Current Issues in Molecular Biology

13 pages, 5994 KiB

Open AccessArticle

Cloning and Molecular Characterization of HSL and Its Expression Pattern in HPG Axis and Testis during Different Stages in Bactrian Camel

by Jinghong Nan, Qi Wang, Qiu Yan, Jie Wang, Yong Zhang and Xingxu Zhao

Curr. Issues Mol. Biol. 2022, 44(8), 3779-3791; https://doi.org/10.3390/cimb44080259 - 21 Aug 2022

Cited by 2 | Viewed by 1896

Abstract

Hormone-sensitive lipase (HSL) is a key enzyme in animal fat metabolism and is involved in the rate-limiting step of catalyzing the decomposition of fat and cholesterol. It also plays an important regulatory role in maintaining seminiferous epithelial structure, androgen synthesis and primordial germ [...] Read more.

Hormone-sensitive lipase (HSL) is a key enzyme in animal fat metabolism and is involved in the rate-limiting step of catalyzing the decomposition of fat and cholesterol. It also plays an important regulatory role in maintaining seminiferous epithelial structure, androgen synthesis and primordial germ cell differentiation. We previously reported that HSL is involved the synthesis of steroids in Bactrian camels, although it is unclear what role it plays in testicular development. The present study was conducted to characterize the biological function and expression pattern of the HSL gene in the hypothalamic pituitary gonadal (HPG) axis and the development of testis in Bactrian camels. We analyzed cloning of the cDNA sequence of the HSL gene of Bactrian camels by RT-PCR, as well as the structural features of HSL proteins, using bioinformatics software, such as ProtParam, TMHMM, Signal P 4.1, SOPMA and MEGA 7.0. We used qRT-PCR, Western blotting and immunofluorescence staining to clarify the expression pattern of HSL in the HPG axis and testis of two-week-old (2W), two-year-old (2Y), four-year-old (4Y) and six-year-old (6Y) Bactrian camels. According to sequence analysis, the coding sequence (CDS) region of the HSL gene is 648 bp in length and encodes 204 amino acids. According to bioinformatics analysis, the nucleotide and amino acid sequence of Bactrian camel HSL are most similar to those of Camelus pacos and Camelusdromedarius, with the lowest sequence similarity with Mus musculus. In adult Bactrian camel HPG axis tissues, both HSL mRNA and protein expression were significantly higher in the testis than in other tissues (hypothalamus, pituitary and pineal tissues) (p < 0.05). The expression of mRNA in the testis increased with age and was the highest in six-year-old testis (p < 0.01). The protein expression levels of HSL in 2Y and 6Y testis were clearly higher than in 2W and 4Y testis tissues (p < 0.01). Immunofluorescence results indicate that the HSL protein was mainly localized in the germ cells, Sertoli cells and Leydig cells from Bactrian camel testis, and strong positive signals were detected in epididymal epithelial cells, basal cells, spermatocytes and smooth muscle cells, with partially expression in hypothalamic glial cells, pituitary suspensory cells and pineal cells. According to the results of gene ontology (GO) analysis enrichment, HSL indirectly regulates the anabolism of steroid hormones through interactions with various targets. Therefore, we conclude that the HSL gene may be associated with the development and reproduction of Bactrian camels in different stages of maturity, and these results will contribute to further understanding of the regulatory mechanisms of HSL in Bactrian camel reproduction. Full article

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

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9 pages, 537 KiB

Open AccessBrief Report

Molecular Profiling of Tumor Tissue in Mexican Patients with Colorectal Cancer

by Beatriz Armida Flores-López, María de la Luz Ayala-Madrigal, José Miguel Moreno-Ortiz, Jorge Peregrina-Sandoval, Miguel Ángel Trujillo-Rojas, José Luis Venegas-Rodríguez, Rosario Hernández-Ramírez, Martha Alejandra Fernández-Galindo and Melva Gutiérrez-Angulo

Curr. Issues Mol. Biol. 2022, 44(8), 3770-3778; https://doi.org/10.3390/cimb44080258 - 20 Aug 2022

Viewed by 2176

Abstract

Colorectal cancer is a heterogeneous disease with multiple genomic changes that influence the clinical management of patients; thus, the search for new molecular targets remains necessary. The aim of this study was to identify genetic variants in tumor tissues from Mexican patients with [...] Read more.

Colorectal cancer is a heterogeneous disease with multiple genomic changes that influence the clinical management of patients; thus, the search for new molecular targets remains necessary. The aim of this study was to identify genetic variants in tumor tissues from Mexican patients with colorectal cancer, using massive parallel sequencing. A total of 4813 genes were analyzed in tumoral DNA from colorectal cancer patients, using the TruSight One Sequencing panel. From these, 192 variants with clinical associations were found distributed in 168 different genes, of which 46 variants had not been previous reported in the literature or databases, although genes harboring those variants had already been described in colorectal cancer. Enrichment analysis of the affected genes was performed using Reactome software; pathway over-representation showed significance for disease, signal transduction, and immune system subsets in all patients, while exclusive subsets such as DNA repair, autophagy, and RNA metabolism were also found. Those characteristics, whether individual or shared, could give tumors specific capabilities for survival, aggressiveness, or response to treatment. Our results can be useful for future investigations targeting specific characteristics of tumors in colorectal cancer patients. The identification of exclusive or common pathways in colorectal cancer patients could be important for better diagnosis and personalized cancer treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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13 pages, 1999 KiB

Open AccessArticle

The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease

by Tanya Tacheva, Shanbeh Zienolddiny-Narui, Dimo Dimov, Denitsa Vlaykova, Iva Miteva and Tatyana Vlaykova

Curr. Issues Mol. Biol. 2022, 44(8), 3757-3769; https://doi.org/10.3390/cimb44080257 - 20 Aug 2022

Cited by 2 | Viewed by 2184

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large [...] Read more.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p ≤ 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases)

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11 pages, 2080 KiB

Open AccessArticle

Genetically Engineered Hepatitis C Virus-like Particles (HCV-LPs) Tagged with SP94 Peptide to Acquire Selectivity to Liver Cancer Cells via Grp78

by Dina Mofed, Mohamed A. Wahba and Tamer Z. Salem

Curr. Issues Mol. Biol. 2022, 44(8), 3746-3756; https://doi.org/10.3390/cimb44080256 - 20 Aug 2022

Cited by 3 | Viewed by 3187

Abstract

Targeted cancer therapy is a challenging area that includes multiple chemical and biological vehicles. Virus-like particles (VLPs) combine safety and efficacy in their roles as potential vaccines and drug delivery vehicles. In this study, we propose a novel drug delivery system based on [...] Read more.

Targeted cancer therapy is a challenging area that includes multiple chemical and biological vehicles. Virus-like particles (VLPs) combine safety and efficacy in their roles as potential vaccines and drug delivery vehicles. In this study, we propose a novel drug delivery system based on HCV-LPs engineered with SP94 and RGD peptides mediated by a specific molecular chaperone (Grp78) associated with cancer drug resistance. The PCR primers were designed for engineering two constructs, SP94-EGFP-CORE-HIS and RGD-EGFP-CORE-HIS, by sequential PCR reactions. The two fragments were cloned into pFastBac Dual under the polyhedrin promoter and then used to produce two recombinant baculoviruses (AcSP94 and AcRGD). The VLP’s expression was optimized by recombinant virus infection with different MOIs, ranging from 1 to 20 MOI. Recombinant VLP2 were purified by Ni-NTA and their sizes and shapes were confirmed with TEM. They were incubated with different types of cells prior to examination using the fluorescence microscope to test the binding specificity. The effect of the overexpression of the Grp78 on the binding affinity of the engineered VLPs was tested in HepG2 and HeLa cells. The protocol optimization revealed that MOI 10 produced the highest fluorescence intensities after 72 h for the two recombinant proteins (SP94-core and RGD-core). Moreover, the binding assay tested on different types of mammalian cells (HeLa, HEK-293T, and HepG2 cells) showed green fluorescence on the periphery of all tested cell lines when using the RGD-core protein; while, the SP94-core protein showed green fluorescence only with the liver cancer cells, HepG2 and HuH7. Overexpression of Grp78 in HepG2 and HeLa cells enhanced the binding efficiency of the engineered VLPs. We confirmed that the SP94 peptide can be specifically used to target liver cancer cells, while the RGD peptide is sufficiently functional for most types of cancer cells. The overexpression of the Grp78 improved the binding capacity of both SP94 and RGD peptides. It is worth noting that the SP94 peptide can function properly as a recombinant peptide, and not only as a chemically conjugated peptide, as heretofore commonly used. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)

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11 pages, 596 KiB

Open AccessArticle

Single Nucleotide Polymorphisms May Increase the Risk of Aspiration Pneumonia in Post-Stroke Patients with Dysphagia

by Hae-Yeon Park, Hyun-Mi Oh, Tae-Woo Kim, Youngkook Kim, Geun-Young Park, Hyemi Hwang and Sun Im

Curr. Issues Mol. Biol. 2022, 44(8), 3735-3745; https://doi.org/10.3390/cimb44080255 - 19 Aug 2022

Cited by 1 | Viewed by 2340

Abstract

This study aimed to evaluate whether genetic polymorphism is associated with an increased risk of infection, specifically post-stroke aspiration pneumonia. Blood samples were obtained from a total of 206 post-stroke participants (males, n = 136; mean age, 63.8 years). Genotyping was performed for [...] Read more.

This study aimed to evaluate whether genetic polymorphism is associated with an increased risk of infection, specifically post-stroke aspiration pneumonia. Blood samples were obtained from a total of 206 post-stroke participants (males, n = 136; mean age, 63.8 years). Genotyping was performed for catechol-O-methyltransferase (rs4680, rs165599), dopamine receptors (DRD1; rs4532, DRD2; rs1800497, DRD3; rs6280), brain-derived neurotrophic factor (rs6265), apolipoprotein E (rs429358, rs7412), and the interleukin-1 receptor antagonist gene (rs4251961). The subjects were stratified into two groups, aged < 65 (young) and ≥ 65 (elderly). Functional parameters and swallowing outcomes were measured at enrollment and at 3 months post-onset. The primary outcome was the incidence of aspiration pneumonia. Analysis of the association between genetic polymorphisms and aspiration pneumonia history showed that a minor C rs429358 allele was associated with the occurrence of aspiration pneumonia in the young group, both in the additive and the dominant models (odds ratio: 4.53; 95% CI: 1.60–12.84, p = 0.004). In the multivariable analysis, the minor C rs429358 allele increased the risk of post-stroke aspiration pneumonia in young stroke patients by 5.35 (95% CI: 1.64–20.88). In contrast, no such association was observed in the elderly group. Apolipoprotein E polymorphism may affect the risk of post-stroke aspiration pneumonia. Full article

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

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24 pages, 2395 KiB

Open AccessArticle

Transcriptomes of Wet Skin Biopsies Predict Outcomes after Ionizing Radiation Exposure with Potential Dosimetric Applications in a Mouse Model

by Abdulnaser Alkhalil, John Clifford, Stacyann M. Miller, Aarti Gautam, Marti Jett, Rasha Hammamieh, Lauren T. Moffatt and Jeffrey W. Shupp

Curr. Issues Mol. Biol. 2022, 44(8), 3711-3734; https://doi.org/10.3390/cimb44080254 - 18 Aug 2022

Viewed by 1850

Abstract

Countermeasures for radiation diagnosis, prognosis, and treatment are trailing behind the proliferation of nuclear energy and weaponry. Radiation injury mechanisms at the systems biology level are not fully understood. Here, mice skin biopsies at h2, d4, d7, d21, and d28 after exposure to [...] Read more.

Countermeasures for radiation diagnosis, prognosis, and treatment are trailing behind the proliferation of nuclear energy and weaponry. Radiation injury mechanisms at the systems biology level are not fully understood. Here, mice skin biopsies at h2, d4, d7, d21, and d28 after exposure to 1, 3, 6, or 20 Gy whole-body ionizing radiation were evaluated for the potential application of transcriptional alterations in radiation diagnosis and prognosis. Exposure to 20 Gy was lethal by d7, while mice who received 1, 3, or 6 Gy survived the 28-day time course. A Sammon plot separated samples based on survival and time points (TPs) within lethal (20 Gy) and sublethal doses. The differences in the numbers, regulation mode, and fold change of significantly differentially transcribed genes (SDTGs, p < 0.05 and FC > 2) were identified between lethal and sublethal doses, and down and upregulation dominated transcriptomes during the first post-exposure week, respectively. The numbers of SDTGs and the percentages of upregulated ones revealed stationary downregulation post-lethal dose in contrast to responses to sublethal doses which were dynamic and largely upregulated. Longitudinal up/downregulated SDTGs ratios suggested delayed and extended responses with increasing IR doses in the sublethal range and lethal-like responses in late TPs. This was supported by the distributions of common and unique genes across TPs within each dose. Several genes with potential dosimetric marker applications were identified. Immune, fibrosis, detoxification, hematological, neurological, gastric, cell survival, migration, and proliferation radiation response pathways were identified, with the majority predicted to be activated after sublethal and inactivated after lethal exposures, particularly during the first post-exposure week. Full article

(This article belongs to the Special Issue Molecular Biology in Targeted Radionuclide Therapy Radiopharmaceutical Design)

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16 pages, 847 KiB

Open AccessReview

Molecular Aspects of MicroRNAs and Phytohormonal Signaling in Response to Drought Stress: A Review

by Hafiz Muhammad Ahmad, Xiukang Wang, Munazza Ijaz, Mahmood-Ur-Rahman, Sadaf Oranab, Muhammad Amjad Ali and Sajid Fiaz

Curr. Issues Mol. Biol. 2022, 44(8), 3695-3710; https://doi.org/10.3390/cimb44080253 - 16 Aug 2022

Cited by 19 | Viewed by 3341

Abstract

Phytohormones play an essential role in plant growth and development in response to environmental stresses. However, plant hormones require a complex signaling network combined with other signaling pathways to perform their proper functions. Thus, multiple phytohormonal signaling pathways are a prerequisite for understanding [...] Read more.

Phytohormones play an essential role in plant growth and development in response to environmental stresses. However, plant hormones require a complex signaling network combined with other signaling pathways to perform their proper functions. Thus, multiple phytohormonal signaling pathways are a prerequisite for understanding plant defense mechanism against stressful conditions. MicroRNAs (miRNAs) are master regulators of eukaryotic gene expression and are also influenced by a wide range of plant development events by suppressing their target genes. In recent decades, the mechanisms of phytohormone biosynthesis, signaling, pathways of miRNA biosynthesis and regulation were profoundly characterized. Recent findings have shown that miRNAs and plant hormones are integrated with the regulation of environmental stress. miRNAs target several components of phytohormone pathways, and plant hormones also regulate the expression of miRNAs or their target genes inversely. In this article, recent developments related to molecular linkages between miRNAs and phytohormones were reviewed, focusing on drought stress. Full article

(This article belongs to the Special Issue Advanced Research in Plant Metabolomics)

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14 pages, 2760 KiB

Open AccessArticle

Multifunctionality of Clausena harmandiana Extract and Its Active Constituents against Alzheimer’s Disease

by Chantana Boonyarat, Chavi Yenjai, Orawan Monthakantirat, Rawiwun Kaewamatawong, Pattaporn Poonsawas, Jinda Wangboonskul, Suchada Chaiwiwatrakul and Pornthip Waiwut

Curr. Issues Mol. Biol. 2022, 44(8), 3681-3694; https://doi.org/10.3390/cimb44080252 - 15 Aug 2022

Cited by 5 | Viewed by 2364

Abstract

This study was designed to investigate the effects of the root-bark extract of Clausena harmandiana (CH) and its active constituents (nordentatin and 7-methoxyheptaphylline) on pharmacological activities regarding selected targets associated with AD, namely, its antioxidant activity, inhibition of Aβ aggregation, acetylcholinesterase (AChE) activity, [...] Read more.

This study was designed to investigate the effects of the root-bark extract of Clausena harmandiana (CH) and its active constituents (nordentatin and 7-methoxyheptaphylline) on pharmacological activities regarding selected targets associated with AD, namely, its antioxidant activity, inhibition of Aβ aggregation, acetylcholinesterase (AChE) activity, and neuroprotective effects. The effect of the CH extract on the cognitive impairment induced by scopolamine was also evaluated in mice. The effects of the CH extract and its active constituents on radical scavenging, Aβ aggregation, and AChE activity were investigated with a 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assay, a thioflavin-T assay, and Ellman’s method. The neuroprotective effects of the extract against hydrogen-peroxide and Aβ toxicity were evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In addition, the effects on cognitive impairment induced by scopolamine in mice were evaluated using Morris-water-maze and modified-Y-maze test models. The results of the present study demonstrate that the root-bark extract of CH shows multimodal actions relevant to the AD pathological cascade, including antioxidant effects, the inhibition of Aβ aggregation, the inhibition of AChE function, and neuroprotection against oxidative stress and Aβ toxicity. The extracts could improve both the short- and long-term memory deficits induced by scopolamine in mice. Full article

(This article belongs to the Topic Molecular Events Underlying the Furtherance of Neurodegenerative Disorders by Environmental Factors)

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15 pages, 1710 KiB

Open AccessArticle

Basic Analysis of the Cerebrospinal Fluid: An Important Framework for Laboratory Diagnostics of the Impairment of the Central Nervous System

by Petr Kelbich, Karel Hrach, Jan Spicka, Petr Vachata, Tomas Radovnicky, Eva Hanuljakova and Jan Krejsek

Curr. Issues Mol. Biol. 2022, 44(8), 3666-3680; https://doi.org/10.3390/cimb44080251 - 14 Aug 2022

Viewed by 3148

Abstract

Laboratory analysis of basic cerebrospinal fluid (CSF) parameters is considered as essential for any CSF evaluation. It can provide rapidly very valuable information about the status of the central nervous system (CNS). Our retrospective study evaluated parameters of basic CSF analysis in cases [...] Read more.

Laboratory analysis of basic cerebrospinal fluid (CSF) parameters is considered as essential for any CSF evaluation. It can provide rapidly very valuable information about the status of the central nervous system (CNS). Our retrospective study evaluated parameters of basic CSF analysis in cases of either infectious or non-infectious CNS involvement. Neutrophils are effector cells of innate immunity. Predominance of neutrophils was found in 98.2% of patients with purulent inflammation in CNS. Lymphocytes are cellular substrate of adaptive immunity. We found their predominance in 94.8% of patients with multiple sclerosis (MS), 66.7% of patients with tick-borne encephalitis (TBE), 92.2% of patients with neuroborreliosis, 83.3% of patients with inflammatory response with oxidative burst of macrophages in CNS and 75.0% of patients with malignant infiltration of meninges (MIM). The simultaneous assessment of aerobic and anaerobic metabolism in CSF using the coefficient of energy balance (KEB) allows us to specify the type of inflammation in CNS. We found predominantly aerobic metabolism (KEB > 28.0) in 100.0% CSF of patients with normal CSF findings and in 92.8% CSF of patients with MS. Predominant faintly anaerobic metabolism (28.0 > KEB > 20.0) in CSF was found in 71.8% patients with TBE and in 64.7% patients with neuroborreliosis. Strong anaerobic metabolism (KEB < 10.0) was found in the CSF of 99.1% patients with purulent inflammation, 100.0% patients with inflammatory response with oxidative burst of macrophages and in 80.6% patients with MIM. Joint evaluation of basic CSF parameters provides sufficient information about the immune response in the CSF compartment for rapid and reliable diagnosis of CNS involvement. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Demyelinating Disorders of the Central Nervous System)

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18 pages, 4271 KiB

Open AccessArticle

Presence of Human Papillomavirus DNA in Malignant Neoplasia and Non-Malignant Breast Disease

by Erika Maldonado-Rodríguez, Marisa Hernández-Barrales, Adrián Reyes-López, Susana Godina-González, Perla I. Gallegos-Flores, Edgar L. Esparza-Ibarra, Irma E. González-Curiel, Jesús Aguayo-Rojas, Adrián López-Saucedo, Gretel Mendoza-Almanza and Jorge L. Ayala-Luján

Curr. Issues Mol. Biol. 2022, 44(8), 3648-3665; https://doi.org/10.3390/cimb44080250 - 13 Aug 2022

Cited by 9 | Viewed by 3852

Abstract

Breast cancer is the leading cause of cancer death among women worldwide. Multiple extrinsic and intrinsic factors are associated with this disease’s development. Various research groups worldwide have reported the presence of human papillomavirus (HPV) DNA in samples of malignant breast tumors. Although [...] Read more.

Breast cancer is the leading cause of cancer death among women worldwide. Multiple extrinsic and intrinsic factors are associated with this disease’s development. Various research groups worldwide have reported the presence of human papillomavirus (HPV) DNA in samples of malignant breast tumors. Although its role in mammary carcinogenesis is not fully understood, it is known that the HPV genome, once inserted into host cells, has oncogenic capabilities. The present study aimed to detect the presence of HPV DNA in 116 breast tissue biopsies and classify them according to their histology. It was found that 50.9% of the breast biopsies analyzed were malignant neoplasms, of which 74.6% were histologically classified as infiltrating ductal carcinoma. In biopsies with non-malignant breast disease, fibroadenoma was the most common benign neoplasm (39.1%). Detection of HPV DNA was performed through nested PCR using the external primer MY09/11 and the internal primer GP5+/6+. A hybridization assay genotyped HPV. HPV DNA was identified in 20.3% (12/59) of malignant neoplasms and 35% non-malignant breast disease (16/46). It was also detected in 27.3% (3/11) of breast tissue biopsies without alteration. However, there are no statistically significant differences between these groups and the existence of HPV DNA (p = 0.2521). Its presence was more frequent in non-malignant alterations than in malignant neoplasias. The most frequent genotypes in the HPV-positive samples were low-risk (LR) HPV-42 followed by high-risk (HR) HPV-31. Full article

(This article belongs to the Special Issue Molecules at Play in Cancer)

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16 pages, 3549 KiB

Open AccessArticle

The Transgene Expression of the Immature Form of the HCV Core Protein (C191) and the LncRNA MEG3 Increases Apoptosis in HepG2 Cells

by Dina Mofed, Salwa Sabet, Ahmed A. Baiomy and Tamer Z. Salem

Curr. Issues Mol. Biol. 2022, 44(8), 3632-3647; https://doi.org/10.3390/cimb44080249 - 12 Aug 2022

Cited by 3 | Viewed by 2585

Abstract

Long non-coding RNAs (lncRNAs) are regulated in cancer cells, including lncRNA MEG3, which is downregulated in Hepatocellular Carcinoma (HCC). In addition, hepatitis C virus (HCV) core proteins are known to dysregulate important cellular pathways that are linked to HCC development. In this study, [...] Read more.

Long non-coding RNAs (lncRNAs) are regulated in cancer cells, including lncRNA MEG3, which is downregulated in Hepatocellular Carcinoma (HCC). In addition, hepatitis C virus (HCV) core proteins are known to dysregulate important cellular pathways that are linked to HCC development. In this study, we were interested in evaluating the overexpression of lncRNA MEG3, either alone or in combination with two forms of HCV core protein (C173 and C191) in HepG2 cells. Cell viability was assessed by MTT assay. Transcripts’ levels of key genes known to be regulated in HCC, such as p53, DNMT1, miRNA152, TGF-b, and BCL-2, were measured by qRT-PCR. Protein expression levels of caspase-3 and MKI67 were determined by immunocytochemistry and apoptosis assays. The co-expression of lncRNA MEG3 and C191 resulted in a marked increase and accumulation of dead cells and a reduction in cell viability. In addition, a marked increase in the expression of tumor suppressor genes (p53 and miRNA152), as well as a marked decrease in the expression of oncogenes (DNMT1, BCL2, and TGF-b), were detected. Moreover, apoptosis assay results revealed a significant increase in total apoptosis (early and late). Finally, immunocytochemistry results detected a significant increase in apoptotic marker caspase-3 and a decrease in tumor marker MKI67. In this study, transgene expression of C191 and lncRNA MEG3 showed induction in apoptosis in HepG2 cells greater than the expression of each one alone. These results suggest potential anticancer characteristics. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases)

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11 pages, 5044 KiB

Open AccessArticle

Development of an Improved Method for the Isolation and Culture of Newborn Sheep Primary Hepatocytes

by Bowen Chen, Xiaoning Dou, Dan Zhang, Tiaoguo Liu, Bohui Yang and Zengkui Lu

Curr. Issues Mol. Biol. 2022, 44(8), 3621-3631; https://doi.org/10.3390/cimb44080248 - 12 Aug 2022

Cited by 2 | Viewed by 2717

Abstract

The liver plays a crucial role in metabolism, synthesis, biotransformation, secretion, and excretion. Hepatocytes are the main cells of the liver and can be used as a cell model to study liver function. The classic method of collagenase perfusion to isolate hepatocytes is [...] Read more.

The liver plays a crucial role in metabolism, synthesis, biotransformation, secretion, and excretion. Hepatocytes are the main cells of the liver and can be used as a cell model to study liver function. The classic method of collagenase perfusion to isolate hepatocytes is a two-step technique that is time-consuming, labor-intensive, and has high technical requirements. Therefore, in this study, we compared different methods for isolating and culturing primary hepatocytes. We found that the 0.25% trypsin and 0.1 mg/mL type IV collagenase mixture at a 1:1 ratio showed the most efficient cell digestion, and William’s Medium E complete medium showed the best growth and proliferation. The isolated cells showed the typical irregular polygonal morphology of hepatocytes. Periodic acid–Schiff staining and immunofluorescence confirmed that the isolated cells were positive for glycogen and hepatocyte-specific markers cytokeratin 18, AFP, and albumin. On subculturing, stable cell lines were obtained. Therefore, we optimized the isolation and in vitro culture method to obtain highly pure (>95%) sheep primary hepatocytes from newborn sheep liver tissue. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity: New Insights and Therapeutic Challenges)

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10 pages, 2285 KiB

Open AccessArticle

Autophagy Is Possibly Involved in Osteoblast Responses to Mechanical Loadings

by Yanghui Xing, Liang Song and Yingying Zhang

Curr. Issues Mol. Biol. 2022, 44(8), 3611-3620; https://doi.org/10.3390/cimb44080247 - 11 Aug 2022

Cited by 4 | Viewed by 1870

Abstract

Both mechanical loading and autophagy play important roles in regulating bone growth and remodeling, but the relationship between the two remains unclear. In this study, we examined bone structure with micro-CT imaging and measured bone mechanical properties with three-point bending experiments using bones [...] Read more.

Both mechanical loading and autophagy play important roles in regulating bone growth and remodeling, but the relationship between the two remains unclear. In this study, we examined bone structure with micro-CT imaging and measured bone mechanical properties with three-point bending experiments using bones from wild-type (WT) mice and conditional knockout (cKO) mice with Atg7 deletion in their osteoblasts. We found that the knockout mice had significantly less bone volume, bone thickness, bone ultimate breaking force, and bone stiffness compared to wild-type mice. Additionally, bone marrow cells from knockout mice had reduced differentiation and mineralization capacities in terms of alkaline phosphatase and calcium secretion, as well as Runx2 and osteopontin expression. Knockout mice also had significantly less relative bone formation rate due to mechanical loading. Furthermore, we found that the osteoblasts from wild-type mice had stronger responses to mechanical stimulation compared to autophagy-deficient osteoblasts from knockout mice. When inhibiting autophagy with 3 MA in wild-type osteoblasts, we found similar results as we did in autophagy-deficient osteoblasts. We also found that mechanical loading-induced ATP release is able to regulate ERK1/2, Runx2, alkaline phosphatase, and osteopontin activities. These results suggest that the ATP pathway may play an important role in the possible involvement of autophagy in osteoblast mechanobiology. Full article

(This article belongs to the Special Issue Recent Advances in Musculoskeletal Regenerative Medicine)

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13 pages, 1940 KiB

Open AccessArticle

Corema album Leaves Mediate DNA Damage in Triple-Negative Breast Cancer Cells

by Ana Sofia Cerquido, Martin Vojtek, Rita Ribeiro-Oliveira, Salomé Gonçalves-Monteiro, Maria João Barroca, Aida Moreira da Silva, Olga Viegas, Victor Freitas, Joana Beatriz Sousa, Isabel M. P. L. V. O. Ferreira and Carmen Diniz

Curr. Issues Mol. Biol. 2022, 44(8), 3598-3610; https://doi.org/10.3390/cimb44080246 - 11 Aug 2022

Cited by 4 | Viewed by 2332

Abstract

Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode [...] Read more.

Corema (C.) album is a shrub endemic to the Atlantic coast and has been described as yielding beneficial effects for human health. Nevertheless, studies concerning the bioactivity of C. album leaves are scarce. This study aims at investigating the anticancer potential and mode of action, of an hydroethanolic extract of C. album leaves (ECAL) on triple-negative breast cancer. This is a poor survival breast cancer subtype, owing to its high risk of distant reappearance, metastasis rates and the probability of relapse. The ECAL ability to prevent tumor progression through (i) the inhibition of cell proliferation (cell viability); (ii) the induction of apoptosis (morphological changes, TUNEL assay, caspase-3 cleaved) and (iii) the induction of DNA damage (PARP1 and γH2AX) with (iv) the involvement of NF-κB and of ERK1/2 pathways (AlphaScreen assay) was evaluated. ECAL activated the apoptotic pathway (through caspase-3) along with the inhibition of ERK and NF-κB pathways causing DNA damage and cell death. The large polyphenolic content of ECAL was presumed to be accountable for these effects. The extract of C. album leaves can target multiple pathways and, thus, can block more than one possible means of disease progression, evidencing the anticancer therapeutic potential from a plant source. Full article

(This article belongs to the Special Issue Dietary Bioactive Compounds and Breast Cancer)

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25 pages, 2787 KiB

Open AccessReview

Clinical and Molecular Implications of Osteopontin in Heart Failure

by Argen Mamazhakypov, Meerim Sartmyrzaeva, Akpay Sh. Sarybaev, Ralph Schermuly and Akylbek Sydykov

Curr. Issues Mol. Biol. 2022, 44(8), 3573-3597; https://doi.org/10.3390/cimb44080245 - 11 Aug 2022

Cited by 12 | Viewed by 4183

Abstract

The matricellular protein osteopontin modulates cell–matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. [...] Read more.

The matricellular protein osteopontin modulates cell–matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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21 pages, 3776 KiB

Open AccessArticle

Exploring the Novel Computational Drug Target and Associated Key Pathways of Oral Cancer

by Fatema Akhter, Fawzia Haif Al Kahtani, Zainah Mohammed Sambawa, Deema Abdulrahman Alhassan, Reema Abdulaziz AlSaif, Tahsinul Haque, Mohammad Khursheed Alam, Md. Tanvir Hasan, Md. Rakibul Islam, Kawsar Ahmed and Rehana Basri

Curr. Issues Mol. Biol. 2022, 44(8), 3552-3572; https://doi.org/10.3390/cimb44080244 - 9 Aug 2022

Cited by 1 | Viewed by 2901

Abstract

Oral cancer (OC) is a serious health concern that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft [...] Read more.

Oral cancer (OC) is a serious health concern that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. The publicly available repository the Gene Expression Omnibus (GEO) was to the source for the collection of OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected for analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to calculate the upregulated and downregulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein–protein interaction (PPI) networks were built to identify the most active genes, and a clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study OC-associated DEGs in-depth. Finally, top gene performers from PPI networks were used to apply drug signature analysis. After applying filtration and cut-off criteria, 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the cell cycle and influenza A. The PPI network holds 88 nodes and 492 edges, and CDC6 had the highest number of connections. Four clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of OC pathophysiology and the development of new therapies for OC. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)

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19 pages, 3733 KiB

Open AccessArticle

1-L Transcription in Alzheimer’s Disease

by Jozef Nahalka

Curr. Issues Mol. Biol. 2022, 44(8), 3533-3551; https://doi.org/10.3390/cimb44080243 - 9 Aug 2022

Cited by 5 | Viewed by 3271

Abstract

Alzheimer’s disease is a very complex disease and better explanations and models are needed to understand how neurons are affected and microglia are activated. A new model of Alzheimer’s disease is presented here, the β-amyloid peptide is considered an important RNA recognition/binding peptide. [...] Read more.

Alzheimer’s disease is a very complex disease and better explanations and models are needed to understand how neurons are affected and microglia are activated. A new model of Alzheimer’s disease is presented here, the β-amyloid peptide is considered an important RNA recognition/binding peptide. 1-L transcription revealed compatible sequences with AAUAAA (PAS signal) and UUUC (class III ARE rich in U) in the Aβ peptide, supporting the peptide–RNA regulatory model. When a hypothetical model of fibril selection with the prionic character of amyloid assemblies is added to the peptide-RNA regulatory model, the downregulation of the PI3K-Akt pathway and the upregulation of the PLC-IP3 pathway are well explained. The model explains why neurons are less protected from inflammation and why microglia are activated; why mitochondria are destabilized; why the autophagic flux is destabilized; and why the post-transcriptional attenuation of the axonal signal “noise” is interrupted. For example, the model suggests that Aβ peptide may post-transcriptionally control ELAVL2 (ELAV-like RNA binding protein 2) and DCP2 (decapping mRNA protein 2), which are known to regulate RNA processing, transport, and stability. Full article

(This article belongs to the Special Issue Aging, Age-Related Changes in the Brain and the Progression of Alzheimer’s Disease)

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15 pages, 2597 KiB

Open AccessArticle

Nitric Oxide Synthesis Metabolites—As Potential Markers in Chronic Kidney Disease in Children

by Joanna Piechowicz, Andrzej Gamian, Ositadima Chukwu and Dorota Polak-Jonkisz

Curr. Issues Mol. Biol. 2022, 44(8), 3518-3532; https://doi.org/10.3390/cimb44080242 - 7 Aug 2022

Cited by 3 | Viewed by 2250

Abstract

Nitric oxide (NO) is an important signaling molecule for many physiological and pathological processes. Diseases associated with abnormal NO synthesis include cardiovascular diseases, insulin-dependent diabetes, or chronic kidney disease (CKD). The aim of the paper was to evaluate NO synthesis metabolites, i.e., asymmetric [...] Read more.

Nitric oxide (NO) is an important signaling molecule for many physiological and pathological processes. Diseases associated with abnormal NO synthesis include cardiovascular diseases, insulin-dependent diabetes, or chronic kidney disease (CKD). The aim of the paper was to evaluate NO synthesis metabolites, i.e., asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), dimethylamine (DMA), arginine, citrulline in plasma of patients with different severity of CKD and to seek possible links between these parameters and the development of this disease. Forty-eight CKD children and thirty-three age-matched controls were examined. Patients were divided into groups depending on the CKD stages (Group II-stage II, Group III-stage III, Group IV-stage IV, and Group RRT children on dialysis). To determine the concentrations of the above-mentioned metabolites in plasma liquid chromatography-mass spectrometry was used. There were significant differences observed in levels of ADMA, SDMA, DMA, and citrulline between control vis CKD groups (p values ranging from <0.001 to 0.029). Plasma arginine concentration was also higher in CKD patients compared to the control group but statistically insignificant. ADMA levels in CKD children were statistically significantly higher in relation to particular stages of CKD (RRT vis II stage of CKD: p = 0.01; RRT vis III-IV stages of CKD: p < 0.046). Citrulline levels in CKD children were statistically significantly higher in RRT group vis control (p < 0.001). Children with CKD develop disturbances in most metabolites of NO synthesis. Dialysis children treated show the greatest disturbances of plasma ADMA and citrulline levels. ADMA seems to be a good indicator of the gradual progression of the CKD, which is proved by the negative correlation with eGFR. Full article

(This article belongs to the Special Issue Bioactive Compounds of Natural Products on Metabolic Disorders and Complications)

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22 pages, 5253 KiB

Open AccessArticle

Classifying Integrated Signature Molecules in Macrophages of Rheumatoid Arthritis, Osteoarthritis, and Periodontal Disease: An Omics-Based Study

by Prachi Sao, Yamini Chand, Lamya Ahmed Al-Keridis, Mohd Saeed, Nawaf Alshammari and Sachidanand Singh

Curr. Issues Mol. Biol. 2022, 44(8), 3496-3517; https://doi.org/10.3390/cimb44080241 - 6 Aug 2022

Cited by 1 | Viewed by 2518

Abstract

Rheumatoid arthritis (RA), osteoarthritis (OA), and periodontal disease (PD) are chronic inflammatory diseases that are globally prevalent, and pose a public health concern. The search for a potential mechanism linking PD to RA and OA continues, as it could play a significant role [...] Read more.

Rheumatoid arthritis (RA), osteoarthritis (OA), and periodontal disease (PD) are chronic inflammatory diseases that are globally prevalent, and pose a public health concern. The search for a potential mechanism linking PD to RA and OA continues, as it could play a significant role in disease prevention and treatment. Recent studies have linked RA, OA, and PD to Porphyromonas gingivalis (PG), a periodontal bacterium, through a similar dysregulation in an inflammatory mechanism. This study aimed to identify potential gene signatures that could assist in early diagnosis as well as gain insight into the molecular mechanisms of these diseases. The expression data sets with the series IDs GSE97779, GSE123492, and GSE24897 for macrophages of RA, OA synovium, and PG stimulated macrophages (PG-SM), respectively, were retrieved and screened for differentially expressed genes (DEGs). The 72 common DEGs among RA, OA, and PG-SM were further subjected to gene–gene correlation analysis. A GeneMANIA interaction network of the 47 highly correlated DEGs comprises 53 nodes and 271 edges. Network centrality analysis identified 15 hub genes, 6 of which are DEGs (API5, ATE1, CCNG1, EHD1, RIN2, and STK39). Additionally, two significantly up-regulated non-hub genes (IER3 and RGS16) showed interactions with hub genes. Functional enrichment analysis of the genes showed that “apoptotic regulation” and “inflammasomes” were among the major pathways. These eight genes can serve as important signatures/targets, and provide new insights into the molecular mechanism of PG-induced RA, OA, and PD. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 953 KiB

Open AccessReview

The Nutraceuticals as Modern Key to Achieve Erythrocyte Oxidative Stress Fighting in Osteoarthritis

by Alessia Mariano, Irene Bigioni, Francesco Misiti, Luigi Fattorini, Anna Scotto d’Abusco and Angelo Rodio

Curr. Issues Mol. Biol. 2022, 44(8), 3481-3495; https://doi.org/10.3390/cimb44080240 - 5 Aug 2022

Cited by 19 | Viewed by 3112

Abstract

Osteoarthritis (OA), the most common joint disease, shows an increasing prevalence in the aging population in industrialized countries. OA is characterized by low-grade chronic inflammation, which causes degeneration of all joint tissues, such as articular cartilage, subchondral bone, and synovial membrane, leading to [...] Read more.

Osteoarthritis (OA), the most common joint disease, shows an increasing prevalence in the aging population in industrialized countries. OA is characterized by low-grade chronic inflammation, which causes degeneration of all joint tissues, such as articular cartilage, subchondral bone, and synovial membrane, leading to pain and loss of functionality. Erythrocytes, the most abundant blood cells, have as their primary function oxygen transport, which induces reactive oxygen species (ROS) production. For this reason, the erythrocytes have several mechanisms to counteract ROS injuries, which cause damage to lipids and proteins of the cell membrane. Oxidative stress and inflammation are highly correlated and are both causes of joint disorders. In the synovial fluid and blood of osteoarthritis patients, erythrocyte antioxidant enzyme expression is decreased. To date, OA is a non-curable disease, treated mainly with non-steroidal anti-inflammatory drugs and corticosteroids for a prolonged period of time, which cause several side effects; thus, the search for natural remedies with anti-inflammatory and antioxidant activities is always ongoing. In this review, we analyze several manuscripts describing the effect of traditional remedies, such as Harpagophytum procumbens, Curcumin longa, and Boswellia serrata extracts, in the treatments of OA for their anti-inflammatory, analgesic, and antioxidant activity. The effects of such remedies have been studied both in in vitro and in vivo models, considering both joint cells and erythrocytes. Full article

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

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16 pages, 2214 KiB

Open AccessArticle

Liraglutide Exerts Protective Effects by Downregulation of PPARγ, ACSL1 and SREBP-1c in Huh7 Cell Culture Models of Non-Alcoholic Steatosis and Drug-Induced Steatosis

by Tea Omanovic Kolaric, Tomislav Kizivat, Vjera Mihaljevic, Milorad Zjalic, Ines Bilic-Curcic, Lucija Kuna, Robert Smolic, Aleksandar Vcev, George Y. Wu and Martina Smolic

Curr. Issues Mol. Biol. 2022, 44(8), 3465-3480; https://doi.org/10.3390/cimb44080239 - 2 Aug 2022

Cited by 7 | Viewed by 2944

Abstract

(1) Background: With the aging of the population and polypharmacy encountered in the elderly, drug-induced steatosis (DIS) has become frequent cause of non-alcoholic steatosis (NAS). Indeed, NAS and DIS may co-exist, making the ability to distinguish between the entities ever more important. The [...] Read more.

(1) Background: With the aging of the population and polypharmacy encountered in the elderly, drug-induced steatosis (DIS) has become frequent cause of non-alcoholic steatosis (NAS). Indeed, NAS and DIS may co-exist, making the ability to distinguish between the entities ever more important. The aim of our study was to study cell culture models of NAS and DIS and determine the effects of liraglutide (LIRA) in those models. (2) Methods: Huh7 cells were treated with oleic acid (OA), or amiodarone (AMD) to establish models of NAS and DIS, respectively. Cells were treated with LIRA and cell viability was assessed by MTT, lipid accumulation by Oil-Red-O staining and triglyceride assay, and intracellular signals involved in hepatosteatosis were quantitated by RT-PCR. (3) Results: After exposure to various OA and AMD concentrations, those that achieved 80% of cells viabilities were used in further experiments to establish NAS and DIS models using 0.5 mM OA and 20 µM AMD, respectively. In both models, LIRA increased cell viability (p < 0.01). Lipid accumulation was increased in both models, with microsteatotic pattern in DIS, and macrosteatotic pattern in NAS which corresponds to greater triglyceride accumulation in latter. LIRA ameliorated these changes (p < 0.001), and downregulated expression of lipogenic ACSL1, PPARγ, and SREBP-1c pathways in the liver (p < 0.01) (4) Conclusions: LIRA ameliorates hepatocyte steatosis in Huh7 cell culture models of NAS and DIS. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases)

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10 pages, 1088 KiB

Open AccessArticle

RUNX1 and RUNX3 Genes Expression Level in Adult Acute Lymphoblastic Leukemia—A Case Control Study

by Dagmara Szmajda-Krygier, Adrian Krygier, Krzysztof Jamroziak, Anna Korycka-Wołowiec, Marta Żebrowska-Nawrocka and Ewa Balcerczak

Curr. Issues Mol. Biol. 2022, 44(8), 3455-3464; https://doi.org/10.3390/cimb44080238 - 1 Aug 2022

Cited by 1 | Viewed by 2319

Abstract

The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study [...] Read more.

The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study was the assessment of relative RUNX1 and RUNX3 genes expression level among adult ALL cases and a geographically and ethnically matched control group. The relative RUNX1 and RUNX3 genes expression level was assessed by qPCR. The investigated group comprised 60 adult patients newly diagnosed with ALL. The obtained results were compared with a group of 40 healthy individuals, as well as clinical and hematological parameters of patients, and submitted for statistical analysis. ALL patients tend to have significantly higher RUNX1 gene expression level compared with controls. This observation is also true for risk group stratification where high-risk (HR) patients presented higher levels of RUNX1. A higher RUNX1 transcript level correlates with greater leukocytosis while RUNX3 expression is reduced in Philadelphia chromosome bearers. The conducted study sustains the hypothesis that both a reduction and increase in the transcript level of RUNX family genes may be involved in leukemia pathogenesis, although their interaction is complex. In this context, overexpression of the RUNX1 gene in adult ALL cases in particular seems interesting. Obtained results should be interpreted with caution. Further analysis in this research field is needed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Leukemia)

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11 pages, 1059 KiB

Open AccessArticle

Heterogeneous Immunolocalisation of Zinc Transporters ZIP6, ZIP10 and ZIP14 in Human Normo- and Asthenozoospermic Spermatozoa

by Isidora Protic, Igor Golic, Snezana Vidakovic, Bato Korac and Aleksandra Korac

Curr. Issues Mol. Biol. 2022, 44(8), 3444-3454; https://doi.org/10.3390/cimb44080237 - 31 Jul 2022

Cited by 1 | Viewed by 2146

Abstract

Zinc (in the form of Zn²⁺) is necessary for male fertility. Both Zn²⁺ quantity and its localisation have been detected in seminal plasma and ejaculated spermatozoa, suggesting its active uptake via zinc import transporters (ZIPs). Immunofluorescence was used to characterise [...] Read more.

Zinc (in the form of Zn²⁺) is necessary for male fertility. Both Zn²⁺ quantity and its localisation have been detected in seminal plasma and ejaculated spermatozoa, suggesting its active uptake via zinc import transporters (ZIPs). Immunofluorescence was used to characterise the expression and localisation of three distinct types of ZIP transporters in ejaculated spermatozoa of normo- and asthenozoospermic sperm samples. ZIP6, ZIP10 and ZIP14 showed heterogeneous sperm cell expression and different compartmental distribution. In both types of sperm samples, ZIP6 and ZIP14 were predominantly localised in the sperm head, while ZIP10 was found along the sperm tail. Compartmental localisation of ZIPs in asthenozoospermia was not changed. However, regarding sub-compartmental localisation in sperm head regions, for ZIP6 asthenozoospermia only decreased its acorn/crescent-like pattern. In contrast, ZIP14 immunostaining was altered in favour of crescent-like, as opposed to acorn-like and acorn/crescent-like patterns. The specific ZIPs localisation may reflect their different roles in sperm cell integrity and motility and may change over time. This is the first report of their specific compartmental and sub-compartmental localisation in ejaculated human sperm cells. Further research will lead to a greater understanding of the roles of ZIPs in sperm cell biology, which could positively influence procedures for human infertility therapy. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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16 pages, 2486 KiB

Open AccessArticle

Resistance of Human Liver Mesenchymal Stem Cells to FAS-Induced Cell Death

by Irina V. Kholodenko, Alisa M. Gisina, Garik V. Manukyan, Alexander G. Majouga, Elena V. Svirshchevskaya, Roman V. Kholodenko and Konstantin N. Yarygin

Curr. Issues Mol. Biol. 2022, 44(8), 3428-3443; https://doi.org/10.3390/cimb44080236 - 30 Jul 2022

Cited by 5 | Viewed by 2639

Abstract

Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, [...] Read more.

Mesenchymal stem cells (MSCs) have a pronounced therapeutic potential in various pathological conditions. Though therapeutic effects of MSC transplantation have been studied for a long time, the underlying mechanisms are still not clear. It has been shown that transplanted MSCs are rapidly eliminated, presumably by apoptosis. As the mechanisms of MSC apoptosis are not fully understood, in the present work we analyzed MSC sensitivity to Fas-induced apoptosis using MSCs isolated from the biopsies of liver fibrosis patients (L-MSCs). The level of cell death was analyzed by flow cytometry in the propidium iodide test. The luminescent ATP assay was used to measure cellular ATP levels; and the mitochondrial membrane potential was assessed using the potential-dependent dye JC-1. We found that human L-MSCs were resistant to Fas-induced cell death over a wide range of FasL and anti-Fas mAb concentrations. At the same time, intrinsic death signal inducers CoCl₂ and staurosporine caused apoptosis of L-MSCs in a dose-dependent manner. Despite the absence of Fas-induced cell death treatment of L-MSCs with low concentrations of FasL or anti-Fas mAb resulted in a cellular ATP level decrease, while high concentrations of the inducers caused a decline of the mitochondrial membrane potential. Pre-incubation of L-MSCs with the pro-inflammatory cytokine TNF-α did not promote L-MSC cell death. Our data indicate that human L-MSCs have increased resistance to receptor-mediated cell death even under inflammatory conditions. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells (MSC), Exosomes, and Other MSC Products in Research and Clinics)

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15 pages, 3638 KiB

Open AccessArticle

Effects of Dietary Inclusion of β-Hydroxy-β-Methylbutyrate on Growth Performance, Fat Deposition, Bile Acid Metabolism, and Gut Microbiota Function in High-Fat and High-Cholesterol Diet-Challenged Layer Chickens

by Qichao Liao, Tian Wu, Qinghua Fu, Peng Wang, Yameng Zhao, Yan Li, Haihan Xiao, Lei Zhou and Ziyi Song

Curr. Issues Mol. Biol. 2022, 44(8), 3413-3427; https://doi.org/10.3390/cimb44080235 - 30 Jul 2022

Cited by 9 | Viewed by 2601

Abstract

Excessive lipid deposition in layer chickens due to inappropriate feeding adversely affects egg production; however, nutritional manipulation methods to deal with this issue are still limited. β-hydroxy-β-methylbutyrate (HMB), a metabolite of L-leucine, was recently reported as a lipid-lowering nutrient in mice and pigs, [...] Read more.

Excessive lipid deposition in layer chickens due to inappropriate feeding adversely affects egg production; however, nutritional manipulation methods to deal with this issue are still limited. β-hydroxy-β-methylbutyrate (HMB), a metabolite of L-leucine, was recently reported as a lipid-lowering nutrient in mice and pigs, although its role in layers had not been investigated. Here, we employed high-fat and high-cholesterol diet (HFHCD)−challenged growing layers as an obese model to explore HMB function in the regulation of lipid metabolism and the potential mechanisms involved. We found that dietary supplementation with (0.05% or 0.10%) HMB significantly reduced HFHCD−induced bodyweight growth in layers, mainly due to reduction in abdominal fat deposition. Mechanistically, HMB supplementation enhanced hepatic bile acid synthesis from cholesterol through elevating expression of Cyp7a1, a gene coding a key enzyme in bile acid synthesis. Furthermore, 16S rRNA gene sequencing revealed that HMB supplementation remodeled the diversity and composition of the layers’ cecal microbiota, and the abundance of Bacteroidetes at the phylum level were especially affected. Correlation analysis further indicated a strong negative association between Bacteroidetes abundance and lipid metabolism−related parameters. Taken together, these data suggest that dietary HMB supplementation could improve abdominal fat deposition in layers, probably through modulating hepatic bile acid synthesis and gut microbiota function. Full article

(This article belongs to the Special Issue Bioactive Compounds of Natural Products on Metabolic Disorders and Complications)

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15 pages, 1914 KiB

Open AccessArticle

Development of Novel Therapeutics for Schizophrenia Treatment Based on a Selective Positive Allosteric Modulation of α1-Containing GABAARs—In Silico Approach

by Vladimir Đorđević, Milan Petković, Jelena Živković, Goran M. Nikolić and Aleksandar M. Veselinović

Curr. Issues Mol. Biol. 2022, 44(8), 3398-3412; https://doi.org/10.3390/cimb44080234 - 29 Jul 2022

Cited by 1 | Viewed by 2072

Abstract

For the development of atypical antipsychotics, the selective positive allosteric modulation of the ionotropic GABAA receptor (GABAAR) has emerged as a promising approach. In the presented research, two unrelated methods were used for the development of QSAR models for selective positive allosteric modulation [...] Read more.

For the development of atypical antipsychotics, the selective positive allosteric modulation of the ionotropic GABAA receptor (GABAAR) has emerged as a promising approach. In the presented research, two unrelated methods were used for the development of QSAR models for selective positive allosteric modulation of 1-containing GABAARs with derivatives of imidazo [1,2-a]-pyridine. The development of conformation-independent QSAR models, based on descriptors derived from local molecular graph invariants and SMILES notation, was achieved with the Monte Carlo optimization method. From the vast pool of 0D, 1D, and 2D molecule descriptors, the GA-MLR method developed additional QSAR models. Various statistical methods were utilised for the determination of the developed models’ robustness, predictability, and overall quality, and according to the obtained results, all QSAR models are considered good. The molecular fragments that have a positive or negative impact on the studied activity were obtained from the studied molecules’ SMILES notations, and according to the obtained results, nine novel compounds were designed. The binding affinities to GABAAR of designed compounds were assessed with the application of molecular docking studies and the obtained results showed a high correlation with results obtained from QSAR modeling. To assess all designed molecules’ “drug-likeness”, their physicochemical descriptors were computed and utilised for the prediction of medicinal chemistry friendliness, pharmacokinetic properties, ADME parameters, and druglike nature. Full article

(This article belongs to the Special Issue Bioactive Compounds on Mental Disorders)

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20 pages, 1964 KiB

Open AccessReview

Topical Reappraisal of Molecular Pharmacological Approaches to Endothelial Dysfunction in Diabetes Mellitus Angiopathy

by Constantin Munteanu, Mariana Rotariu, Marius-Alexandru Turnea, Aurelian Anghelescu, Irina Albadi, Gabriela Dogaru, Sînziana Calina Silișteanu, Elena Valentina Ionescu, Florentina Carmen Firan, Anca Mirela Ionescu, Carmen Oprea and Gelu Onose

Curr. Issues Mol. Biol. 2022, 44(8), 3378-3397; https://doi.org/10.3390/cimb44080233 - 28 Jul 2022

Cited by 20 | Viewed by 2977

Abstract

Diabetes mellitus (DM) is a frequent medical problem, affecting more than 4% of the population in most countries. In the context of diabetes, the vascular endothelium can play a crucial pathophysiological role. If a healthy endothelium—which is a dynamic endocrine organ with autocrine [...] Read more.

Diabetes mellitus (DM) is a frequent medical problem, affecting more than 4% of the population in most countries. In the context of diabetes, the vascular endothelium can play a crucial pathophysiological role. If a healthy endothelium—which is a dynamic endocrine organ with autocrine and paracrine activity—regulates vascular tone and permeability and assures a proper balance between coagulation and fibrinolysis, and vasodilation and vasoconstriction, then, in contrast, a dysfunctional endothelium has received increasing attention as a potential contributor to the pathogenesis of vascular disease in diabetes. Hyperglycemia is indicated to be the major causative factor in the development of endothelial dysfunction. Furthermore, many shreds of evidence suggest that the progression of insulin resistance in type 2 diabetes is parallel to the advancement of endothelial dysfunction in atherosclerosis. To present the state-of-the-art data regarding endothelial dysfunction in diabetic micro- and macroangiopathy, we constructed this literature review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We interrogated five medical databases: Elsevier, PubMed, PMC, PEDro, and ISI Web of Science. Full article

(This article belongs to the Topic Blood Physiology: Molecular Mechanisms of Vascular Wall Functioning)

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14 pages, 2525 KiB

Open AccessArticle

Pro-Angiogenetic Effects of Purified Extracts from Helix aspersa during Zebrafish Development

by Daniela Zizioli, Andrea Mastinu, Alessia Muscò, Sara Anna Bonini, Dario Finazzi, Rosaria Avisani, Giovanni Battista Kron Morelli, Sergio Pecorelli and Maurizio Memo

Curr. Issues Mol. Biol. 2022, 44(8), 3364-3377; https://doi.org/10.3390/cimb44080232 - 27 Jul 2022

Cited by 4 | Viewed by 2414

Abstract

Helix aspersa is a species of land snail belonging to the Helicidae family, widespread in the Mediterranean and continental area up to Northern Europe. In some areas it is appreciated as a food, but is mostly considered a parasite of gardens and cultivated [...] Read more.

Helix aspersa is a species of land snail belonging to the Helicidae family, widespread in the Mediterranean and continental area up to Northern Europe. In some areas it is appreciated as a food, but is mostly considered a parasite of gardens and cultivated fields. The mucus of Helix aspersa has found multiple applications in the cosmetic and health fields. In the present study, we investigated for the first time the angiogenetic properties of purified extracts from Helix aspersa using a transgenic zebrafish line Tg (kdrl:EGFP). The angiogenesis induced by purified snail extracts was demonstrated by their capability to increase the three well-established parameters of angiogenesis: generation of intersegmental vessels, modeling of caudal venous plexus, and formation of sub-intestinal venous plexus. The effects appeared to be mediated by the vascular endothelial growth factor (VEGF) pathway, being prevented by pretreatment of embryos with the selective VEGF receptor antagonist SU5416, and supported by the increased VEGF mRNA levels found in snail-extract-treated embryos. Insufficient vascular supply is underlined by low VEGF signaling, primarily because of its indispensable role in preventing capillary loss. Our findings might have a pharmacological impact by counteracting VEGF hypofunction and promoting angiogenesis to maintain adequate microvascular and vascular density in normal and suffering tissues and organs. Full article

(This article belongs to the Special Issue Food-Derived Bioactive Compounds in Health and Disease)

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13 pages, 15933 KiB

Open AccessArticle

Genome-Wide Identification of DUF26 Domain-Containing Genes in Dongxiang Wild Rice and Analysis of Their Expression Responses under Submergence

by Cheng Huang, Dianwen Wang, Hongping Chen, Wei Deng, Dazhou Chen, Ping Chen and Jilin Wang

Curr. Issues Mol. Biol. 2022, 44(8), 3351-3363; https://doi.org/10.3390/cimb44080231 - 27 Jul 2022

Cited by 4 | Viewed by 2223

Abstract

The DUF26 domain-containing protein is an extracellular structural protein, which plays an important role in signal transduction. Dongxiang wild rice (Oryza rufipogon Griff.) is the northern-most common wild rice in China. Using domain analysis, 85 DUF26 domain-containing genes were identified in Dongxiang [...] Read more.

The DUF26 domain-containing protein is an extracellular structural protein, which plays an important role in signal transduction. Dongxiang wild rice (Oryza rufipogon Griff.) is the northern-most common wild rice in China. Using domain analysis, 85 DUF26 domain-containing genes were identified in Dongxiang wild rice (DXWR) and further divided into four categories. The DUF26 domain-containing genes were unevenly distributed on chromosomes, and there were 18 pairs of tandem repeats. Gene sequence analysis showed that there were significant differences in the gene structure and motif distribution of the DUF26 domain in different categories. Motifs 3, 8, 9, 13, 14, 16, and 18 were highly conserved in all categories. It was also found that there were eight plasmodesmata localization proteins (PDLPs) with a unique motif 19. Collinearity analysis showed that DXWR had a large number of orthologous genes with wheat, maize, sorghum and zizania, of which 17 DUF26 domain-containing genes were conserved in five gramineous crops. Under the stress of anaerobic germination and seedling submergence treatment, 33 DUF26 domain-containing genes were differentially expressed in varying degrees. Further correlation analysis with the expression of known submergence tolerance genes showed that these DUF26 domain-containing genes may jointly regulate the submergence tolerance process with these known submergence tolerance genes in DXWR. Full article

(This article belongs to the Special Issue Genetic Sight: Plant Traits during Postharvest)

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16 pages, 1575 KiB

Open AccessSystematic Review

A Systematic Review on the Effect of Nutraceuticals on Antidepressant-Induced Sexual Dysfunctions: From Basic Principles to Clinical Applications

by Carmen Concerto, Alessandro Rodolico, Valeria Meo, Donatella Chiappetta, Marina Bonelli, Ludovico Mineo, Giulia Saitta, Sebastiano Stuto, Maria Salvina Signorelli, Antonino Petralia, Giuseppe Lanza and Eugenio Aguglia

Curr. Issues Mol. Biol. 2022, 44(8), 3335-3350; https://doi.org/10.3390/cimb44080230 - 25 Jul 2022

Cited by 1 | Viewed by 5419

Abstract

Sexual dysfunctions are common side effects reported by patients during antidepressant treatment. When they occur, patients often discontinue psychopharmacological therapy, with a negative impact on the underlying psychiatric disease. Recently, great attention has been paid to the use of nutraceuticals in the management [...] Read more.

Sexual dysfunctions are common side effects reported by patients during antidepressant treatment. When they occur, patients often discontinue psychopharmacological therapy, with a negative impact on the underlying psychiatric disease. Recently, great attention has been paid to the use of nutraceuticals in the management of psychiatric disorders, although a systematic review on their effects as a treatment option for antidepressant-induced sexual dysfunctions (AISD) is lacking. Here, we conducted a systematic search in the following databases: MEDLINE (through PubMed), EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. We searched eligible studies among parallel or crossover randomized controlled trials (RCTs) in adult populations. After this process, a total of 10 articles that evaluated the effect of six different nutraceuticals versus placebo were included: Maca Root, S-adenosyl-L-methionine (SAMe), Rosa Damascena, Ginkgo Biloba, Saffron, and Yohimbine. Overall, a high dose of Maca Root and the use of SAMe or Saffron may improve AISD. Additionally, the administration of Rosa Damascena seemed to be more effective in men than in women, whereas no evidence of effects emerged for Gingko Biloba and Yohimbine. Given the mixed results still available, future RCTs should consider larger samples and confounding factors, such as depressive status and individual vulnerability. Full article

(This article belongs to the Special Issue Bioactive Compounds on Mental Disorders)

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Curr. Issues Mol. Biol., Volume 44, Issue 8 (August 2022) – 35 articles

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