leukocyte antigen (HLA) class II on the development of classical type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) have not been fully elucidated. We retrospectively investigated the HLA-DRB1 and -DQB1 genes of 72 patients with classical T1D and 102 patients with LADA in the Japanese population and compared the frequencies of HLA-DRB1 and -DQB1 alleles between these patients and the Japanese populations previously reported by another institution. We also performed a blind association analysis with all amino acid positions in classical T1D and LADA, and compared the associations of HLA-DRB1 and -DQB1 amino acid positions in classical T1D and LADA. The frequency of DRß-Phe-13 was significantly higher and those of DRß-Arg-13 and DQß-Gly-70 were significantly lower in patients with classical T1D and LADA than in controls. The frequencies of DRß-His-13 and DQß-Glu-70 were significantly higher in classical T1D patients than in controls. The frequency of DRß-Ser-13 was significantly lower and that of DQß-Arg-70 was significantly higher in LADA patients than in controls. HLA-DRß1 position 13 and HLA-DQß1 position 70 could be critical amino acid positions in the development of classical T1D and LADA. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

14 pages, 2099 KiB

Open AccessArticle

Anti-Inflammatory Effect of Pineapple Rhizome Bromelain through Downregulation of the NF-B- and MAPKs-Signaling Pathways in Lipopolysaccharide (LPS)-Stimulated RAW264.7 Cells

by Orapin Insuan, Phornphimon Janchai, Benchaluk Thongchuai, Rujirek Chaiwongsa, Supaporn Khamchun, Somphot Saoin, Wimonrut Insuan, Peraphan Pothacharoen, Waraporn Apiwatanapiwat, Antika Boondaeng and Pilanee Vaithanomsat

Curr. Issues Mol. Biol. 2021, 43(1), 93-106; https://doi.org/10.3390/cimb43010008 - 7 May 2021

Cited by 21 | Viewed by 6524

Abstract

Bromelain is a mixture of proteolytic enzymes derived from pineapple (Ananas comosus) fruit and stem possessing several beneficial properties, particularly anti-inflammatory activity. However, the molecular mechanisms underlying the anti-inflammatory effects of bromelain are unclear. This study investigated the anti-inflammatory effects and [...] Read more.

Bromelain is a mixture of proteolytic enzymes derived from pineapple (Ananas comosus) fruit and stem possessing several beneficial properties, particularly anti-inflammatory activity. However, the molecular mechanisms underlying the anti-inflammatory effects of bromelain are unclear. This study investigated the anti-inflammatory effects and inhibitory molecular mechanisms of crude and purified rhizome bromelains on lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells. RAW264.7 cells were pre-treated with various concentrations of crude bromelain (CB) or purified bromelain (PB), and then treated with LPS. The production levels of pro-inflammatory cytokines and mediators, including nitric oxide (NO), interleukin (IL)-6, and tumor necrosis factor (TNF)- were determined by Griess and ELISA assays. The expressions of inducible nitric oxide synthetase (iNOS), cyclooxygenase (COX)-2, nuclear factor kappa B (NF-B), and mitogen-activated protein kinases (MAPKs)-signaling pathway-related proteins were examined by western blot analysis. The pre-treatment of bromelain dose-dependently reduced LPS-induced pro-inflammatory cytokines and mediators, which correlated with downregulation of iNOS and COX-2 expressions. The inhibitory potency of PB was stronger than that of CB. PB also suppressed phosphorylated NF-B (p65), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha, extracellular signal-regulated kinases, c-Jun amino-terminal kinases, and p38 proteins in LPS-treated cells. PB then exhibited potent anti-inflammatory effects on LPS-induced inflammatory responses in RAW264.7 cells by inhibiting the NF-B and MAPKs-signaling pathways. Full article

(This article belongs to the Special Issue Linking Genomic Changes with Cancer in the NGS Era)

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14 pages, 9395 KiB

Open AccessArticle

Vitamin D Deficiency Reduces Vascular Reactivity of Coronary Arterioles in Male Rats

by Zoltán Fontányi, Réka Eszter Sziva, Éva Pál, Leila Hadjadj, Anna Monori-Kiss, Eszter Mária Horváth, Rita Benkő, Attila Magyar, Andrea Heinzlmann, Zoltán Benyó, György L. Nádasy, Gabriella Masszi and Szabolcs Várbíró

Curr. Issues Mol. Biol. 2021, 43(1), 79-92; https://doi.org/10.3390/cimb43010007 - 7 May 2021

Cited by 5 | Viewed by 3192

Abstract

Background: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of [...] Read more.

Background: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of male rats in cases of different vitamin D supply. Methods: Four-week-old male Wistar rats were divided into a control group (n = 11) with optimal vitamin D supply (300 IU/kgbw/day) and a VDD group (n = 11, <0.5 IU/kgbw/day). After 8 weeks of treatment, intramural coronary artery segments were microprepared, their pharmacological reactivity was examined by in vitro microangiometry, and their receptor expression was investigated by immunohistochemistry. Results: Thromboxane A₂ (TXA₂)-agonist induced reduced vasoconstriction, testosterone (T) and 17-β-estradiol (E2) relaxations were significantly decreased, a significant decrease in thromboxane receptor (TP) expression was shown, and the reduction in estrogen receptor-α (ERα) expression was on the border of significance in the VDD group. Conclusions: VD-deficient male coronary arteries showed deteriorated pharmacological reactivity to TXA₂ and sexual steroids (E2, T). Insufficient vasoconstrictor capacity was accompanied by decreased TP receptor expression, and vasodilator impairments were mainly functional. The decrease in vasoconstrictor and vasodilator responses results in narrowed adaptational range of coronaries, causing inadequate coronary perfusion that might contribute to the increased CV risk in VDD. Full article

(This article belongs to the Special Issue Involvement of Medicinal Plants and Food in the Molecular Mechanisms of Disease Prevention)

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14 pages, 10206 KiB

Open AccessArticle

Network Pharmacology and Molecular Docking Combined to Analyze the Molecular and Pharmacological Mechanism of Pinellia ternata in the Treatment of Hypertension

by Zhaowei Zhai, Xinru Tao, Mohammad Murtaza Alami, Shaohua Shu and Xuekui Wang

Curr. Issues Mol. Biol. 2021, 43(1), 65-78; https://doi.org/10.3390/cimb43010006 - 1 May 2021

Cited by 18 | Viewed by 6320

Abstract

Hypertension is a cardiovascular disease that causes great harm to health and life, affecting the function of important organs and accompanied by a variety of secondary diseases, which need to be treated with drugs for a long time. P. ternata alone or combination [...] Read more.

Hypertension is a cardiovascular disease that causes great harm to health and life, affecting the function of important organs and accompanied by a variety of secondary diseases, which need to be treated with drugs for a long time. P. ternata alone or combination with western medicine has played an important role in traditional Chinese medicine. Although P. ternata is used clinically to treat hypertension, its functional molecular mechanism and pharmacological mechanism have not been elucidated. Therefore, in this study, the potentially effective components, and targets of P. ternata in the treatment of hypertension were screened by the method of network pharmacology, and the mechanism of P. ternata in the treatment of hypertension was analyzed by constructing a component-target relationship network, PPI interaction network, targets’ function analysis, and molecular docking. In the study, 12 potentially effective components and 88 targets were screened, and 3 potential protein modules were found and analyzed after constructing a PPI network using targets. In addition, 10 targets were selected as core targets of the PPI network. After that, the targets were analyzed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the molecular docking method is used to study the interaction between the targets and the active components. The above evidence shows that the mechanism of P. ternata in the treatment of hypertension is complicated, as it acts in many ways, mainly by affecting nerve signal transmission, cell proliferation, and apoptosis, calcium channels, and so on. The binding between targets and active components mainly depends on Pi bonds and hydrogen bonds. Using the method of network pharmacology and molecular docking to analyze the mechanism of P. ternata in the treatment of hypertension will help to provide a better scientific basis for the combined use of traditional Chinese medicine and western medicine, and will better help to improve the quality of P. ternata and point out its direction. Full article

(This article belongs to the Special Issue Involvement of Medicinal Plants and Food in the Molecular Mechanisms of Disease Prevention)

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13 pages, 1021 KiB

Open AccessReview

Toll-Like Receptor and Cytokine Responses to Infection with Endogenous and Exogenous Koala Retrovirus, and Vaccination as a Control Strategy

by Mohammad Enamul Hoque Kayesh, Md Abul Hashem and Kyoko Tsukiyama-Kohara

Curr. Issues Mol. Biol. 2021, 43(1), 52-64; https://doi.org/10.3390/cimb43010005 - 30 Apr 2021

Cited by 5 | Viewed by 3375

Abstract

Koala populations are currently declining and under threat from koala retrovirus (KoRV) infection both in the wild and in captivity. KoRV is assumed to cause immunosuppression and neoplastic diseases, favoring chlamydiosis in koalas. Currently, 10 KoRV subtypes have been identified, including an endogenous [...] Read more.

Koala populations are currently declining and under threat from koala retrovirus (KoRV) infection both in the wild and in captivity. KoRV is assumed to cause immunosuppression and neoplastic diseases, favoring chlamydiosis in koalas. Currently, 10 KoRV subtypes have been identified, including an endogenous subtype (KoRV-A) and nine exogenous subtypes (KoRV-B to KoRV-J). The host’s immune response acts as a safeguard against pathogens. Therefore, a proper understanding of the immune response mechanisms against infection is of great importance for the host’s survival, as well as for the development of therapeutic and prophylactic interventions. A vaccine is an important protective as well as being a therapeutic tool against infectious disease, and several studies have shown promise for the development of an effective vaccine against KoRV. Moreover, CRISPR/Cas9-based genome editing has opened a new window for gene therapy, and it appears to be a potential therapeutic tool in many viral infections, which could also be investigated for the treatment of KoRV infection. Here, we discuss the recent advances made in the understanding of the immune response in KoRV infection, as well as the progress towards vaccine development against KoRV infection in koalas. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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Curr. Issues Mol. Biol., Volume 43, Issue 1 (June 2021) – 34 articles

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