Current Issues in Molecular Biology

25 pages, 1861 KiB

Open AccessReview

An Overview of Systemic Targeted Therapy in Renal Cell Carcinoma, with a Focus on Metastatic Renal Cell Carcinoma and Brain Metastases

by Liliana Eleonora Semenescu, Amira Kamel, Vasile Ciubotaru, Silvia Mara Baez-Rodriguez, Mircea Furtos, Alexandra Costachi, Anica Dricu and Ligia Gabriela Tătăranu

Curr. Issues Mol. Biol. 2023, 45(9), 7680-7704; https://doi.org/10.3390/cimb45090485 - 21 Sep 2023

Cited by 1 | Viewed by 1275

Abstract

The most commonly diagnosed malignancy of the urinary system is represented by renal cell carcinoma. Various subvariants of RCC were described, with a clear-cell type prevailing in about 85% of all RCC tumors. Patients with metastases from renal cell carcinoma did not have [...] Read more.

The most commonly diagnosed malignancy of the urinary system is represented by renal cell carcinoma. Various subvariants of RCC were described, with a clear-cell type prevailing in about 85% of all RCC tumors. Patients with metastases from renal cell carcinoma did not have many effective therapies until the end of the 1980s, as long as hormonal therapy and chemotherapy were the only options available. The outcomes were unsatisfactory due to the poor effectiveness of the available therapeutic options, but then interferon-alpha and interleukin-2 showed treatment effectiveness, providing benefits but only for less than half of the patients. However, it was not until 2004 that targeted therapies emerged, prolonging the survival rate. Currently, new technologies and strategies are being developed to improve the actual efficacy of available treatments and their prognostic aspects. This article summarizes the mechanisms of action, importance, benefits, adverse events of special interest, and efficacy of immunotherapy in metastatic renal cell carcinoma, with a focus on brain metastases. Full article

(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)

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12 pages, 2313 KiB

Open AccessArticle

Unraveling the Potential of Isorhamnetin as an Adjuvant in Depression Treatment with Escitalopram

by Omar Gammoh, Esam Y. Qnais, Rabaa Y. Athamneh, Bilal Al-Jaidi, Deniz Al-Tawalbeh, Sara Altaber, Abdelrahim Alqudah, Alaa A. A. Aljabali and Murtaza M. Tambuwala

Curr. Issues Mol. Biol. 2023, 45(9), 7668-7679; https://doi.org/10.3390/cimb45090484 - 21 Sep 2023

Viewed by 1414

Abstract

Oxidative stress and inflammation are implicated in depression. While selective serotonin reuptake inhibitors (SSRIs) like escitalopram are commonly prescribed as first-line treatments, their inconsistent efficacy and delayed onset of action necessitates the exploration of adjunctive therapies. Isorhamnetin, a flavonol, has shown antioxidant and [...] Read more.

Oxidative stress and inflammation are implicated in depression. While selective serotonin reuptake inhibitors (SSRIs) like escitalopram are commonly prescribed as first-line treatments, their inconsistent efficacy and delayed onset of action necessitates the exploration of adjunctive therapies. Isorhamnetin, a flavonol, has shown antioxidant and anti-inflammatory properties that makes exploring its antidepressant effect attractive. This study aims to investigate the adjuvant potential of isorhamnetin in combination with escitalopram to enhance its antidepressant efficacy in a lipopolysaccharide (LPS)-induced depression model using Swiss albino mice. Behavioral paradigms, such as the forced swim test and open field test, were employed to assess depressive symptoms, locomotion, and sedation. Additionally, enzyme-linked immunosorbent assays were utilized to measure Nrf2, BDNF, HO-1, NO, and IL-6 levels in the prefrontal cortex and hippocampus. The results demonstrate that isorhamnetin significantly improves the antidepressant response of escitalopram, as evidenced by reduced floating time in the forced swim test. Moreover, isorhamnetin enhanced antidepressant effects of escitalopram and effectively restored depleted levels of Nrf2, BDNF, and HO-1 in the cortex caused by LPS-induced depression. Isorhamnetin shows promise in enhancing the efficacy of conventional antidepressant therapy through antioxidant and anti-inflammatory effects. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity, 2nd Volume)

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15 pages, 3268 KiB

Open AccessArticle

6-Hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline Alleviates Oxidative Stress and NF-κB-Mediated Inflammation in Rats with Experimental Parkinson’s Disease

by Evgenii D. Kryl’skii, Grigorii A. Razuvaev, Tatyana N. Popova, Svetlana M. Medvedeva and Khidmet S. Shikhaliev

Curr. Issues Mol. Biol. 2023, 45(9), 7653-7667; https://doi.org/10.3390/cimb45090483 - 21 Sep 2023

Cited by 1 | Viewed by 926

Abstract

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of [...] Read more.

A study was conducted to investigate the effects of different doses of 6-hydroxy-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline (HTHQ) on motor coordination scores, brain tissue morphology, the expression of tyrosine hydroxylase, the severity of oxidative stress parameters, the levels of the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) factor, and the inflammatory response in rats during the development of rotenone-induced Parkinsonism. The findings indicate that HTHQ, with its antioxidant attributes, reduced the levels of 8-isoprostane, lipid oxidation products, and protein oxidation products. The decrease in oxidative stress due to HTHQ led to a reduction in the mRNA content of proinflammatory cytokines and myeloperoxidase activity, accompanying the drop in the expression of the factor NF-κB. These alterations promoted an improvement in motor coordination scores and increased tyrosine hydroxylase levels, whereas histopathological changes in the brain tissue of the experimental animals were attenuated. HTHQ exhibited greater effectiveness than the comparative drug rasagiline based on the majority of variables. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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3 pages, 198 KiB

Open AccessEditorial

New Sight: Enzymes as Targets for Drug Development

by Sung-Kun Kim

Curr. Issues Mol. Biol. 2023, 45(9), 7650-7652; https://doi.org/10.3390/cimb45090482 - 20 Sep 2023

Viewed by 896

Abstract

In the dynamic realm of medical research, a resounding chord is struck by recent studies that have propelled drug discovery to new horizons across a spectrum of disciplines [...] Full article

(This article belongs to the Special Issue New Sight: Enzymes as Targets for Drug Development)

8 pages, 1561 KiB

Open AccessCase Report

Safety and Efficacy of Neoadjuvant Chemoimmunotherapy in Gastric Cancer Patients with a PD-L1 Positive Status: A Case Report

by Alexandra V. Avgustinovich, Olga V. Bakina, Sergey G. Afanas’ev, Liudmila V. Spirina and Alexander M. Volkov

Curr. Issues Mol. Biol. 2023, 45(9), 7642-7649; https://doi.org/10.3390/cimb45090481 - 19 Sep 2023

Cited by 1 | Viewed by 897

Abstract

Introduction: The landscape of gastric cancer treatment has changed owing to the widespread use of immune checkpoint inhibitors. Autophagy, involved in regulating the immune system, is a potential trigger of immunity in tumors. This study aims to find molecular-based evidence for the effectiveness [...] Read more.

Introduction: The landscape of gastric cancer treatment has changed owing to the widespread use of immune checkpoint inhibitors. Autophagy, involved in regulating the immune system, is a potential trigger of immunity in tumors. This study aims to find molecular-based evidence for the effectiveness of FLOT chemotherapy with immune checkpoint inhibitors in gastric cancer patients. Materials and Methods: Three patients with advanced gastric cancer received FLOT neoadjuvant chemotherapy with immunotherapy and surgery. IHC was used to determine the PD-L1 status. Real-time PCR was used to analyze expression patterns of transcriptional growth factors, AKT/mTOR signaling components, PD-1, PD-L1, PD-L2 and LC3B. The LC3B content was measured via Western blotting analysis. Results: The combination of FLOT neoadjuvant chemotherapy and immunotherapy was found to be efficient in patients with a PD-L1-positive status. Gastric tumors with a PD-L1-positive status exhibited autophagy activation and decreased PD-1 expression. Conclusions: FLOT chemotherapy combined with immune checkpoint inhibitors showed high efficacy in gastric cancer patients with a positive PD-L1 status. Autophagy was involved in activating the tumor immunity. Further research is needed to clarify the mechanism of effective anticancer treatment. Full article

(This article belongs to the Special Issue Molecular-Based Approaches in Therapy for Gastrointestinal Cancers, 2nd Edition)

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12 pages, 1855 KiB

Open AccessArticle

p62 Is a Potential Biomarker for Risk of Malignant Transformation of Oral Potentially Malignant Disorders (OPMDs)

by Ryo Takasaki, Fumihiko Uchida, Shohei Takaoka, Ryota Ishii, Satoshi Fukuzawa, Eiji Warabi, Naomi Ishibashi-Kanno, Kenji Yamagata, Hiroki Bukawa and Toru Yanagawa

Curr. Issues Mol. Biol. 2023, 45(9), 7630-7641; https://doi.org/10.3390/cimb45090480 - 19 Sep 2023

Viewed by 868

Abstract

To determine the intracellular behavior of p62, a marker of selective autophagy, in oral potentially malignant disorders (OPMDs). This retrospective study includes 70 patients who underwent biopsy or surgical resection and were definitively diagnosed with OPMDs. Immunohistochemical staining for p62, XPO1, p53, and [...] Read more.

To determine the intracellular behavior of p62, a marker of selective autophagy, in oral potentially malignant disorders (OPMDs). This retrospective study includes 70 patients who underwent biopsy or surgical resection and were definitively diagnosed with OPMDs. Immunohistochemical staining for p62, XPO1, p53, and ki67 was performed on all samples and positive cell occupancy was calculated. We statistically investigated the correlation between protein expression in OPMDs and the association between malignant transformation, clinicopathological characteristics, and occupancy. ki67 expression was negatively correlated with p62 expression in the nucleus (p < 0.01) and positively correlated with p62 expression in the cytoplasm (p < 0.01). For malignant transformation, the expression of p62 in the nucleus (p = 0.03) was significantly lower in malignant transformation cases, whereas the expression of p62 in the cytoplasm (p = 0.03) and the aggregation expression (p < 0.01) were significantly higher. Our results suggest that the function of p62 is altered by its subcellular localization. In addition, defects in selective autophagy occur in cases of malignant transformation, suggesting that p62 is a potential biomarker of the risk of malignant transformation of OPMDs. Full article

(This article belongs to the Special Issue Oral Cancer: Prophylaxis, Etiopathogenesis and Treatment)

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13 pages, 1701 KiB

Open AccessArticle

Effect of the Aqueous Extract of Chrysobalanus icaco Leaves on Maternal Reproductive Outcomes and Fetal Development in Wistar Rats

by Natalie Emanuelle Ribeiro Rodrigues, Alisson Rodrigo da Silva Oliveira, Sandrine Maria de Arruda Lima, Daniel Medeiros Nunes, Priscilla Barbosa Sales de Albuquerque, Maria das Graças Carneiro da Cunha, Almir Gonçalves Wanderley, Flavio Manoel Rodrigues da Silva Júnior, José Bruno Nunes Ferreira Silva, Álvaro Aguiar Coelho Teixeira and Teresinha Gonçalves da Silva

Curr. Issues Mol. Biol. 2023, 45(9), 7617-7629; https://doi.org/10.3390/cimb45090479 - 19 Sep 2023

Cited by 1 | Viewed by 974

Abstract

Toxicological studies on medicinal plants are essential to ensure their safety and effectiveness in treating various diseases. Despite the species Chrysobalanus icaco L. being popularly used in the treatment of several diseases due to the pharmacological properties of its bioactive compounds, there are [...] Read more.

Toxicological studies on medicinal plants are essential to ensure their safety and effectiveness in treating various diseases. Despite the species Chrysobalanus icaco L. being popularly used in the treatment of several diseases due to the pharmacological properties of its bioactive compounds, there are few studies in the literature regarding its toxicity regarding reproduction. Therefore, the purpose of this study was to assess the potential embryotoxic and teratogenic effects of the aqueous extract of C. icaco leaves (AECi) on Wistar rats. Animals were given AECi at doses of 100, 200, and 400 mg/kg during the pre-implantation and organogenesis periods. Data were analyzed using ANOVA followed by Tukey’s test and Kruskal–Wallis. Pregnant rats treated during the pre-implantation period showed no signs of reproductive toxicity. Rats that received AECi at 100, 200, and 400 mg/kg during organogenesis did not exhibit any signs of maternal systemic toxicity or significant differences in gestational and embryotoxic parameters. Some skeletal changes were observed in the treated groups. Therefore, it can be suggested that AECi at doses of 100, 200, and 400 mg/kg is safe for treated animals and does not induce reproductive toxicity under the experimental conditions applied, but it also caused low systemic toxicity. Full article

(This article belongs to the Topic Safety and Toxicological Risks of Medicinal Plants and Natural Products: Mechanistic Insights)

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35 pages, 959 KiB

Open AccessReview

Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis

by Antonio Torres-Montaner

Curr. Issues Mol. Biol. 2023, 45(9), 7582-7616; https://doi.org/10.3390/cimb45090478 - 19 Sep 2023

Viewed by 1102

Abstract

Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage [...] Read more.

Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage is an obligatory step preceding its stabilization. During tissue turnover, the telomeres of cells undergoing differentiation can be damaged as a consequence of defective DNA repair caused by endogenous or exogenous agents. This may result in the emergence of new mechanism of telomere maintenance which is the final outcome of DNA damage and the initial signal that triggers malignant transformation. Instead, transformation of stem cells is directly induced by primary derangement of telomere maintenance mechanisms. The newly modified telomere complex may promote survival of cancer stem cells, independently of telomere maintenance. An inherent resistance of stem cells to transformation may be linked to specific, robust mechanisms that help maintain telomere integrity. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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10 pages, 287 KiB

Open AccessArticle

Colorectal Cancer Archaeome: A Metagenomic Exploration, Tunisia

by Nour El Houda Mathlouthi, Hamadou Oumarou Hama, Imen Belguith, Slim Charfi, Tahya Boudawara, Jean-Christophe Lagier, Leila Ammar Keskes, Ghiles Grine and Radhouane Gdoura

Curr. Issues Mol. Biol. 2023, 45(9), 7572-7581; https://doi.org/10.3390/cimb45090477 - 19 Sep 2023

Cited by 2 | Viewed by 1658

Abstract

Colorectal cancer (CRC) is a serious public health problem known to have a multifactorial etiology. The association between gut microbiota and CRC has been widely studied; however, the link between archaea and CRC has not been sufficiently studied. To investigate the involvement of [...] Read more.

Colorectal cancer (CRC) is a serious public health problem known to have a multifactorial etiology. The association between gut microbiota and CRC has been widely studied; however, the link between archaea and CRC has not been sufficiently studied. To investigate the involvement of archaea in colorectal carcinogenesis, we performed a metagenomic analysis of 68 formalin-embedded paraffin fixed tissues from tumoral (n = 33) and healthy mucosa (n = 35) collected from 35 CRC Tunisian patients. We used two DNA extraction methods: Generead DNA FFPE kit (Qiagen, Germantown, MD, USA) and Chelex. We then sequenced the samples using Illumina Miseq. Interestingly, DNA extraction exclusively using Chelex generated enough DNA for sequencing of all samples. After data filtering and processing, we reported the presence of archaeal sequences, which represented 0.33% of all the reads generated. In terms of abundance, we highlighted a depletion in methanogens and an enrichment in Halobacteria in the tumor tissues, while the correlation analysis revealed a significant association between the Halobacteria and the tumor mucosa (p < 0.05). We reported a strong correlation between Natrialba magadii, Sulfolobus acidocaldarius, and tumor tissues, and a weak correlation between Methanococcus voltae and healthy adjacent mucosa. Here, we demonstrated the feasibility of archaeome analysis from formol fixed paraffin-embedded (FFPE) tissues using simple protocols ranging from sampling to data analysis, and reported a significant association between Halobacteria and tumor tissues in Tunisian patients with CRC. The importance of our study is that it represents the first metagenomic analysis of Tunisian CRC patients’ gut microbiome, which consists of sequencing DNA extracted from paired tumor-adjacent FFPE tissues collected from CRC patients. The detection of archaeal sequences in our samples confirms the feasibility of carrying out an archaeome analysis from FFPE tissues using a simple DNA extraction protocol. Our analysis revealed the enrichment of Halobacteria, especially Natrialba magadii, in tumor mucosa compared to the normal mucosa in CRC Tunisian patients. Other species were also associated with CRC, including Sulfolobus acidocaldarius and Methanococcus voltae, which is a methanogenic archaea; both species were found to be correlated with adjacent healthy tissues. Full article

(This article belongs to the Special Issue Molecular-Based Approaches in Therapy for Gastrointestinal Cancers)

15 pages, 1757 KiB

Open AccessReview

Pathophysiological Implications of Interstitial Cajal-like Cells (ICC-like) in Uterus: A Comparative Study with Gastrointestinal ICCs

by Laura López-Pingarrón, Henrique Almeida, Desirée Pereboom-Maicas and Joaquín J. García

Curr. Issues Mol. Biol. 2023, 45(9), 7557-7571; https://doi.org/10.3390/cimb45090476 - 15 Sep 2023

Viewed by 1425

Abstract

The main function of interstitial cells of Cajal (ICCs) is to regulate gastrointestinal peristalsis by acting as a “pacemaker” cell by generating spontaneous slow electrical waves. In 2005, electron microscopy revealed a cell type similar to ICCs (ICC-like) outside the gastrointestinal tract, with [...] Read more.

The main function of interstitial cells of Cajal (ICCs) is to regulate gastrointestinal peristalsis by acting as a “pacemaker” cell by generating spontaneous slow electrical waves. In 2005, electron microscopy revealed a cell type similar to ICCs (ICC-like) outside the gastrointestinal tract, with contractile activity and c-Kit⁺ immunohistochemistry shared with ICCs. Among the locations where ICC-like cells have been observed, it is in the uterus where they have a significant functional and pathophysiological role. These cells are involved in obstetric phenomena of contractile action, such as ascending sperm transport, embryo implantation, pregnancy, delivery, and the expulsion of menstrual debris. Within the pathophysiology related to these cells, we find obstetric alterations such as recurrent miscarriages, premature deliveries, abolition of uterine contractions, and failures of embryo implantation, in addition to other common conditions in the fertile age, such as endometriosis and leiomyoma. Full article

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

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19 pages, 4555 KiB

Open AccessArticle

Ouabain Induces Transcript Changes and Activation of RhoA/ROCK Signaling in Cultured Epithelial Cells (MDCK)

by Jacqueline Martínez-Rendón, Lorena Hinojosa, Beatriz Xoconostle-Cázares, José Abrahán Ramírez-Pool, Aída Castillo, Marcelino Cereijido and Arturo Ponce

Curr. Issues Mol. Biol. 2023, 45(9), 7538-7556; https://doi.org/10.3390/cimb45090475 - 14 Sep 2023

Cited by 2 | Viewed by 1220

Abstract

Ouabain, an organic compound with the ability to strengthen the contraction of the heart muscle, was originally derived from plants. It has been observed that certain mammalian species, including humans, naturally produce ouabain, leading to its classification as a new type of hormone. [...] Read more.

Ouabain, an organic compound with the ability to strengthen the contraction of the heart muscle, was originally derived from plants. It has been observed that certain mammalian species, including humans, naturally produce ouabain, leading to its classification as a new type of hormone. When ouabain binds to Na⁺/K⁺-ATPase, it elicits various physiological effects, although these effects are not well characterized. Previous studies have demonstrated that ouabain, within the concentration range found naturally in the body (10 nmol/L), affects the polarity of epithelial cells and their intercellular contacts, such as tight junctions, adherens junctions, and gap junctional communication. This is achieved by activating signaling pathways involving cSrc and Erk1/2. To further investigate the effects of ouabain within the hormonally relevant concentration range (10 nmol/L), mRNA-seq, a high-throughput sequencing technique, was employed to identify differentially expressed transcripts. The discovery that the transcript encoding MYO9A was among the genes affected prompted an exploration of whether RhoA and its downstream effector ROCK were involved in the signaling pathways through which ouabain influences cell-to-cell contacts in epithelial cells. Supporting this hypothesis, this study reveals the following: (1) Ouabain increases the activation of RhoA. (2) Treatment with inhibitors of RhoA activation (Y27) and ROCK (C3) eliminates the enhancing effect of ouabain on the tight junction seal and intercellular communication via gap junctions. These findings further support the notion that ouabain acts as a hormone to emphasize the epithelial phenotype. Full article

(This article belongs to the Collection Application of Natural and Pseudo Natural Products in Drug Discovery and Development)

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25 pages, 769 KiB

Open AccessReview

The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review

by Lyudmila V. Bel’skaya, Ivan A. Gundyrev and Denis V. Solomatin

Curr. Issues Mol. Biol. 2023, 45(9), 7513-7537; https://doi.org/10.3390/cimb45090474 - 13 Sep 2023

Cited by 2 | Viewed by 2321

Abstract

This review summarizes the role of amino acids in the diagnosis, risk assessment, imaging, and treatment of breast cancer. It was shown that the content of individual amino acids changes in breast cancer by an average of 10–15% compared with healthy controls. For [...] Read more.

This review summarizes the role of amino acids in the diagnosis, risk assessment, imaging, and treatment of breast cancer. It was shown that the content of individual amino acids changes in breast cancer by an average of 10–15% compared with healthy controls. For some amino acids (Thr, Arg, Met, and Ser), an increase in concentration is more often observed in breast cancer, and for others, a decrease is observed (Asp, Pro, Trp, and His). The accuracy of diagnostics using individual amino acids is low and increases when a number of amino acids are combined with each other or with other metabolites. Gln/Glu, Asp, Arg, Leu/Ile, Lys, and Orn have the greatest significance in assessing the risk of breast cancer. The variability in the amino acid composition of biological fluids was shown to depend on the breast cancer phenotype, as well as the age, race, and menopausal status of patients. In general, the analysis of changes in the amino acid metabolism in breast cancer is a promising strategy not only for diagnosis, but also for developing new therapeutic agents, monitoring the treatment process, correcting complications after treatment, and evaluating survival rates. Full article

(This article belongs to the Special Issue Advanced Molecular Solutions for Cancer Therapy)

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21 pages, 5788 KiB

Open AccessArticle

Anti-Diabetic Potential of Sargassum horneri and Ulva australis Extracts In Vitro and In Vivo

by Young-Hyeon Lee, Hye-Ran Kim, Min-Ho Yeo, Sung-Chun Kim, Ho-Bong Hyun, Young-Min Ham, Yong-Hwan Jung, Hye-Sook Kim and Kyung-Soo Chang

Curr. Issues Mol. Biol. 2023, 45(9), 7492-7512; https://doi.org/10.3390/cimb45090473 - 13 Sep 2023

Cited by 1 | Viewed by 1223

Abstract

Sargassum horneri (SH) and Ulva australis (UA) are marine waste resources that cause environmental and economic problems when entering or multiplying the coastal waters of Jeju Island. We analyzed their anti-diabetic efficacy to assess their reusability as functional additives. The alpha-glucosidase inhibitory activity [...] Read more.

Sargassum horneri (SH) and Ulva australis (UA) are marine waste resources that cause environmental and economic problems when entering or multiplying the coastal waters of Jeju Island. We analyzed their anti-diabetic efficacy to assess their reusability as functional additives. The alpha-glucosidase inhibitory activity of SH and UA extracts was confirmed, and the effect of UA extract was higher than that of SH. After the induction of insulin-resistant HepG2 cells, the effects of the two marine extracts on oxidative stress, intracellular glucose uptake, and glycogen content were compared to the positive control, metformin. Treatment of insulin-resistant HepG2 cells with SH and UA resulted in a concentration-dependent decrease in oxidative stress and increased intracellular glucose uptake and glycogen content. Moreover, SH and UA treatment upregulated the expression of IRS-1, AKT, and GLUT4, which are suppressed in insulin resistance, to a similar degree to metformin, and suppressed the expression of FoxO1, PEPCK involved in gluconeogenesis, and GSK-3β involved in glycogen metabolism. The oral administration of these extracts to rats with streptozotocin-induced diabetes led to a higher weight gain than that in the diabetic group. Insulin resistance and oral glucose tolerance are alleviated by the regulation of blood glucose. Thus, the SH and UA extracts may be used in the development of therapeutic agents or supplements to improve insulin resistance. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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16 pages, 2391 KiB

Open AccessArticle

Administration of Tamoxifen Can Regulate Changes in Gene Expression during the Acute Phase of Traumatic Spinal Cord Injury

by Eibar E. Cabrera-Aldana, Yalbi I. Balderas-Martinez, Rafael Velázquez-Cruz, Luis B. Tovar-y-Romo, Rosalba Sevilla-Montoya, Angelina Martínez-Cruz, Claudia Martinez-Cordero, Margarita Valdes-Flores, Monica Santamaria-Olmedo, Alberto Hidalgo-Bravo and Gabriel Guízar-Sahagún

Curr. Issues Mol. Biol. 2023, 45(9), 7476-7491; https://doi.org/10.3390/cimb45090472 - 13 Sep 2023

Viewed by 1002

Abstract

Traumatic spinal cord injury (SCI) causes irreversible damage leading to incapacity. Molecular mechanisms underlying SCI damage are not fully understood, preventing the development of novel therapies. Tamoxifen (TMX) has emerged as a promising therapy. Our aim was to identify transcriptome changes in the [...] Read more.

Traumatic spinal cord injury (SCI) causes irreversible damage leading to incapacity. Molecular mechanisms underlying SCI damage are not fully understood, preventing the development of novel therapies. Tamoxifen (TMX) has emerged as a promising therapy. Our aim was to identify transcriptome changes in the acute phase of SCI and the effect of Tamoxifen on those changes in a rat model of SCI. Four groups were considered: (1) Non-injured without TMX (Sham/TMX-), (2) Non-injured with TMX (Sham/TMX+), (3) injured without TMX (SCI/TMX-), and (4) injured with TMX (SCI/TMX+). Tamoxifen was administered intraperitoneally 30 min after injury, and spinal cord tissues were collected 24 h after injury. Clariom S Assays Array was used for transcriptome analysis. After comparing Sham/TMX- versus SCI/TMX-, 708 genes showed differential expression. The enriched pathways were the SCI pathway and pathways related to the inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression, with no pathways enriched. Our results showed differential expression of genes related to the inflammatory response after SCI, and Tamoxifen seems to regulate gene expression changes in Ccr2 and Mmp12. Our study contributes data regarding the potential value of tamoxifen as a therapeutic resource for traumatic SCI during the acute phase. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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27 pages, 2529 KiB

Open AccessArticle

In Silico Investigation of AKT2 Gene and Protein Abnormalities Reveals Potential Association with Insulin Resistance and Type 2 Diabetes

by M. E. Elangeeb, Imadeldin Elfaki, M. A. Elkhalifa, Khalid M. Adam, A. O. Alameen, Ahmed Kamaleldin Elfadl, Ibrahim Altedlawi Albalawi, Kholoud S. Almasoudi, Reema Almotairi, Basim S. O. Alsaedi, Marwan H. Alhelali, Mohammad Muzaffar Mir, Dnyanesh Amle and Rashid Mir

Curr. Issues Mol. Biol. 2023, 45(9), 7449-7475; https://doi.org/10.3390/cimb45090471 - 12 Sep 2023

Viewed by 1266

Abstract

Type 2 diabetes (T2D) develops from insulin resistance (IR) and the dysfunction of pancreatic beta cells. The AKT2 protein is very important for the protein signaling pathway, and the non-synonymous SNP (nsSNPs) in AKT2 gene may be associated with T2D. nsSNPs can result [...] Read more.

Type 2 diabetes (T2D) develops from insulin resistance (IR) and the dysfunction of pancreatic beta cells. The AKT2 protein is very important for the protein signaling pathway, and the non-synonymous SNP (nsSNPs) in AKT2 gene may be associated with T2D. nsSNPs can result in alterations in protein stability, enzymatic activity, or binding specificity. The objective of this study was to investigate the effect of nsSNPs on the AKT2 protein structure and function that may result in the induction of IR and T2D. The study identified 20 variants that were considered to be the most deleterious based on a range of analytical tools included (SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, and I-Mut). Two mutations, p.A179T and p.L183Q, were selected for further investigation based on their location within the protein as determined by PyMol. The results indicated that mutations, p.A179T and p.L183Q alter the protein stability and functional characteristics, which could potentially affect its function. In order to conduct a more in-depth analysis of these effects, a molecular dynamics simulation was performed for wildtype AKT2 and the two mutants (p.A179T and p.L183Q). The simulation evaluated various parameters, including temperature, pressure, density, RMSD, RMSF, SASA, and Region, over a period of 100 ps. According to the simulation results, the wildtype AKT2 protein demonstrated higher stability in comparison to the mutant variants. The mutations p.A179T and p.L183Q were found to cause a reduction in both protein stability and functionality. These findings underscore the significance of the effects of nsSNPs (mutations p.A179T and p.L183Q) on the structure and function of AKT2 that may lead to IR and T2D. Nevertheless, they require further verifications in future protein functional, protein–protein interaction, and large-scale case–control studies. When verified, these results will help in the identification and stratification of individuals who are at risk of IR and T2D for the purpose of prevention and treatment. Full article

(This article belongs to the Special Issue Understanding Adipose Tissue: A Molecular Perspective)

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17 pages, 2395 KiB

Open AccessArticle

MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma

by Masaki Murata, Vladimir Bilim, Yuko Shirono, Akira Kazama, Kaede Hiruma, Masayuki Tasaki and Yoshihiko Tomita

Curr. Issues Mol. Biol. 2023, 45(9), 7432-7448; https://doi.org/10.3390/cimb45090470 - 11 Sep 2023

Viewed by 1129

Abstract

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic [...] Read more.

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3β in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3β. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3′ untranslated region of GSK-3β, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3β protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3β expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field. Full article

(This article belongs to the Collection Molecular Mechanisms in Human Diseases)

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15 pages, 2974 KiB

Open AccessArticle

Identification of Potential Protein Targets in Extracellular Vesicles Isolated from Chemotherapy-Treated Ovarian Cancer Cells

by Chia-Yi Chan, Yi-Chun Ni, Hieu Duc Nguyen, Yung-Fu Wu and Kuen-Haur Lee

Curr. Issues Mol. Biol. 2023, 45(9), 7417-7431; https://doi.org/10.3390/cimb45090469 - 11 Sep 2023

Cited by 1 | Viewed by 1448

Abstract

Despite the ongoing clinical trials and the introduction of novel treatments over the past few decades, ovarian cancer remains one of the most fatal malignancies in women worldwide. Platinum- and paclitaxel-based chemotherapy is effective in treating the majority of patients with ovarian cancer. [...] Read more.

Despite the ongoing clinical trials and the introduction of novel treatments over the past few decades, ovarian cancer remains one of the most fatal malignancies in women worldwide. Platinum- and paclitaxel-based chemotherapy is effective in treating the majority of patients with ovarian cancer. However, more than 70% of patients experience recurrence and eventually develop chemoresistance. To improve clinical outcomes in patients with ovarian cancer, novel technologies must be developed for identifying molecular alterations following drug-based treatment of ovarian cancer. Recently, extracellular vesicles (EVs) have gained prominence as the mediators of tumor progression. In this study, we used mass spectrometry to identify the changes in EV protein signatures due to different chemotherapeutic agents used for treating ovarian cancer. By examining these alterations, we identified the specific protein induction patterns of cisplatin alone, paclitaxel alone, and a combination of cisplatin and paclitaxel. Specifically, we found that drug sensitivity was correlated with the expression levels of ANXA5, CD81, and RAB5C in patients receiving cisplatin with paclitaxel. Our findings suggest that chemotherapy-induced changes in EV protein signatures are crucial for the progression of ovarian cancer. Full article

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

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13 pages, 1334 KiB

Open AccessArticle

ERBB2-Mutant Gastrointestinal Tumors Represent Heterogeneous Molecular Biology, Particularly in Microsatellite Instability, Tumor Mutation Burden, and Co-Mutated Genes: An In Silico Study

by Shiro Uchida and Takashi Sugino

Curr. Issues Mol. Biol. 2023, 45(9), 7404-7416; https://doi.org/10.3390/cimb45090468 - 11 Sep 2023

Viewed by 1402

Abstract

During recent years, activating mutations in ERBB2 have been reported in solid tumors of various organs, and clinical trials targeting ERBB2-mutant tumors have been conducted. However, no effective treatment has been established for gastrointestinal tumors targeting ERBB2 mutations. ERBB2-mutant tumors have [...] Read more.

During recent years, activating mutations in ERBB2 have been reported in solid tumors of various organs, and clinical trials targeting ERBB2-mutant tumors have been conducted. However, no effective treatment has been established for gastrointestinal tumors targeting ERBB2 mutations. ERBB2-mutant tumors have a higher tumor mutation burden (TMB) and microsatellite instability (MSI) than ERBB2 non-mutant tumors, but not all ERBB2-mutant tumors are TMB- and MSI-high. Thus, a more detailed classification of ERBB2-mutant tumors based on the underlying molecular mechanisms is required. Herein, we classified ERBB2 mutations into three groups—group 1: both ERBB2 mutations and amplifications; group 2: ERBB2 mutations annotated as putative driver mutations but without amplifications; group 3: ERBB2 mutations annotated as non-driver mutations (passenger mutations or unknown significance) and those that were not amplified in gastrointestinal tumors. Esophageal adenocarcinoma, gastric cancer, and colorectal cancer presented significantly higher MSI and TMB in the ERBB2-mutant group than in the ERBB2-wild-type group. The proportions of TMB- and MSI-high tumors and frequency of co-mutated downstream genes differed among the groups. We identified TMB- and MSI-high groups; this classification is considered important for guiding the selection of drugs for ERBB2-mutant tumors with downstream genetic mutations. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer, 2nd Edition)

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16 pages, 4255 KiB

Open AccessArticle

Effects of Di-(2-Ethylhexyl) Phthalate (DEHP) on Gamete Quality Parameters of Male Koi Carp (Cyprinus carpio)

by Kampan Bisai, Vikash Kumar, Arpita Roy, Satya Narayan Parida, Souvik Dhar, Basanta Kumar Das, Bijay Kumar Behera and Manoj Kumar Pati

Curr. Issues Mol. Biol. 2023, 45(9), 7388-7403; https://doi.org/10.3390/cimb45090467 - 11 Sep 2023

Viewed by 1171

Abstract

In this study, we evaluated gamete quality parameters of mature male koi carp (Cyprinus carpio) exposed to three different concentrations (1, 10, and 100 µg/L) of di-(2-ethylhexyl) phthalate (DEHP). After 60 days of exposure, there was a significant decrease in the [...] Read more.

In this study, we evaluated gamete quality parameters of mature male koi carp (Cyprinus carpio) exposed to three different concentrations (1, 10, and 100 µg/L) of di-(2-ethylhexyl) phthalate (DEHP). After 60 days of exposure, there was a significant decrease in the gonadosomatic index (GSI) of males exposed to 10 and 100 µg/L of DEHP. Histological analysis of the testes revealed impaired histoarchitecture, including inflammatory cells, intratubular vacuoles, and swollen seminiferous tubules in treatment groups. Gamete quality parameters like sperm production, motility, spermatocrit, and sperm density values were significantly decreased at the 10 and 100 µg/L concentrations. Biochemical compositions, including glucose, cholesterol, and total protein levels, were significantly changed in the treatment groups. Similarly, the ionic compositions of seminal fluid (Na, K, Ca, and Mg) also varied in the treatment groups. Furthermore, the 11-ketotestosterone levels were decreased, and the 17-β estradiol levels were increased in the DEHP-treated groups. The mRNA expression levels of reproduction-related genes, including Fshr, Lhr, Ar, Erα, and Erβ, were significantly changed in the DEHP-treated males in a dose-dependent manner. In conclusion, the findings of this study confirmed that environmentally relevant exposure to DEHP may contribute to a decline in the gamete quality of male fishes. Full article

(This article belongs to the Special Issue Reproductive Biology and Germ Cell Development)

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14 pages, 4200 KiB

Open AccessArticle

Identifying Network Biomarkers in Early Diagnosis of Hepatocellular Carcinoma via miRNA–Gene Interaction Network Analysis

by Zhiyuan Yang, Yuanyuan Qi, Yijing Wang, Xiangyun Chen, Yuerong Wang and Xiaoli Zhang

Curr. Issues Mol. Biol. 2023, 45(9), 7374-7387; https://doi.org/10.3390/cimb45090466 - 10 Sep 2023

Cited by 1 | Viewed by 1134

Abstract

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. Methods: We [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer at the histological level. Despite the emergence of new biological technology, advanced-stage HCC remains largely incurable. The prediction of a cancer biomarker is a key problem for targeted therapy in the disease. Methods: We performed a miRNA–gene integrated analysis to identify differentially expressed miRNAs (DEMs) and genes (DEGs) of HCC. The DEM–DEG interaction network was constructed and analyzed. Gene ontology enrichment and survival analyses were also performed in this study. Results: By the analysis of healthy and tumor samples, we found that 94 DEGs and 25 DEMs were significantly differentially expressed in different datasets. Gene ontology enrichment analysis showed that these 94 DEGs were significantly enriched in the term “Liver” with a statistical p-value of 1.71 × 10⁻²⁶. Function enrichment analysis indicated that these genes were significantly overrepresented in the term “monocarboxylic acid metabolic process” with a p-value = 2.94 × 10⁻¹⁸. Two sets (fourteen genes and five miRNAs) were screened by a miRNA–gene integrated analysis of their interaction network. The statistical analysis of these molecules showed that five genes (CLEC4G, GLS2, H2AFZ, STMN1, TUBA1B) and two miRNAs (hsa-miR-326 and has-miR-331-5p) have significant effects on the survival prognosis of patients. Conclusion: We believe that our study could provide critical clinical biomarkers for the targeted therapy of HCC. Full article

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

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22 pages, 2982 KiB

Open AccessArticle

Dose-Dependent Shift in Relative Contribution of Homologous Recombination to DNA Repair after Low-LET Ionizing Radiation Exposure: Empirical Evidence and Numerical Simulation

by Oleg Belov, Anna Chigasova, Margarita Pustovalova, Andrey Osipov, Petr Eremin, Natalia Vorobyeva and Andreyan N. Osipov

Curr. Issues Mol. Biol. 2023, 45(9), 7352-7373; https://doi.org/10.3390/cimb45090465 - 09 Sep 2023

Cited by 1 | Viewed by 862

Abstract

Understanding the relative contributions of different repair pathways to radiation-induced DNA damage responses remains a challenging issue in terms of studying the radiation injury endpoints. The comparative manifestation of homologous recombination (HR) after irradiation with different doses greatly determines the overall effectiveness of [...] Read more.

Understanding the relative contributions of different repair pathways to radiation-induced DNA damage responses remains a challenging issue in terms of studying the radiation injury endpoints. The comparative manifestation of homologous recombination (HR) after irradiation with different doses greatly determines the overall effectiveness of recovery in a dividing cell after irradiation, since HR is an error-free mechanism intended to perform the repair of DNA double-strand breaks (DSB) during S/G2 phases of the cell cycle. In this article, we present experimentally observed evidence of dose-dependent shifts in the relative contributions of HR in human fibroblasts after X-ray exposure at doses in the range 20–1000 mGy, which is also supported by quantitative modeling of DNA DSB repair. Our findings indicate that the increase in the radiation dose leads to a dose-dependent decrease in the relative contribution of HR in the entire repair process. Full article

(This article belongs to the Special Issue Understanding Cellular Radiation Responses for Radiation Therapy)

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16 pages, 2905 KiB

Open AccessArticle

2-Methoxyestradiol as an Antiproliferative Agent for Long-Term Estrogen-Deprived Breast Cancer Cells

by Masayo Hirao-Suzuki, Koki Kanameda, Masufumi Takiguchi, Narumi Sugihara and Shuso Takeda

Curr. Issues Mol. Biol. 2023, 45(9), 7336-7351; https://doi.org/10.3390/cimb45090464 - 09 Sep 2023

Viewed by 1128

Abstract

To identify effective treatment modalities for breast cancer with acquired resistance, we first compared the responsiveness of estrogen receptor-positive breast cancer MCF-7 cells and long-term estrogen-deprived (LTED) cells (a cell model of endocrine therapy-resistant breast cancer) derived from MCF-7 cells to G-1 and [...] Read more.

To identify effective treatment modalities for breast cancer with acquired resistance, we first compared the responsiveness of estrogen receptor-positive breast cancer MCF-7 cells and long-term estrogen-deprived (LTED) cells (a cell model of endocrine therapy-resistant breast cancer) derived from MCF-7 cells to G-1 and 2-methoxyestradiol (2-MeO-E2), which are microtubule-destabilizing agents and agonists of the G protein-coupled estrogen receptor 1 (GPER1). The expression of GPER1 in LTED cells was low (~0.44-fold), and LTED cells displayed approximately 1.5-fold faster proliferation than MCF-7 cells. Although G-1 induced comparable antiproliferative effects on both MCF-7 and LTED cells (IC₅₀ values of >10 µM), 2-MeO-E2 exerted antiproliferative effects selective for LTED cells with an IC₅₀ value of 0.93 μM (vs. 6.79 μM for MCF-7 cells) and induced G2/M cell cycle arrest. Moreover, we detected higher amounts of β-tubulin proteins in LTED cells than in MCF-7 cells. Among the β-tubulin (TUBB) isotype genes, the highest expression of TUBB2B (~3.2-fold) was detected in LTED cells compared to that in MCF-7 cells. Additionally, siTUBB2B restores 2-MeO-E2-mediated inhibition of LTED cell proliferation. Other microtubule-targeting agents, i.e., paclitaxel, nocodazole, and colchicine, were not selective for LTED cells. Therefore, 2-MeO-E2 can be an antiproliferative agent to suppress LTED cell proliferation. Full article

(This article belongs to the Special Issue Advanced Molecular Solutions for Cancer Therapy)

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17 pages, 3787 KiB

Open AccessArticle

NMOSD IgG Impact Retinal Cells in Murine Retinal Explants

by Hannah Nora Wolf, Veronika Ehinger, Larissa Guempelein, Pratiti Banerjee, Tania Kuempfel, Joachim Havla and Diana Pauly

Curr. Issues Mol. Biol. 2023, 45(9), 7319-7335; https://doi.org/10.3390/cimb45090463 - 07 Sep 2023

Viewed by 1011

Abstract

Neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory diseases of the central nervous system, characterized by autoantibodies against aquaporin-4. The symptoms primarily involve severe optic neuritis and longitudinally extensive transverse myelitis. Although the disease progression is typically relapse-dependent, recent studies revealed retinal neuroaxonal [...] Read more.

Neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory diseases of the central nervous system, characterized by autoantibodies against aquaporin-4. The symptoms primarily involve severe optic neuritis and longitudinally extensive transverse myelitis. Although the disease progression is typically relapse-dependent, recent studies revealed retinal neuroaxonal degeneration unrelated to relapse activity, potentially due to anti-aquaporin-4-positive antibodies interacting with retinal glial cells such as Müller cells. In this exploratory study, we analysed the response of mouse retinal explants to NMOSD immunoglobulins (IgG). Mouse retinal explants were treated with purified IgG from patient or control sera for one and three days. We characterized tissue response patterns through morphological changes, chemokine secretion, and complement expression. Mouse retinal explants exhibited a basic proinflammatory response ex vivo, modified by IgG addition. NMOSD IgG, unlike control IgG, increased gliosis and decreased chemokine release (CCL2, CCL3, CCL4, and CXCL-10). Complement component expression by retinal cells remained unaltered by either IgG fraction. We conclude that human NMOSD IgG can possibly bind in the mouse retina, altering the local cellular environment. This intraretinal stress may contribute to retinal degeneration independent of relapse activity in NMOSD, suggesting a primary retinopathy. Full article

(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)

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15 pages, 4557 KiB

Open AccessArticle

Transcriptomic and Hormone Analyses Provide Insight into the Regulation of Axillary Bud Outgrowth of Eucommia ulmoides Oliver

by Ying Zhang, Dandan Du, Hongling Wei, Shengnan Xie, Xuchen Tian, Jing Yang, Siqiu Xiao, Zhonghua Tang, Dewen Li and Ying Liu

Curr. Issues Mol. Biol. 2023, 45(9), 7304-7318; https://doi.org/10.3390/cimb45090462 - 07 Sep 2023

Viewed by 1006

Abstract

An essential indicator of Eucommia ulmoides Oliver (E. ulmoides) is the axillary bud; the growth and developmental capacity of axillary buds could be used to efficiently determine the structural integrity of branches and plant regeneration. We obtained axillary buds in different [...] Read more.

An essential indicator of Eucommia ulmoides Oliver (E. ulmoides) is the axillary bud; the growth and developmental capacity of axillary buds could be used to efficiently determine the structural integrity of branches and plant regeneration. We obtained axillary buds in different positions on the stem, including upper buds (CK), tip buds (T1), and bottom buds (T2), which provided optimal materials for the study of complicated regulatory networks that control bud germination. This study used transcriptomes to analyze the levels of gene expression in three different types of buds, and the results showed that 12,131 differentially expressed genes (DEGs) were discovered via the pairwise comparison of transcriptome data gathered from CK to T2, while the majority of DEGs (44.38%) were mainly found between CK and T1. These DEGs were closely related to plant hormone signal transduction and the amino acid biosynthesis pathway. We also determined changes in endogenous hormone contents during the process of bud germination. Interestingly, except for indole-3-acetic acid (IAA) content, which showed a significant upward trend (p < 0.05) in tip buds on day 4 compared with day 0, the other hormones showed no significant change during the process of germination. Then, the expression patterns of genes involved in IAA biosynthesis and signaling were examined through transcriptome analysis. Furthermore, the expression levels of genes related to IAA biosynthesis and signal transduction were upregulated in tip buds. Particularly, the expression of the IAA degradation gene Gretchen Hagen 3 (GH3.1) was downregulated on day 4, which may support the concept that endogenous IAA promotes bud germination. Based on these data, we propose that IAA synthesis and signal transduction lead to morphological changes in tip buds during the germination process. On this basis, suggestions to improve the efficiency of the production and application of E. ulmoides are put forward to provide guidance for future research. Full article

(This article belongs to the Section Molecular Plant Sciences)

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18 pages, 1210 KiB

Open AccessArticle

DNA Methylation Patterns in Relation to Acute Severity and Duration of Anxiety and Depression

by Eva Vidovič, Sebastian Pelikan, Marija Atanasova, Katarina Kouter, Indre Pileckyte, Aleš Oblak, Brigita Novak Šarotar, Alja Videtič Paska and Jurij Bon

Curr. Issues Mol. Biol. 2023, 45(9), 7286-7303; https://doi.org/10.3390/cimb45090461 - 06 Sep 2023

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Abstract

Depression and anxiety are common mental disorders that often occur together. Stress is an important risk factor for both disorders, affecting pathophysiological processes through epigenetic changes that mediate gene–environment interactions. In this study, we explored two proposed models about the dynamic nature of [...] Read more.

Depression and anxiety are common mental disorders that often occur together. Stress is an important risk factor for both disorders, affecting pathophysiological processes through epigenetic changes that mediate gene–environment interactions. In this study, we explored two proposed models about the dynamic nature of DNA methylation in anxiety and depression: a stable change, in which DNA methylation accumulates over time as a function of the duration of clinical symptoms of anxiety and depression, or a flexible change, in which DNA methylation correlates with the acute severity of clinical symptoms. Symptom severity was assessed using clinical questionnaires for anxiety and depression (BDI-II, IDS-C, and HAM-A), and the current episode and the total lifetime symptom duration was obtained from patients’ medical records. Peripheral blood DNA methylation levels were determined for the BDNF, COMT, and SLC6A4 genes. We found a significant negative correlation between COMT_1 amplicon methylation and acute symptom scores, with BDI-II (R(22) = 0.190, p = 0.033), IDS-C (R(22) = 0.199, p = 0.029), and HAM-A (R(22) = 0.231, p = 0.018) all showing a similar degree of correlation. Our results suggest that DNA methylation follows flexible dynamics, with methylation levels closely associated with acute clinical presentation rather than with the duration of anxiety and depression. These results provide important insights into the dynamic nature of DNA methylation in anxiety and affective disorders and contribute to our understanding of the complex interplay between stress, epigenetics, and individual phenotype. Full article

(This article belongs to the Special Issue The Regulation and Mechanisms of Genomics in Psychiatry)

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11 pages, 1782 KiB

Open AccessReview

Effect of Carcinomas on Autosomal Trait Screening: A Review Article

by Husein Alhatim, Muhammad Nazrul Hakim Abdullah, Suhaili Abu Bakar and Sayed Amin Amer

Curr. Issues Mol. Biol. 2023, 45(9), 7275-7285; https://doi.org/10.3390/cimb45090460 - 04 Sep 2023

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Abstract

This review highlights the effect of carcinomas on the results of the examination of autosomal genetic traits for identification and paternity tests when carcinoid tissue is the only source and no other samples are available. In DNA typing or genetic fingerprinting, variable elements [...] Read more.

This review highlights the effect of carcinomas on the results of the examination of autosomal genetic traits for identification and paternity tests when carcinoid tissue is the only source and no other samples are available. In DNA typing or genetic fingerprinting, variable elements are isolated and identified within the base pair sequences that form the DNA. The person’s probable identity can be determined by analysing nucleotide sequences in particular regions of DNA unique to everyone. Genetics plays an increasingly important role in the risk stratification and management of carcinoma patients. The available information from previous studies has indicated that in some incidents, including mass disasters and crimes such as terrorist incidents, biological evidence may not be available at the scene of the accident, except for some unknown human remains found in the form of undefined human tissues. If these tissues have cancerous tumours, it may affect the examination of the genetic traits derived from these samples, thereby resulting in a failure to identify the person. Pathology units, more often, verify the identity of the patients who were diagnosed with cancer in reference to their deceased tumorous relatives. Genetic fingerprinting (GF) is also used in paternity testing when the alleged parent disappeared or died and earlier was diagnosed and treated for cancer. Full article

(This article belongs to the Special Issue Genomic Analysis of Common Disease)

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18 pages, 7464 KiB

Open AccessArticle

In Silico Bioinformatics Analysis on the Role of Long Non-Coding RNAs as Drivers and Gatekeepers of Androgen-Independent Prostate Cancer Using LNCaP and PC-3 Cells

by Mandisa Mbeje, Jeyalakshmi Kandhavelu, Clement Penny, Mmamoletla Kgoebane-Maseko, Zodwa Dlamini and Rahaba Marima

Curr. Issues Mol. Biol. 2023, 45(9), 7257-7274; https://doi.org/10.3390/cimb45090459 - 01 Sep 2023

Viewed by 1307

Abstract

Prostate cancer (PCa) is the leading cancer in men globally. The association between PCa and long non-coding RNAs (lncRNAs) has been reported. Aberrantly expressed lncRNAs have been documented in each of the cancer “hallmarks”. Androgen signaling plays an important role in PCa progression. [...] Read more.

Prostate cancer (PCa) is the leading cancer in men globally. The association between PCa and long non-coding RNAs (lncRNAs) has been reported. Aberrantly expressed lncRNAs have been documented in each of the cancer “hallmarks”. Androgen signaling plays an important role in PCa progression. This study aimed to profile the aberrantly expressed lncRNAs in androgen-dependent (LNCaP) PCa compared to androgen-independent (PC-3) PCa cells. This was achieved by using a 384-well plate of PCa lncRNA gene panel. Differential expression of ±2 up or downregulation was determined using the CFX Maestro software v2.1. LncSEA and DIANA-miRPath were used to identify the enriched pathways. Telomerase RNA component (TERC) lncRNA was illustrated to participate in various tumourigenic classes by in silico bioinformatics analysis and was thus selected for validation using RT-qPCR. Further bioinformatics analysis revealed the involvement of differentially expressed lncRNAs in oncogenic pathways. Some lncRNAs undergo hypermethylation, others are encapsulated by exosomes, while others interact with several microRNAs (miRNAs), favouring tumourigenic pathways. Notably, TERC lncRNA was shown to interact with tumour-suppressor miRNAs hsa-miR-4429 and hsa-miR-320b. This interaction in turn activates TGF-β-signaling and ECM-receptor interaction pathways, favouring the progression of PCa. Understanding lncRNAs as competitive endogenous RNA molecules and their interactions with miRNAs may aid in the identification of novel prognostic PCa biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Studying the Function of RNAs Using Omics Approaches)

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15 pages, 1697 KiB

Open AccessReview

Research Progress on Anthocyanin-Mediated Regulation of ‘Black’ Phenotypes of Plant Organs

by Fei Wang, Jinliao Chen, Ruonan Tang, Ruixin Wang, Sagheer Ahmad, Zhongjian Liu and Donghui Peng

Curr. Issues Mol. Biol. 2023, 45(9), 7242-7256; https://doi.org/10.3390/cimb45090458 - 01 Sep 2023

Cited by 1 | Viewed by 1732

Abstract

The color pattern is one of the most important characteristics of plants. Black stands out among the vibrant colors due to its rare and distinctive nature. While some plant organs appear black, they are, in fact, dark purple. Anthocyanins are the key compounds [...] Read more.

The color pattern is one of the most important characteristics of plants. Black stands out among the vibrant colors due to its rare and distinctive nature. While some plant organs appear black, they are, in fact, dark purple. Anthocyanins are the key compounds responsible for the diverse hues in plant organs. Cyanidin plays an important role in the deposition of black pigments in various plant organs, such as flower, leaf, and fruit. A number of structural genes and transcription factors are involved in the metabolism of anthocyanins in black organs. It has been shown that the high expression of R2R3-MYB transcription factors, such as PeMYB7, PeMYB11, and CsMYB90, regulates black pigmentation in plants. This review provides a comprehensive overview of the anthocyanin pathways that are involved in the regulation of black pigments in plant organs, including flower, leaf, and fruit. It is a great starting point for further investigation into the molecular regulation mechanism of plant color and the development of novel cultivars with black plant organs. Full article

(This article belongs to the Special Issue Molecular Breeding and Genetics Research in Plants)

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14 pages, 3282 KiB

Open AccessArticle

Molecular Docking Integrated with Network Pharmacology Explores the Therapeutic Mechanism of Cannabis sativa against Type 2 Diabetes

by Juan Manuel Guzmán-Flores, Victoriano Pérez-Vázquez, Fernando Martínez-Esquivias, Mario Alberto Isiordia-Espinoza and Juan Manuel Viveros-Paredes

Curr. Issues Mol. Biol. 2023, 45(9), 7228-7241; https://doi.org/10.3390/cimb45090457 - 01 Sep 2023

Cited by 1 | Viewed by 2344

Abstract

The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. [...] Read more.

The incidence of type 2 diabetes (T2D) is rising, and finding new treatments is important. C. sativa is a plant suggested as a potential treatment for T2D, but how it works needs to be clarified. This study explored the pharmacological mechanism of C. sativa in treating T2D. We identified the active compounds in C. sativa and their targets. From there, we examined the genes associated with T2D and found overlapping genes. We conducted an enrichment analysis and created a protein–protein and target–compound interactions network. We confirmed the binding activities of the hub proteins and compounds with molecular docking. We identified thirteen active compounds from C. sativa, which have 150 therapeutic targets in T2D. The enrichment analysis showed that these proteins are involved in the hormone, lipid, and stress responses. They bind transcription factors and metals and participate in the insulin, PI3K/Akt, HIF-1, and FoxO signaling pathways. We found four hub proteins (EGFR, ESR1, HSP90AA1, and SRC) that bind to the thirteen bioactive compounds. This was verified using molecular docking. Our findings suggest that C. sativa’s antidiabetic action is carried out through the insulin signaling pathway, with the participation of HIF-1 and FoxO. Full article

(This article belongs to the Special Issue Natural Products in Biomedicine and Pharmacotherapy)

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16 pages, 2646 KiB

Open AccessArticle

Prokaryotic Expression, Purification, and Antibacterial Activity of the Hepcidin Peptide of Crescent Sweetlips (Plectorhinchus cinctus)

by Peixin Wang, Zhongjing Lin, Shaoling Lin, Baodong Zheng, Yi Zhang and Jiamiao Hu

Curr. Issues Mol. Biol. 2023, 45(9), 7212-7227; https://doi.org/10.3390/cimb45090456 - 31 Aug 2023

Viewed by 1001

Abstract

The hepcidin peptide of crescent sweetlips (Plectorhinchus cinctus) is a cysteine-rich, cationic antimicrobial peptide that plays a crucial role in the innate immune system’s defense against invading microbes. The aim of this study was to identify the optimal parameters for prokaryotic [...] Read more.

The hepcidin peptide of crescent sweetlips (Plectorhinchus cinctus) is a cysteine-rich, cationic antimicrobial peptide that plays a crucial role in the innate immune system’s defense against invading microbes. The aim of this study was to identify the optimal parameters for prokaryotic expression and purification of this hepcidin peptide and characterize its antibacterial activity. The recombinant hepcidin peptides were expressed in Escherichia coli strain Arctic Express (DE3), with culture and induction conditions optimized using response surface methodology (RSM). The obtained hepcidin peptides were then purified before tag cleavage, and their antibacterial activity was determined. The obtained results revealed that induction temperature had the most significant impact on the production of soluble recombinant peptides. The optimum induction conditions were determined to be an isopropylthio-β-galactoside (IPTG) concentration of 0.21 mmol/L, induction temperature of 18.81 °C, and an induction time of 16.01 h. Subsequently, the recombinant hepcidin peptide was successfully purified using Ni-IDA affinity chromatography followed by SUMO protease cleavage. The obtained hepcidin peptide (without His-SUMO tag) demonstrated strong antimicrobial activity in vitro against V. parahaemolyticus, E. coli, and S. aureus. The results showed prokaryotic (E. coli) expression is a feasible way to produce the hepcidin peptide of crescent sweetlips in a cost-effective way, which has great potential to be used as an antimicrobial agent in aquaculture. Full article

(This article belongs to the Special Issue Advanced Research in Antimicrobial and Antiviral Drugs)

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