Current Issues in Molecular Biology

16 pages, 4035 KiB

Open AccessArticle

Ginsenoside Re Regulates Oxidative Stress through the PI3K/Akt/Nrf2 Signaling Pathway in Mice with Scopolamine-Induced Memory Impairments

by Xin Li, Kai Zheng, Hao Chen and Wei Li

Curr. Issues Mol. Biol. 2024, 46(10), 11359-11374; https://doi.org/10.3390/cimb46100677 (registering DOI) - 13 Oct 2024

Abstract

While Ginsenoside Re has been shown to protect the central nervous system, reports of its effects on memory in the model of scopolamine-induced memory impairment are rare. The aim of this study was to investigate the effects of Ginsenoside Re on scopolamine (SCOP)-induced [...] Read more.

While Ginsenoside Re has been shown to protect the central nervous system, reports of its effects on memory in the model of scopolamine-induced memory impairment are rare. The aim of this study was to investigate the effects of Ginsenoside Re on scopolamine (SCOP)-induced memory damage and the mechanism of action. Male ICR mice were treated with SCOP (3 mg/kg) for 7 days and with or without Ginsenoside Re for 14 days. As evidenced by behavioral studies (escape latency and cross platform position), brain tissue morphology, and oxidative stress indicators after Ginsenoside Re treatment, the memory damage caused by SCOP was significantly ameliorated. Further mechanism research indicated that Ginsenoside Re inhibited cell apoptosis by regulating the PI3K/Akt/Nrf2 pathway, thereby exerting a cognitive impairment improvement effect. This research suggests that Ginsenoside Re could protect against SCOP-induced memory defects possibly through inhibiting oxidative stress and cell apoptosis. Full article

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

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10 pages, 8024 KiB

Open AccessArticle

Knockdown of Gas6 Exerts Anti-Esophageal Cancer Effects by Inhibiting the PI3K/AKT Pathway

by Shuang Gao, Yu Wang, Ming Huang, Jianxin Guo, Zhongbing Wu and Jing Li

Curr. Issues Mol. Biol. 2024, 46(10), 11349-11358; https://doi.org/10.3390/cimb46100676 (registering DOI) - 13 Oct 2024

Abstract

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the digestive tract with strong migratory and invasive abilities. Gas6 is closely associated with the progression of many malignant tumors; however, the role of Gas6 in the progression of esophageal cancer is unclear. [...] Read more.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the digestive tract with strong migratory and invasive abilities. Gas6 is closely associated with the progression of many malignant tumors; however, the role of Gas6 in the progression of esophageal cancer is unclear. Here, we report that the knockdown of Gas6 inhibited esophageal cancer cell proliferation, migration, and invasion. In addition, Gas6 knockdown downregulated the levels of P-PI3K and P-AKT. Taken together, the findings confirm that Gas6 knockdown can inhibit esophageal cancer progression and can exert anti-tumor effects on esophageal cancer through the PI3K/AKT pathway. Full article

(This article belongs to the Special Issue Tumorigenesis and Tumor Microenvironment)

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13 pages, 8204 KiB

Open AccessArticle

Catecholamines Attenuate LPS-Induced Inflammation through β2 Adrenergic Receptor Activation- and PKA Phosphorylation-Mediated TLR4 Downregulation in Macrophages

by Cong Wang, Guo-Gang Feng, Junko Takagi, Yoshihiro Fujiwara, Tsuyoshi Sano and Hideaki Note

Curr. Issues Mol. Biol. 2024, 46(10), 11336-11348; https://doi.org/10.3390/cimb46100675 (registering DOI) - 12 Oct 2024

Abstract

Inflammation is a tightly regulated process involving immune receptor recognition, immune cell migration, inflammatory mediator secretion, and pathogen elimination, all essential for combating infection and restoring damaged tissue. However, excessive inflammatory responses drive various human diseases. The autonomic nervous system (ANS) is known [...] Read more.

Inflammation is a tightly regulated process involving immune receptor recognition, immune cell migration, inflammatory mediator secretion, and pathogen elimination, all essential for combating infection and restoring damaged tissue. However, excessive inflammatory responses drive various human diseases. The autonomic nervous system (ANS) is known to regulate inflammatory responses; however, the detailed mechanisms underlying this regulation remain incompletely understood. Herein, we aimed to study the anti-inflammatory effects and mechanism of action of the ANS in RAW264.7 cells. Quantitative PCR and immunoblotting assays were used to assess lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) expression. The anti-inflammatory effects of catecholamines (adrenaline, noradrenaline, and dopamine) and acetylcholine were examined in LPS-treated cells to identify the receptors involved. Catecholamines inhibited LPS-induced TNFα expression by activating the β2 adrenergic receptor (β2-AR). β2-AR activation in turn downregulated the expression of Toll-like receptor 4 (TLR4) by stimulating protein kinase A (PKA) phosphorylation, resulting in the suppression of TNFα levels. Collectively, our findings reveal a novel mechanism underlying the inhibitory effect of catecholamines on LPS-induced inflammatory responses, whereby β2-AR activation and PKA phosphorylation downregulate TLR4 expression in macrophages. These findings could provide valuable insights for the treatment of inflammatory diseases and anti-inflammatory drug development. Full article

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

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10 pages, 2763 KiB

Open AccessCommunication

Evaluation of Rz2 Gene Expression in Sugar Beet Hybrids Infected with Beet Necrotic Yellow Vein Virus

by Ruslan Moisseyev, Alexandr Pozharskiy, Aisha Taskuzhina, Marina Khusnitdinova, Ualikhan Svanbayev, Zagipa Sapakhova and Dilyara Gritsenko

Curr. Issues Mol. Biol. 2024, 46(10), 11326-11335; https://doi.org/10.3390/cimb46100674 (registering DOI) - 12 Oct 2024

Abstract

Sugar beet hybrids are essential in modern agriculture due to their superior yields, disease resistance, and adaptability. This study investigates the role of the Rz2 gene in conferring resistance to beet necrotic yellow vein virus (BNYVV) in 14 sugar beet hybrids cultivated in [...] Read more.

Sugar beet hybrids are essential in modern agriculture due to their superior yields, disease resistance, and adaptability. This study investigates the role of the Rz2 gene in conferring resistance to beet necrotic yellow vein virus (BNYVV) in 14 sugar beet hybrids cultivated in Kazakhstan, including local and European varieties. The Rz2 gene, encoding a CC-NB-LRR protein, is a known resistance factor against BNYVV. Using RT-qPCR, we assessed Rz2 expression and detected BNYVV in bait plants inoculated with virus-infested soil. Our findings identified two highly resistant varieties: the Kazakh cultivar ‘Abulhair’ and the French line 22b5006. Additionally, the Kazakh cultivar ‘Pamyati Abugalieva’ and the French hybrid ‘Bunker’ exhibited increased resistance, suggesting involvement of other resistance loci. Notably, the Danish hybrid ‘Alando’, despite resistance to rhizomania, did not effectively resist BNYVV, highlighting possible evasion of its genetic factors by local virus strains. Our results emphasize the importance of Rz2 in resistance breeding programs and advocate for further research on additional resistance genes and the genetic variability of BNYVV in Kazakhstan. This work pioneers the molecular evaluation of BNYVV resistance in sugar beet in Kazakhstan, contributing to sustainable disease management and improved sugar beet production. Full article

(This article belongs to the Section Molecular Plant Sciences)

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12 pages, 6140 KiB

Open AccessArticle

Hepatotoxicity Induced by Methyl Eugenol: Insights from Toxicokinetics, Metabolomics, and Gut Microbiota

by Liang Chen, Jiaxin Li, Qian Li and Qingwen Sun

Curr. Issues Mol. Biol. 2024, 46(10), 11314-11325; https://doi.org/10.3390/cimb46100673 - 11 Oct 2024

Abstract

Due to continuous application as a flavoring agent in the pesticide, pharmaceutical, and food industries, methyl eugenol (ME) persists in the environment and causes deleterious impacts including cytotoxicity, genotoxicity, and liver damage. This study utilized a comprehensive approach, integrating toxicokinetics, metabolomics, and gut [...] Read more.

Due to continuous application as a flavoring agent in the pesticide, pharmaceutical, and food industries, methyl eugenol (ME) persists in the environment and causes deleterious impacts including cytotoxicity, genotoxicity, and liver damage. This study utilized a comprehensive approach, integrating toxicokinetics, metabolomics, and gut microbiota analysis, to explore the mechanisms behind ME-induced hepatotoxicity in mice. The study observed significant rises in ALT and AST levels, along with significant weight loss, indicating severe liver damage. Toxicokinetic data showed delayed Tmax and plasma accumulation after 28 days of repeated ME exposure at doses of 20 mg/kg, 40 mg/kg, and 60 mg/kg. The metabolomic analysis pinpointed four critical pathways—TCA cycle; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; and tyrosine metabolism—linked to 20 potential biomarkers. Gut microbiota analysis revealed that extended ME exposure led to microbial imbalance, particularly altering the populations of Akkermansia, Prevotella, and Ruminococcus, which are key to amino acid metabolism and the TCA cycle, thus contributing to hepatotoxicity. However, the causal relationship between changes in gut microbiota and liver metabolite levels still requires further in-depth research. This study underscores the significant role of liver metabolites and gut microbiota in ME-induced liver damage. Full article

(This article belongs to the Section Molecular Pharmacology)

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11 pages, 315 KiB

Open AccessArticle

Production of Protein Hydrolysates Teff (Eragrostis tef) Flour with Antioxidant and Angiotensin-I-Converting Enzyme (ACE-I) Inhibitory Activity Using Pepsin and Cynara cardunculus L. Extract

by Gregorio Molina-Valero, Laura Buendía-Moreno, Cindy Bande-De León, Estefanía Bueno-Gavilá and Luis Tejada

Curr. Issues Mol. Biol. 2024, 46(10), 11303-11313; https://doi.org/10.3390/cimb46100672 - 11 Oct 2024

Abstract

In recent years, several studies have shown the antioxidant and antihypertensive potential of bioactive peptides. Thus, bioactive peptides are likely to be a valuable substance for the development of functional foods. There are a wide variety of sources of these peptides, including several [...] Read more.

In recent years, several studies have shown the antioxidant and antihypertensive potential of bioactive peptides. Thus, bioactive peptides are likely to be a valuable substance for the development of functional foods. There are a wide variety of sources of these peptides, including several cereals. Teff is an Ethiopian-rooted cereal with an interesting nutritional profile, mainly due to its high amount of protein. In this study, teff flour was subjected to a defatting process for optimizing the protein extraction. Such extraction was performed by precipitation from its isoelectric point, a crucial step that separates the protein from other components based on their charge. The protein obtained was subjected to enzymatic hydrolysis by pepsin and Cynara cardunculus L. The antihypertensive (angiotensin-I-converting enzyme ―ACE-I― inhibitory activity) and antioxidant activity (2,2-diphenyl-1-picrylhydrazyl ―DPPH― radical scavenging activity) of the peptides were determined. According to the IC₅₀ values, the results obtained showed that the peptides from teff flour show promising bioactivity compared to other cereals. Furthermore, the peptides from teff flour obtained from C. cardunculus L. showed higher antioxidant activity (defatted teff flour ―DTF―: 0.59 ± 0.05; protein extract ―EP― : 1.04 ± 0.11) than those obtained with pepsin (DTF: 0.87 ± 0.09; EP: 1.73 ± 0.11). However, C. cardunculus L. hydrolyzate peptides showed lower inhibitory activity of ACE-I (DTF: 0.59 ± 0.07; EP: 0.61 ± 0.05) than the pepsin hydrolyzate (DTF: 0.15 ± 0.02; EP: 0.33 ± 0.05). Full article

(This article belongs to the Special Issue Protein and Bioactive Peptides: Bioactivity, Applications and Health Benefits)

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Graphical abstract

7 pages, 551 KiB

Open AccessCommunication

The Interplay between von Hippel–Lindau Tumor Suppressor Gene, Lon Protease, ROS Accumulation, and Inflammation in Clear Cell Renal Cell Carcinoma

by Yao-Chou Tsai and Chan-Yen Kuo

Curr. Issues Mol. Biol. 2024, 46(10), 11296-11302; https://doi.org/10.3390/cimb46100671 - 11 Oct 2024

Abstract

This study explores the role of the von Hippel–Lindau (VHL) tumor suppressor gene and Lon protease in the development of clear cell renal carcinoma (ccRCC) through mechanisms involving inflammation and reactive oxygen species (ROS) accumulation in kidney cells. By examining the impact of [...] Read more.

This study explores the role of the von Hippel–Lindau (VHL) tumor suppressor gene and Lon protease in the development of clear cell renal carcinoma (ccRCC) through mechanisms involving inflammation and reactive oxygen species (ROS) accumulation in kidney cells. By examining the impact of VHL on the early stages of kidney cancer development, this research highlights the contributions of inflammation and ROS, as well as the involvement of Lon protease. The findings reveal increased Lon expression and ROS levels in VHL-knockdown HK-2 cells, along with elevated phospho-c-Jun N-terminal kinase (JNK) levels, emphasizing the complex interplay between VHL, Lon protease, inflammation, and ROS in kidney cell models. These insights point to potential therapeutic pathways for ccRCC. Full article

(This article belongs to the Special Issue The Role of Bioactives in Inflammation)

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14 pages, 8675 KiB

Open AccessBrief Report

TLR4 Downregulation Identifies High-Risk HPV Infection and Integration in H-SIL and Squamous Cell Carcinomas of the Uterine Cervix

by Angela Santoro, Giuseppe Angelico, Damiano Arciuolo, Giulia Scaglione, Belen Padial Urtueta, Gabriella Aquino, Noemy Starita, Maria Lina Tornesello, Rosalia Anna Rega, Maria Carmela Pedicillo, Manuel Mazzucchelli, Ilenia Sara De Stefano, Rosanna Zamparese, Giuseppina Campisi, Giorgio Mori, Gian Franco Zannoni and Giuseppe Pannone

Curr. Issues Mol. Biol. 2024, 46(10), 11282-11295; https://doi.org/10.3390/cimb46100670 - 10 Oct 2024

Abstract

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present [...] Read more.

Growing scientific evidence suggests a link between the expression of toll-like receptor 4 (TLR4) and cervical cancer carcinogenesis. Specifically, a close relation between TLR4 expression and FIGO stage, lymph node metastases, and tumor size has been reported in cervical cancer. In the present study, we aimed to evaluate the relationship between TLR4 expression levels and human papillomavirus (HPV) infection and/or high-risk (hr) HPV integration status in patients with a histological diagnosis of high-grade squamous intraepithelial lesion (H-SIL), and squamous cell carcinoma (SCC) of the uterine cervix. Sixty biopsies of cervical neoplasia, comprising H-SIL (n = 20) and SCC (n = 40), were evaluated for TLR4 expression by immunohistochemistry. All samples were positive for high-risk HPV as confirmed by in situ hybridization (ISH) and broad-spectrum PCR followed by Sanger sequencing analysis. The intensity of TLR4 staining was higher in tissues negative for intraepithelial lesion or malignancy (NILM) than in H-SIL, and further reduced in SCC. Moreover, statistically significant differences have been observed in the percentage of TLR4 expression between NILM and H-SIL and between H-SIL and SCC, with higher percentages of expression in H-SIL than in SCC. Our results showed a significant downregulation of TLR4 in HPV-related H-SIL and SCC, compared to NILM. These data support the hypothesis that TLR4 expression is suppressed in HPV-driven oncogenesis. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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12 pages, 2079 KiB

Open AccessArticle

Usefulness of Galectin-3 as a Biochemical Marker to Detect Ventricular and Supraventricular Arrhythmias in Children

by Ewa Moric-Janiszewska, Joanna Wawszczyk, Aleksandra Morka and Małgorzata Kapral

Curr. Issues Mol. Biol. 2024, 46(10), 11270-11281; https://doi.org/10.3390/cimb46100669 - 10 Oct 2024

Abstract

Galectin-3 (Gal-3) has been demonstrated to play a pivotal role in the pathogenesis of several fibrotic disorders. A number of studies have examined the relationship between galectin-3 levels and cardiac fibrosis in heart failure. Nevertheless, the role of galectin-3 in the etiology of [...] Read more.

Galectin-3 (Gal-3) has been demonstrated to play a pivotal role in the pathogenesis of several fibrotic disorders. A number of studies have examined the relationship between galectin-3 levels and cardiac fibrosis in heart failure. Nevertheless, the role of galectin-3 in the etiology of supraventricular (SVa) and ventricular (Va) arrhythmias remains largely unexamined. The objective of this prospective study was to investigate the potential correlation between galectin concentration and the occurrence of idiopathic cardiac arrhythmias in pediatric patients. Biochemistry analysis was performed on 30 children (11–18 years; 14 boys and 16 girls). The control group consisted of 20 children. Cardiac arrhythmia was confirmed by a 24 h Holter ECG recording. Serum galectin-3 levels were measured via enzyme-linked immunosorbent assay (ELISA). Statistical analysis of the data showed significant associations between creatinine kinase (CK) and Gal-3 in patients with SVa (SVT—supraventricular tachycardia) arrhythmias, suggesting a potential effect of CK on Gal-3 levels. However, no correlation was identified between Gal-3 concentration and the occurrence of cardiac arrhythmias under investigation. We concluded that galectin-3 does not have the potential to be a biomarker in the diagnosis of idiopathic arrhythmias in pediatric patients. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 2671 KiB

Open AccessReview

Pathophysiology, Treatment, and Prognosis of Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome: A Review

by Takuya Kakutani, Riko Kamada and Yotaro Tamai

Curr. Issues Mol. Biol. 2024, 46(10), 11255-11269; https://doi.org/10.3390/cimb46100668 - 9 Oct 2024

Abstract

TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal [...] Read more.

TAFRO syndrome, first reported in 2010, is a systemic inflammatory disease with a rapid onset and potentially fatal course if not treated promptly and appropriately. The name is derived from the initial letters describing the characteristic symptoms of thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly. It is sometimes considered a special subtype of idiopathic multicentric Castleman disease (iMCD) because lymph node biopsies often reveal the pathology findings seen in iMCD. However, its clinical manifestations and prognoses are not well documented. Since the clinical manifestations and prognoses of TAFRO syndrome differ significantly from those of iMCD, it is recognized as an independent disease concept and considered to partially overlap with the pathology of MCD. The pathogenesis of TAFRO syndrome remains largely unknown. Due to the lack of appropriate treatment, it often presents with multiple organ dysfunction and fatality. In this review, we summarized new findings on the pathogenesis of TAFRO syndrome and discussed current effective therapies and future treatment strategies. Full article

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

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19 pages, 5595 KiB

Open AccessArticle

Modulation of Autophagy–Lysosome Axis by African Swine Fever Virus and Its Encoded Protein pEP153R

by Si-Yu Bai, Wenlian Weng, Hua Wang, Zhiying Cui, Jiajun Wu, Yajin Qu, Yuxin Hao, Peng Gao, Yongning Zhang, Lei Zhou, Xinna Ge, Xin Guo, Jun Han and Hanchun Yang

Curr. Issues Mol. Biol. 2024, 46(10), 11236-11254; https://doi.org/10.3390/cimb46100667 - 7 Oct 2024

Abstract

The autophagy–lysosome axis is an evolutionarily conserved intracellular degradation pathway which constitutes an important component of host innate immunity against microbial infections. Here, we show that African swine fever virus (ASFV), one of most devastating pathogens to the worldwide swine industry, can reshape [...] Read more.

The autophagy–lysosome axis is an evolutionarily conserved intracellular degradation pathway which constitutes an important component of host innate immunity against microbial infections. Here, we show that African swine fever virus (ASFV), one of most devastating pathogens to the worldwide swine industry, can reshape the autophagy–lysosome axis by recruiting the critical lysosome membrane proteins (LAMP1 and LAMP2) to viral factories while inhibiting autophagic induction in macrophages. The screening of viral membrane proteins led to the identification of several ASFV membrane proteins, exemplified by viral protein pEP153R, that could significantly alter the subcellular localization of LAMP1/2 when expressed alone in transfected cells. Further analysis showed that pEP153R was also a component of viral factories and could induce endoplasmic reticulum (ER) retention of LAMP1/2, leading to the inhibition of the fusion of autophagosomes with lysosomes. Interestingly, the ASFV mutant lacking EP153R could still actively recruit LAMP into viral factories (VFs) and inhibit autophagic flux, indicating the existence of a functional redundancy of other viral proteins in the absence of pEP153R and highlighting the complexity of ASFV replication biology. Taken together, our results reveal novel information about the interplay of ASFV with the autophagy–lysosome axis and a previously unrecognized function of ASFV protein pEP153R in regulating the cellular autophagic process. Full article

(This article belongs to the Section Molecular Microbiology)

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16 pages, 1795 KiB

Open AccessArticle

In Silico Screening of 1,3,4-Thiadiazole Derivatives as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)

by Steven M. Ewell, Hannah Burton and Bereket Mochona

Curr. Issues Mol. Biol. 2024, 46(10), 11220-11235; https://doi.org/10.3390/cimb46100666 - 6 Oct 2024

Abstract

Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead [...] Read more.

Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead compounds with azole moiety exhibiting VEGFR-2 inhibitory effects. A ligand-based pharmacophore model was constructed using the X-ray crystallographic structure of VEGFR-2 complexed with tivozanib (PDB ID: 4ASE) to screen the ZINC15 database. Following virtual screening, six compounds demonstrated promising docking scores and drug-likeness comparable to tivozanib. These hits underwent detailed pharmacokinetic analysis to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Furthermore, Density Functional Theory (DFT) analysis was employed to investigate the molecular orbital properties of the top hits from molecular docking. Molecular dynamics (MD) simulations were conducted to evaluate the conformational stability of the complexes over a 100 ns run. Results indicated that the compounds (ZINC8914312, ZINC8739578, ZINC8927502, and ZINC17138581) exhibited the most promising lead requirements for inhibiting VEGFR-2 and suppressing angiogenesis in cancer therapy. This integrated approach, combining pharmacophore modeling, molecular docking, ADMET studies, DFT analysis, and MD simulations, provides valuable insights into the identification of potential anti-cancer agents targeting VEGFR-2. Full article

(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)

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13 pages, 3017 KiB

Open AccessArticle

Platycladus orientalis Leaf Extract Promotes Hair Growth via Non-Receptor Tyrosine Kinase ACK1 Activation

by Jaeyoon Kim, Jang Ho Joo, Juhyun Kim, Heena Rim, Jae young Shin, Yun-Ho Choi, Kyoungin Min, So Young Lee, Seung-Hyun Jun and Nae-Gyu Kang

Curr. Issues Mol. Biol. 2024, 46(10), 11207-11219; https://doi.org/10.3390/cimb46100665 - 5 Oct 2024

Abstract

Platycladus orientalis is a traditional oriental herbal medicinal plant that is widely used as a component of complex prescriptions for alopecia treatment in Eastern Asia. The effect of PO on hair growth and its underlying mechanism, however, have not been demonstrated or clarified. [...] Read more.

Platycladus orientalis is a traditional oriental herbal medicinal plant that is widely used as a component of complex prescriptions for alopecia treatment in Eastern Asia. The effect of PO on hair growth and its underlying mechanism, however, have not been demonstrated or clarified. In this study, we investigated the hair-growth-promoting effect of PO in cultured human dermal papilla cells (hDPCs). Platycladus orientalis leaf extract (POLE) was found to stimulate the proliferation of hDPCs. POLE with higher quercitrin concentration, especially, showed a high level of cellular viability. In the context of cellular senescence, POLE decreased the expression of p16 (CDKN2A) and p21(CDKN1A), which resulted in enhanced proliferation. In addition, growth factor receptors, FGFR1 and VEGFR2/3, and non-receptor tyrosine kinases, ACK1 and HCK, were significantly activated. In addition, LEF1, a transcription factor of Wnt/β-catenin signaling, was enhanced, but DKK1, an inhibitor of Wnt/β-catenin signaling, was downregulated by POLE treatment in cultured hDPCs. As a consequence, the expression of growth factors such as bFGF, KGF, and VEGF were also increased by POLE. We further investigated the hair-growth-promoting effect of topically administered POLE over a 12-week period. Our data suggest that POLE could support terminal hair growth by stimulating proliferation of DPCs and that enhanced production of growth factors, especially KGF, occurred as a result of tyrosine kinase ACK1 activation. Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products)

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17 pages, 4000 KiB

Open AccessArticle

Protective Effects of Cervus elaphus and Eucommia ulmoides Mixture (KGC01CE) on Muscle Loss and Function in Aged Rats

by Gi-Bang Koo, Han Ol Kwon, Jong Han Kim, Seung Ho Lee, Sung Lye Shim and Kyoung Hwa Jang

Curr. Issues Mol. Biol. 2024, 46(10), 11190-11206; https://doi.org/10.3390/cimb46100664 - 4 Oct 2024

Abstract

Sarcopenia is a condition characterized by a progressive loss of muscle mass and function which are influenced by certain factors such as aging, nutritional deficiencies, and chronic diseases. Despite numerous efforts to prevent or treat sarcopenia, effective therapeutic options for this disease remain [...] Read more.

Sarcopenia is a condition characterized by a progressive loss of muscle mass and function which are influenced by certain factors such as aging, nutritional deficiencies, and chronic diseases. Despite numerous efforts to prevent or treat sarcopenia, effective therapeutic options for this disease remain limited. This study aims to evaluate the effects of KGC01CE treatment, a mixture of Cervus elaphus (Ce) and Eucommia ulmoides (Eu), which are well-known traditional herbal medicines in Asia, on age-related muscle loss and functional decline in aged rats. KGC01CE has been found to be more effective than the individual extracts in inhibiting dexamethasone (DEX)-induced muscle atrophy and improving muscle mass and grip strength in C2C12 cells and aged rats. Moreover, animal studies were conducted to determine the minimum effective dose, and a 12-week oral administration of KGC01CE treatment at doses of 50, 100, and 200 mg/kg to 15-month-old aged rats resulted in a dose-dependent increase in lean mass, muscle mass, grip strength, and muscle cross-sectional area (CSA), which had decreased due to aging. Furthermore, it was shown that KGC01CE activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and inhibited the expression of muscle-degrading proteins MuRF, Atrogin-1, and myostatin. These results suggest that KGC01CE treatment may effectively prevent muscle loss and functional decline, providing a novel therapeutic strategy for sarcopenia. Full article

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

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14 pages, 2309 KiB

Open AccessArticle

GABALAGEN Facilitates Pentobarbital-Induced Sleep by Modulating the Serotonergic System in Rats

by Minsook Ye, Kyoung-min Rheu, Bae-jin Lee and Insop Shim

Curr. Issues Mol. Biol. 2024, 46(10), 11176-11189; https://doi.org/10.3390/cimb46100663 - 4 Oct 2024

Abstract

Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters with beneficial effects including sedative properties. However, despite various clinical trials, scientific evidence regarding the impact on sleep of orally ingested GABA, whether natural or synthesized through biological pathways, is not clear. GABALAGEN (GBL) [...] Read more.

Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters with beneficial effects including sedative properties. However, despite various clinical trials, scientific evidence regarding the impact on sleep of orally ingested GABA, whether natural or synthesized through biological pathways, is not clear. GABALAGEN (GBL) is the product of fermented collagen by Lactobacillus brevis BJ20 (L. brevis BJ20) and Lactobacillus plantarum BJ21 (L. plantarum BJ21), enriched with GABA and characterized by low molecular weight. The aim of this study was to investigate the effect of GBL on sleep improvement via a receptor binding assay in a pentobarbital-induced sleep-related rat model. We utilized a pentobarbital-induced sleep-related rat model to conduct this research. The present study investigated the sedative effects of GBL through electroencephalography (EEG) analysis in the pentobarbital-induced sleep animal model. Exploration of the neural basis of these positive effects involved evaluating orexin in the brain via immunohistochemical methods and 5-HT in the serum using an enzyme-linked immunosorbent assay (ELISA). Furthermore, we conducted a binding assay for 5-HT_2C receptors, as these are considered pivotal targets in the mechanism of action for sleep aids. Diazepam (DZP) was used as a positive control to compare the efficacy of GBL. Results: In the binding assay, GBL displayed binding affinity to the 5-HT_2C receptor (IC50 value, 5.911 µg/mL). Administration of a low dose of GBL (GBL_L; 100 mg/kg) increased non-rapid eye movement sleep time and decreased wake time based on EEG data in pentobarbital-induced rats. Administration of a high dose of GBL (GBL_H; 250 mg/kg) increased non-rapid eye movement sleep time. Additionally, GBL groups significantly increased concentration of the 5-HT level in the serum. GBL_H decreased orexin expression in the lateral hypothalamus. Conclusion: Overall, the sedative effect of GBL may be linked to the activation of serotonergic systems, as indicated by the heightened affinity of the 5-HT_2C receptor binding and elevated levels of 5-HT observed in the serum. This suggests that GBL holds promise as a novel compound for inducing sleep in natural products. Full article

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

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20 pages, 1304 KiB

Open AccessArticle

Quercetin as a Modulator of PTPN22 Phosphomonoesterase Activity: A Biochemical and Computational Evaluation

by Abdulhakeem Olarewaju Sulyman, Tafa Ndagi Akanbi Yusuf, Jamiu Olaseni Aribisala, Kamaldeen Sanni Ibrahim, Emmanuel Oladipo Ajani, Abdulfatai Temitope Ajiboye, Saheed Sabiu and Karishma Singh

Curr. Issues Mol. Biol. 2024, 46(10), 11156-11175; https://doi.org/10.3390/cimb46100662 - 3 Oct 2024

Abstract

Cancer, a group of diseases characterized by uncontrollable cell proliferation and metastasis, remains a global health challenge. This study investigates quercetin, a natural compound found in many fruits and vegetables, for its potential to inhibit the phosphomonoesterase activity of protein tyrosine phosphatase nonreceptor [...] Read more.

Cancer, a group of diseases characterized by uncontrollable cell proliferation and metastasis, remains a global health challenge. This study investigates quercetin, a natural compound found in many fruits and vegetables, for its potential to inhibit the phosphomonoesterase activity of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), a key immune response regulator implicated in cancer and autoimmune diseases. We started by screening seven (7) natural compounds against the activities of PTPN22 in vitro. The initial screening identified quercetin with the highest percentage inhibition (81%) among the screened compounds when compared with ursolic acid that has 84%. After the identification of quercetin, we proceeded by investigating the effect of increasing concentrations of the compound on the activity of PTPN22. In vitro studies showed that quercetin inhibited PTPN22 with an IC₅₀ of 29.59 μM, outperforming the reference standard ursolic acid, which had an IC₅₀ of 37.19 μM. Kinetic studies indicated a non-competitive inhibition by quercetin with a Ki of 550 μM. In silico analysis supported these findings, showing quercetin’s better binding affinity (ΔGbind -24.56 kcal/mol) compared to ursolic acid, attributed to its higher reactivity and electron interaction capabilities at PTPN22′s binding pocket. Both quercetin and ursolic acid improved the structural stability of PTPN22 during simulations. These results suggest quercetin’s potential as an anticancer agent, meriting further research. However, in vivo studies and clinical trials are necessary to fully assess its efficacy and safety, and to better understand its mechanisms of action. Full article

(This article belongs to the Special Issue Pharmacological Activities and Mechanisms of Action of Natural Products)

20 pages, 10682 KiB

Open AccessArticle

Comparative Molecular Docking of Apigenin and Luteolin versus Conventional Ligands for TP-53, pRb, APOBEC3H, and HPV-16 E6: Potential Clinical Applications in Preventing Gynecological Malignancies

by Momir Dunjic, Stefano Turini, Lazar Nejkovic, Nenad Sulovic, Sasa Cvetkovic, Marija Dunjic, Katarina Dunjic and Dina Dolovac

Curr. Issues Mol. Biol. 2024, 46(10), 11136-11155; https://doi.org/10.3390/cimb46100661 - 3 Oct 2024

Abstract

This study presents a comparative analysis of molecular docking data, focusing on the binding interactions of the natural compounds apigenin and luteolin with the proteins TP-53, pRb, and APOBEC, in comparison to conventional pharmacological ligands. Advanced bioinformatics techniques were employed to evaluate and [...] Read more.

This study presents a comparative analysis of molecular docking data, focusing on the binding interactions of the natural compounds apigenin and luteolin with the proteins TP-53, pRb, and APOBEC, in comparison to conventional pharmacological ligands. Advanced bioinformatics techniques were employed to evaluate and contrast binding energies, showing that apigenin and luteolin demonstrate significantly higher affinities for TP-53, pRb, and APOBEC, with binding energies of −6.9 kcal/mol and −6.6 kcal/mol, respectively. These values suggest strong potential for therapeutic intervention against HPV-16. Conventional ligands, by comparison, exhibited lower affinities, with energies ranging from −4.5 to −5.5 kcal/mol. Additionally, protein–protein docking simulations were performed to assess the interaction between HPV-16 E6 oncoprotein and tumor suppressors TP-53 and pRb, which revealed high binding energies around −976.7 kcal/mol, indicative of their complex interaction. A conversion formula was applied to translate these protein–protein interaction energies to a comparable scale for non-protein interactions, further underscoring the superior binding potential of apigenin and luteolin. These findings highlight the therapeutic promise of these natural compounds in preventing HPV-16-induced oncogenesis, warranting further experimental validation for clinical applications. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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12 pages, 768 KiB

Open AccessArticle

Enhanced RBD-Specific Antibody Responses and SARS-CoV-2-Relevant T-Cell Activity in Healthcare Workers Following Booster Vaccination

by Lina Souan, Hikmat Abdel-Razeq and Maher A. Sughayer

Curr. Issues Mol. Biol. 2024, 46(10), 11124-11135; https://doi.org/10.3390/cimb46100660 - 2 Oct 2024

Abstract

COVID-19 continues to impact healthcare workers (HCWs), making it crucial to investigate vaccine response rates. This study examined HCWs’ humoral and cellular immunological responses to COVID-19 booster dosages. We enrolled thirty-four vaccinated HCWs. Twelve received a booster. Post-immunization, the participants’ anti-COVID-19 IgG antibodies [...] Read more.

COVID-19 continues to impact healthcare workers (HCWs), making it crucial to investigate vaccine response rates. This study examined HCWs’ humoral and cellular immunological responses to COVID-19 booster dosages. We enrolled thirty-four vaccinated HCWs. Twelve received a booster. Post-immunization, the participants’ anti-COVID-19 IgG antibodies and IFN-γ secretion were assessed. The median second immunization response time was 406.5 days. Eighteen of twenty-two (81.8%) experienced breakthrough infections after the second vaccination, whereas ten out of twelve individuals who received booster doses had breakthrough infections (83.3%). Six of thirty-four HCWs (17.6%) had no breakthrough infections. Booster-injection recipients had a median antibody titer of 19,592 AU/mL, compared to 7513.55 AU/mL. HCWs with breakthrough infections exhibited a median antibody titer of 13,271.9 AU/mL, compared to 7770.65 AU/mL for those without infections. Breakthrough-infection and booster-injection groups had a slightly higher median T-cell response to antigens 1, 2, and 3. SARS-CoV-2 antibody titer and T-cell responsiveness were positively associated. HCWs sustain cellular and humoral immunity for over 10 months. Irrespective of the type of vaccine, booster injections enhance these immune responses. The results of our research are consistent with previous studies, and a multicenter investigation could validate the findings. Full article

(This article belongs to the Special Issue Molecular Research in Vaccinology and Vaccine Development)

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38 pages, 11513 KiB

Open AccessReview

Use of CRISPR Technology in Gene Editing for Tolerance to Biotic Factors in Plants: A Systematic Review

by Marcelly Santana Mascarenhas, Fernanda dos Santos Nascimento, Anelita de Jesus Rocha, Mileide dos Santos Ferreira, Wanderley Diaciso dos Santos Oliveira, Lucymeire Souza Morais Lino, Tiago Antônio de Oliveira Mendes, Claudia Fortes Ferreira, Janay Almeida dos Santos-Serejo and Edson Perito Amorim

Curr. Issues Mol. Biol. 2024, 46(10), 11086-11123; https://doi.org/10.3390/cimb46100659 - 2 Oct 2024

Abstract

The objective of this systematic review (SR) was to select studies on the use of gene editing by CRISPR technology related to plant resistance to biotic stresses. We sought to evaluate articles deposited in six electronic databases, using pre-defined inclusion and exclusion criteria. [...] Read more.

The objective of this systematic review (SR) was to select studies on the use of gene editing by CRISPR technology related to plant resistance to biotic stresses. We sought to evaluate articles deposited in six electronic databases, using pre-defined inclusion and exclusion criteria. This SR demonstrates that countries such as China and the United States of America stand out in studies with CRISPR/Cas. Among the most studied crops are rice, tomatoes and the model plant Arabidopsis thaliana. The most cited biotic agents include the genera, Xanthomonas, Manaporthe, Pseudomonas and Phytophthora. This SR also identifies several CRISPR/Cas-edited genes and demonstrates that plant responses to stressors are mediated by many complex signaling pathways. The Cas9 enzyme is used in most articles and Cas12 and 13 are used as additional editing tools. Furthermore, the quality of the articles included in this SR was validated by a risk of bias analysis. The information collected in this SR helps to understand the state of the art of CRISPR/Cas aimed at improving resistance to diseases and pests to understand the mechanisms involved in most host–pathogen relationships. This SR shows that the CRISPR/Cas system provides a straightforward method for rapid gene targeting, providing useful information for plant breeding programs. Full article

(This article belongs to the Special Issue Molecular Biology of Plant Genomics and Genetics)

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