Biomolecules

20 pages, 1068 KiB

Open AccessArticle

Endemic Radiation of African Moonfish, Selene dorsalis (Gill 1863), in the Eastern Atlantic: Mitogenomic Characterization and Phylogenetic Implications of Carangids (Teleostei: Carangiformes)

by Emmanuel Ofosu Mireku Ewusi, Soo Rin Lee, Ah Ran Kim, Yunji Go, Hsu Htoo, Sangdeok Chung, Muhammad Hilman Fu’adil Amin, Sapto Andriyono, Hyun-Woo Kim and Shantanu Kundu

Biomolecules 2024, 14(10), 1208; https://doi.org/10.3390/biom14101208 (registering DOI) - 25 Sep 2024

Abstract

This study offers an in-depth analysis of the mitochondrial genome of Selene dorsalis (Gill 1863), a species native to the Eastern Atlantic Ocean. The circular mitochondrial DNA molecule measures 16,541 base pairs and comprises 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, [...] Read more.

This study offers an in-depth analysis of the mitochondrial genome of Selene dorsalis (Gill 1863), a species native to the Eastern Atlantic Ocean. The circular mitochondrial DNA molecule measures 16,541 base pairs and comprises 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA genes, and a control region (CR). The nucleotide composition exhibits a notable adenine-thymine (AT) bias, accounting for 53.13%, which aligns with other species in the Carangidae family. Most PCGs initiate with the ATG codon, with the exception of Cytochrome C oxidase subunit I, which starts with GTG. Analysis of relative synonymous codon usage reveals that leucine and serine are the most prevalent amino acids in the mitochondrial genome of S. dorsalis and its congeners (S. vomer and S. setapinnis). All tRNAs display the typical cloverleaf structure, though tRNA Serine (S1) lacks a dihydrouracil arm. Pairwise comparisons of synonymous and nonsynonymous substitutions for all PCGs yielded values below ‘1’, indicating strong purifying selection. The CR spans 847 bp, representing 5.12% of the mitochondrial genome, and is characterized by high AT content (62.81%). It is situated between tRNA-Pro (TGG) and tRNA-Phe (GAA). The CR contains conserved sequence blocks, with CSB-1 being the longest at 22 bp and CSB-D the shortest at 18 bp. Phylogenetic analysis, using Bayesian and Maximum-likelihood trees constructed from concatenated PCGs across 72 species, successfully differentiates S. dorsalis from other carangids. This study also explores how ocean currents and gyres might influence lineage diversification and parapatric speciation of Selene species between the Atlantic and Pacific Oceans. These results highlight the importance of the mitochondrial genome in elucidating the structural organization and evolutionary dynamics of S. dorsalis and its relatives within marine ecosystems. Full article

14 pages, 8733 KiB

Open AccessArticle

Determining the Effect of Non-Thermal Plasma on the Transmembrane Kinetics of Melittin through Molecular Explorations

by Yanxiu Cui, Tong Zhao, Yanxiong Niu, Xiaolong Wang and Yuantao Zhang

Biomolecules 2024, 14(10), 1207; https://doi.org/10.3390/biom14101207 (registering DOI) - 25 Sep 2024

Abstract

Non-thermal plasma (NTP) synergistic anticancer strategies are a current hotspot of interest at the intersection of plasma biomedicine. Melittin (MEL) has been shown to inhibit cancer in many malignant tumors; however, its clinical application is controversial. Therefore, the transmembrane process and mechanism of [...] Read more.

Non-thermal plasma (NTP) synergistic anticancer strategies are a current hotspot of interest at the intersection of plasma biomedicine. Melittin (MEL) has been shown to inhibit cancer in many malignant tumors; however, its clinical application is controversial. Therefore, the transmembrane process and mechanism of MEL activity in different cell systems were studied and the combination of MEL and NTP was proposed in this paper. The results showed that the electrostatic attraction between MEL and the lipid bilayer contributes to the stable orientation of MEL on the membrane surface. In addition, sialic acid overexpression affects the degree to which MEL binds the membrane system and the stability of the membrane structure. The use of NTP to reduce the dosage of MEL and its related nonspecific cytolysis activity has certain clinical application value. The results of this study provide theoretical support for improving the clinical applicability of MEL and contribute to the further development of plasma biomedicine. Full article

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21 pages, 22151 KiB

Open AccessArticle

Impact of SDF-1 and AMD3100 on Hair Follicle Dynamics in a Chronic Stress Model

by Yinglin Zhao, Wenzi Liang, Zhehui Liu, Xiuwen Chen and Changmin Lin

Biomolecules 2024, 14(10), 1206; https://doi.org/10.3390/biom14101206 (registering DOI) - 25 Sep 2024

Abstract

Chronic stress is a common cause of hair loss, involving inflammatory responses and changes in cellular signaling pathways. This study explores the mechanism of action of the SDF-1/CXCR4 signaling axis in chronic stress-induced hair loss. The research indicates that SDF-1 promotes hair follicle [...] Read more.

Chronic stress is a common cause of hair loss, involving inflammatory responses and changes in cellular signaling pathways. This study explores the mechanism of action of the SDF-1/CXCR4 signaling axis in chronic stress-induced hair loss. The research indicates that SDF-1 promotes hair follicle growth through the PI3K/Akt and JAK/STAT signaling pathways. Transcriptome sequencing analysis was conducted to identify differentially expressed genes in the skin of normal and stressed mice, with key genes SDF-1/CXCR4 selected through machine learning and a protein-protein interaction network established. A chronic stress mouse model was created, with injections of SDF-1 and AMD3100 administered to observe hair growth, weight changes, and behavioral alterations and validate hair follicle activity. Skin SDF-1 concentrations were measured, differentially expressed genes were screened, and pathways were enriched. Activation of the PI3K/Akt and JAK/STAT signaling pathways was assessed, and siRNA technology was used in vitro to inhibit the expression of SDF-1 or CXCR4. SDF-1 promoted hair follicle activity, with the combined injection of SDF-1 and AMD3100 weakening this effect. The activation of the PI3K/Akt and JAK/STAT signaling pathways was observed in the SDF-1 injection group, confirmed by Western blot and immunofluorescence. Silencing SDF-1 through siRNA-mediated inhibition reduced cell proliferation and migration abilities. SDF-1 promotes hair growth in chronic stress mice by activating the PI3K/Akt and JAK/STAT pathways, an effect reversible by AMD3100. The SDF-1/CXCR4 axis may serve as a potential therapeutic target for stress-induced hair loss. Full article

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25 pages, 1779 KiB

Open AccessReview

Myokines May Be the Answer to the Beneficial Immunomodulation of Tailored Exercise—A Narrative Review

by Zheng Lu, Zhuo Wang, Xin-An Zhang and Ke Ning

Biomolecules 2024, 14(10), 1205; https://doi.org/10.3390/biom14101205 (registering DOI) - 25 Sep 2024

Abstract

Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction [...] Read more.

Exercise can regulate the immune function, activate the activity of immune cells, and promote the health of the organism, but the mechanism is not clear. Skeletal muscle is a secretory organ that secretes bioactive substances known as myokines. Exercise promotes skeletal muscle contraction and the expression of myokines including irisin, IL-6, BDNF, etc. Here, we review nine myokines that are regulated by exercise. These myokines have been shown to be associated with immune responses and to regulate the proliferation, differentiation, and maturation of immune cells and enhance their function, thereby serving to improve the health of the organism. The aim of this article is to review the effects of myokines on intrinsic and adaptive immunity and the important role that exercise plays in them. It provides a theoretical basis for exercise to promote health and provides a potential mechanism for the correlation between muscle factor expression and immunity, as well as the involvement of exercise in body immunity. It also provides the possibility to find a suitable exercise training program for immune system diseases. Full article

(This article belongs to the Topic Molecular Mechanisms of Exercise and Healthspan)

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16 pages, 1156 KiB

Open AccessReview

Astrocyte-Mediated Neuroinflammation in Neurological Conditions

by Yanxiang Zhao, Yingying Huang, Ying Cao and Jing Yang

Biomolecules 2024, 14(10), 1204; https://doi.org/10.3390/biom14101204 - 25 Sep 2024

Abstract

Astrocytes are one of the key glial types of the central nervous system (CNS), accounting for over 20% of total glial cells in the brain. Extensive evidence has established their indispensable functions in the maintenance of CNS homeostasis, as well as their broad [...] Read more.

Astrocytes are one of the key glial types of the central nervous system (CNS), accounting for over 20% of total glial cells in the brain. Extensive evidence has established their indispensable functions in the maintenance of CNS homeostasis, as well as their broad involvement in neurological conditions. In particular, astrocytes can participate in various neuroinflammatory processes, e.g., releasing a repertoire of cytokines and chemokines or specific neurotrophic factors, which result in both beneficial and detrimental effects. It has become increasingly clear that such astrocyte-mediated neuroinflammation, together with its complex crosstalk with other glial cells or immune cells, designates neuronal survival and the functional integrity of neurocircuits, thus critically contributing to disease onset and progression. In this review, we focus on the current knowledge of the neuroinflammatory responses of astrocytes, summarizing their common features in neurological conditions. Moreover, we highlight several vital questions for future research that promise novel insights into diagnostic or therapeutic strategies against those debilitating CNS diseases. Full article

(This article belongs to the Special Issue Glial Cross-Talk in Central Nervous System Health and Disease)

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10 pages, 3601 KiB

Open AccessArticle

Insights into VDAC Gating: Room-Temperature X-ray Crystal Structure of mVDAC-1

by Kristofer R. Gonzalez-DeWhitt, Natalia Ermolova, Harrison K. Wang, Doeke R. Hekstra, Thorsten Althoff and Jeff Abramson

Biomolecules 2024, 14(10), 1203; https://doi.org/10.3390/biom14101203 - 24 Sep 2024

Abstract

The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study [...] Read more.

The voltage-dependent anion channel (VDAC) is a crucial mitochondrial protein that facilitates ion and metabolite exchange between mitochondria and the cytosol. Initially characterized over three decades ago, the structure of VDAC-1 was resolved in 2008, revealing a novel β-barrel protein architecture. This study presents the first room-temperature crystal structure of mouse VDAC-1 (mVDAC-1), which is a significant step toward understanding the channel’s gating mechanism. The new structure, obtained at a 3.3 Å resolution, demonstrates notable differences from the previously determined cryogenic structure, particularly in the loop regions, which may be critical for the transition between the ‘open’ and ‘closed’ states of VDAC-1. Comparative analysis of the root-mean-square deviation (R.M.S.D.) and B-factors between the cryogenic and room-temperature structures suggests that these conformational differences, although subtle, are important for VDAC’s functional transitions. The application of electric field-stimulated X-ray crystallography (EF-X) is proposed as a future direction to resolve the ‘closed’ state of VDAC-1 by inducing voltage-driven conformational changes in order to elucidate the dynamic gating mechanism of VDAC-1. Our findings have profound implications for understanding the molecular basis of VDAC’s role in mitochondrial function and its regulation under physiological conditions. Full article

(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)

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25 pages, 4623 KiB

Open AccessReview

Targeting Lactate: An Emerging Strategy for Macrophage Regulation in Chronic Inflammation and Cancer

by Rong Jiang, Wen-Jing Ren, Li-Ying Wang, Wei Zhang, Zhi-Hong Jiang and Guo-Yuan Zhu

Biomolecules 2024, 14(10), 1202; https://doi.org/10.3390/biom14101202 - 24 Sep 2024

Abstract

Lactate accumulation and macrophage infiltration are pivotal features of both chronic inflammation and cancer. Lactate, once regarded merely as an aftereffect of glucose metabolism, is now gaining recognition for its burgeoning spectrum of biological roles and immunomodulatory significance. Recent studies have evidenced that [...] Read more.

Lactate accumulation and macrophage infiltration are pivotal features of both chronic inflammation and cancer. Lactate, once regarded merely as an aftereffect of glucose metabolism, is now gaining recognition for its burgeoning spectrum of biological roles and immunomodulatory significance. Recent studies have evidenced that macrophages display divergent immunophenotypes in different diseases, which play a pivotal role in disease management by modulating macrophage polarization within the disease microenvironment. The specific polarization patterns of macrophages in a high-lactate environment and their contribution to the progression of chronic inflammation and cancer remain contentious. This review presents current evidence on the crosstalk of lactate and macrophage in chronic inflammation and cancer. Additionally, we provide an in-depth exploration of the pivotal yet enigmatic mechanisms through which lactate orchestrates disease pathogenesis, thereby offering novel perspectives to the development of targeted therapeutic interventions for chronic inflammation and cancer. Full article

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19 pages, 6051 KiB

Open AccessArticle

Hepatitis B Virus X Protein Induces Reactive Oxygen Species Generation via Activation of p53 in Human Hepatoma Cells

by Seungyeon Kim, Jimin Park, Jiwoo Han and Kyung Lib Jang

Biomolecules 2024, 14(10), 1201; https://doi.org/10.3390/biom14101201 - 24 Sep 2024

Abstract

Hepatitis B virus (HBV), particularly through the HBx protein, induces oxidative stress during liver infections. This study reveals that HBx increases reactive oxygen species (ROS) via two distinct mechanisms. The first mechanism is p53-independent, likely involving mitochondrial dysfunction, as demonstrated by elevated ROS [...] Read more.

Hepatitis B virus (HBV), particularly through the HBx protein, induces oxidative stress during liver infections. This study reveals that HBx increases reactive oxygen species (ROS) via two distinct mechanisms. The first mechanism is p53-independent, likely involving mitochondrial dysfunction, as demonstrated by elevated ROS levels in p53-deficient Hep3B cells and p53-knocked-down HepG2 cells after HBx expression or HBV infection. The increase in ROS persisted even when p53 transcriptional activity was inhibited by pifithrin-α (PFT-α), a p53 inhibitor. The second mechanism is p53-dependent, wherein HBx activates p53, which then amplifies ROS production through a feedback loop involving ROS and p53. The ability of HBx to elevate ROS levels was higher in HepG2 than in Hep3B cells. Knocking down p53 in HepG2 cells lowered ROS levels, while ectopic p53 expression in Hep3B cells raised ROS. HBx-activated p53 downregulated catalase and upregulated manganese-dependent superoxide dismutase, contributing to ROS amplification. The transcriptional activity of p53 was crucial for these effects, as cells with a p53 R175H mutation or those treated with PFT-α generated less ROS. Additionally, HBx variants with Ser-101 increased p53 and ROS levels, whereas variants with Pro-101 did not. These dual mechanisms of HBx-induced ROS generation are likely significant in the pathogenesis of HBV and may contribute to liver diseases, including hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Advances in p53 Research 2024)

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19 pages, 1779 KiB

Open AccessReview

A Deep Dive into the N-Terminus of STIM Proteins: Structure–Function Analysis and Evolutionary Significance of the Functional Domains

by Sasirekha Narayanasamy, Hwei Ling Ong and Indu S. Ambudkar

Biomolecules 2024, 14(10), 1200; https://doi.org/10.3390/biom14101200 - 24 Sep 2024

Abstract

Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca²⁺ levels ([Ca²⁺]_i) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai [...] Read more.

Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca²⁺ levels ([Ca²⁺]_i) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai proteins play important roles in maintaining [Ca²⁺]_i through store-operated Ca²⁺ entry (SOCE), with STIM being the primary regulatory protein that governs the function of Orai channels. STIM1 and STIM2 are single-pass ER-transmembrane proteins with their N- and C-termini located in the ER lumen and cytoplasm, respectively. The N-terminal EF-SAM domain of STIMs senses [Ca²⁺]_ER changes, while the C-terminus mediates clustering in ER-PM junctions and gating of Orai1. ER-Ca²⁺ store depletion triggers activation of the STIM proteins, which involves their multimerization and clustering in ER-PM junctions, where they recruit and activate Orai1 channels. In this review, we will discuss the structure, organization, and function of EF-hand motifs and the SAM domain of STIM proteins in relation to those of other eukaryotic proteins. Full article

(This article belongs to the Special Issue Role of STIM and Orai in Calcium Signaling)

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4 pages, 2506 KiB

Open AccessCorrection

Correction: Geng et al. Intracellular Delivery of DNA and Protein by a Novel Cell-Permeable Peptide Derived from DOT1L. Biomolecules 2020, 10, 217

by Jingping Geng, Xiangli Guo, Lidan Wang, Richard Q. Nguyen, Fengqin Wang, Changbai Liu and Hu Wang

Biomolecules 2024, 14(10), 1199; https://doi.org/10.3390/biom14101199 - 24 Sep 2024

Abstract

In the original article [...] Full article

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11 pages, 1054 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel Imidazole Derivatives as Antimicrobial Agents

by Huda A. Al-Ghamdi, Fahad A. Almughem, Manal A. Alshabibi, Abrar A. Bakr, Abdullah A. Alshehri, Alhassan H. Aodah, Nourah A. Al Zahrani, Essam A. Tawfik and Laila A. Damiati

Biomolecules 2024, 14(9), 1198; https://doi.org/10.3390/biom14091198 - 23 Sep 2024

Abstract

Imidazole derivatives are considered potential chemical compounds that could be therapeutically effective against several harmful pathogenic microbes. The chemical structure of imidazole, with a five-membered heterocycle, three carbon atoms, and two double bonds, tends to show antibacterial activities. In the present study, novel [...] Read more.

Imidazole derivatives are considered potential chemical compounds that could be therapeutically effective against several harmful pathogenic microbes. The chemical structure of imidazole, with a five-membered heterocycle, three carbon atoms, and two double bonds, tends to show antibacterial activities. In the present study, novel imidazole derivatives were designed and synthesized to be evaluated as antimicrobial agents owing to the low number of attempts to discover new antimicrobial agents and the emerging cases of antimicrobial resistance. Two imidazole compounds were prepared and evaluated as promising candidates regarding in vitro cytotoxicity against human skin fibroblast cells and antimicrobial activity against several bacterial strains. The synthesized imidazole derivatives were chemically identified using nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR). The results demonstrated a relatively high cell viability of one of the imidazole derivatives, i.e., HL2, upon 24 and 48 h cell exposure. Both derivatives were able to inhibit the growth of the tested bacterial strains. This study provides valuable insight into the potential application of imidazole derivatives for treating microbial infections; however, further in vitro and in vivo studies are required to confirm their safety and effectiveness. Full article

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12 pages, 2297 KiB

Open AccessBrief Report

Enhanced Anticancer Activity of 7MeERT over Ertredin: A Comparative Study on Cancer Cell Proliferation and NDUFA12 Binding

by Sonoko Atsumi, Chisato Nosaka, Takefumi Onodera, Hayamitsu Adachi, Takumi Watanabe, Manabu Kawada, Masabumi Shibuya, Se In Park and Ho Jeong Kwon

Biomolecules 2024, 14(9), 1197; https://doi.org/10.3390/biom14091197 - 23 Sep 2024

Abstract

We have previously identified Ertredin (3-(2-amino-5-bromophenyl) quinoxalin-2(1H)-one) as a compound that suppresses 3D spheroid formation and tumorigenesis in NIH3T3 cells induced by Epidermal Growth Factor Receptor variant III (EGFRvIII) transduction. One of its targets has been shown to be NDUFA12 (NADH [...] Read more.

We have previously identified Ertredin (3-(2-amino-5-bromophenyl) quinoxalin-2(1H)-one) as a compound that suppresses 3D spheroid formation and tumorigenesis in NIH3T3 cells induced by Epidermal Growth Factor Receptor variant III (EGFRvIII) transduction. One of its targets has been shown to be NDUFA12 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex Subunit 12), a component protein of oxidative phosphorylation complex I. In this report, we compared the growth inhibitory activity of Ertredin with its methylated analogue 7MeERT (3-(2-amino-5-bromophenyl)-7-methylquinoxalin-2(1H)-one) on human cancer cells. 7MeERT induced the inhibition of the proliferation of various cancer cells similarly to Ertredin and showed higher activity in glioblastoma cells, A431 cells overexpressing EGFR (wild type), and multiple myeloma cells. Molecular docking analysis and a Cellular Thermal Shift Assay (CETSA) suggested that 7MeERT binds to NDUFA12 similarly to Ertredin. The binding of 7MeERT and Ertredin to NDUFA12 in glioblastoma was further supported by the inhibition of the oxygen consumption rate. These results suggest that 7MeERT also binds to NDUFA12, inhibits oxidative phosphorylation, and has a higher anti-cancer cell growth inhibitory activity than Ertredin. Full article

(This article belongs to the Special Issue Biomolecules and Their Impact on Biology and Translational Applications: Celebrating the Pioneering Work of Prof. Ho Jeong Kwon)

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16 pages, 2232 KiB

Open AccessArticle

Engineering a Bifunctional Fusion Purine/Pyrimidine Nucleoside Phosphorylase for the Production of Nucleoside Analogs

by Daniel Hormigo, Jon Del Arco, Javier Acosta, Maximilian J. L. J. Fürst and Jesús Fernández-Lucas

Biomolecules 2024, 14(9), 1196; https://doi.org/10.3390/biom14091196 - 23 Sep 2024

Abstract

Nucleoside phosphorylases (NPs) are pivotal enzymes in the salvage pathway, catalyzing the reversible phosphorolysis of nucleosides to produce nucleobases and α-D-ribose 1-phosphate. Due to their efficiency in catalyzing nucleoside synthesis from purine or pyrimidine bases, these enzymes hold significant industrial importance in the [...] Read more.

Nucleoside phosphorylases (NPs) are pivotal enzymes in the salvage pathway, catalyzing the reversible phosphorolysis of nucleosides to produce nucleobases and α-D-ribose 1-phosphate. Due to their efficiency in catalyzing nucleoside synthesis from purine or pyrimidine bases, these enzymes hold significant industrial importance in the production of nucleoside-based drugs. Given that the thermodynamic equilibrium for purine NPs (PNPs) is favorable for nucleoside synthesis—unlike pyrimidine NPs (PyNPs, UP, and TP)—multi-enzymatic systems combining PNPs with PyNPs, UPs, or TPs are commonly employed in the synthesis of nucleoside analogs. In this study, we report the first development of two engineered bifunctional fusion enzymes, created through the genetic fusion of purine nucleoside phosphorylase I (PNP I) and thymidine phosphorylase (TP) from Thermus thermophilus. These fusion constructs, PNP I/TP-His and TP/PNP I-His, provide an innovative one-pot, single-step alternative to traditional multi-enzymatic synthesis approaches. Interestingly, both fusion enzymes retain phosphorolytic activity for both purine and pyrimidine nucleosides, demonstrating significant activity at elevated temperatures (60–90 °C) and within a pH range of 6–8. Additionally, both enzymes exhibit high thermal stability, maintaining approximately 80–100% of their activity when incubated at 60–80 °C over extended periods. Furthermore, the transglycosylation capabilities of the fusion enzymes were explored, demonstrating successful catalysis between purine (2′-deoxy)ribonucleosides and pyrimidine bases, and vice versa. To optimize reaction conditions, the effects of pH and temperature on transglycosylation activity were systematically examined. Finally, as a proof of concept, these fusion enzymes were successfully employed in the synthesis of various purine and pyrimidine ribonucleoside and 2′-deoxyribonucleoside analogs, underscoring their potential as versatile biocatalysts in nucleoside-based drug synthesis. Full article

(This article belongs to the Section Enzymology)

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16 pages, 7408 KiB

Open AccessArticle

Lactate Suppresses Growth of Esophageal Adenocarcinoma Patient-Derived Organoids through Alterations in Tumor NADH/NAD+ Redox State

by Steven H. Su, Yosuke Mitani, Tianxia Li, Uma Sachdeva, Samuel Flashner, Andres Klein-Szanto, Karen J. Dunbar, Julian Abrams, Hiroshi Nakagawa and Joel Gabre

Biomolecules 2024, 14(9), 1195; https://doi.org/10.3390/biom14091195 - 22 Sep 2024

Abstract

Barrett’s esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria [...] Read more.

Barrett’s esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria and an increase of lactate in the tumor microenvironment, as predicted by metabolic modeling. The role of bacterial lactate in EAC is unknown. Here, we utilize patient-derived organoid (PDO) models of EAC and demonstrate that lactate inhibits the growth and proliferation of EAC PDOs through alterations in the tumor NADH/NAD+ redox state. Further RNA sequencing of EAC PDOs identifies ID1 and RSAD2 as potential regulatory molecules crucial in mediating lactate’s ability to suppress glycolysis and proliferation. Gene ontology analysis also identifies the activation of inflammatory and immunological pathways in addition to alterations in the metabolic pathways in EAC PDOs exposed to lactate, suggesting a multi-faceted role for lactate in the pathogenesis of EAC. Full article

(This article belongs to the Section Molecular Medicine)

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20 pages, 2267 KiB

Open AccessReview

SEPT9_i1 and Septin Dynamics in Oncogenesis and Cancer Treatment

by Piotr Jędrzejczak, Kamil Saramowicz, Justyna Kuś, Julia Barczuk, Wioletta Rozpędek-Kamińska, Natalia Siwecka, Grzegorz Galita, Wojciech Wiese and Ireneusz Majsterek

Biomolecules 2024, 14(9), 1194; https://doi.org/10.3390/biom14091194 - 22 Sep 2024

Abstract

Despite significant advancements in the field of oncology, cancers still pose one of the greatest challenges of modern healthcare. Given the cytoskeleton’s pivotal role in regulating mechanisms critical to cancer development, further studies of the cytoskeletal elements could yield new practical applications. Septins [...] Read more.

Despite significant advancements in the field of oncology, cancers still pose one of the greatest challenges of modern healthcare. Given the cytoskeleton’s pivotal role in regulating mechanisms critical to cancer development, further studies of the cytoskeletal elements could yield new practical applications. Septins represent a group of relatively well-conserved GTP-binding proteins that constitute the fourth component of the cytoskeleton. Septin 9 (SEPT9) has been linked to a diverse spectrum of malignancies and appears to be the most notable septin member in that category. SEPT9 constitutes a biomarker of colorectal cancer (CRC) and has been positively correlated with a high clinical stage in breast cancer, cervical cancer, and head and neck squamous cell carcinoma. SEPT9_i1 represents the most extensively studied isoform of SEPT9, which substantially contributes to carcinogenesis, metastasis, and treatment resistance. Nevertheless, the mechanistic basis of SEPT9_i1 oncogenicity remains to be fully elucidated. In this review, we highlight SEPT9’s and SEPT9_i1’s structures and interactions with Hypoxia Inducible Factor α (HIF-1 α) and C-Jun N-Terminal Kinase (JNK), as well as discuss SEPT9_i1’s contribution to aneuploidy, cell invasiveness, and taxane resistance—key phenomena in the progression of malignancies. Finally, we emphasize forchlorfenuron and other septin inhibitors as potential chemotherapeutics and migrastatics. Full article

(This article belongs to the Special Issue Cytoskeleton Structure and Dynamics in Health and Disease)

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17 pages, 5795 KiB

Open AccessArticle

Single-Atom Ce-N-C Nanozyme Ameliorates Type 2 Diabetes Mellitus by Improving Glucose Metabolism Disorders and Reducing Oxidative Stress

by Yitong Lin, Yanan Wang, Qi Zhang, Ruxin Gao, Fei Chang, Boran Li, Kunlun Huang, Nan Cheng and Xiaoyun He

Biomolecules 2024, 14(9), 1193; https://doi.org/10.3390/biom14091193 - 22 Sep 2024

Abstract

Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance [...] Read more.

Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance and contributing to the development of T2DM via several molecular mechanisms. Besides, the reduction in hepatic glycogen synthesis also leads to a decrease in peripheral insulin sensitivity. Thus, reducing oxidative stress and promoting glycogen synthesis are both targets for improving insulin resistance and treating T2DM. The current study aims to investigate the pharmacological effects of single-atom Ce-N-C nanozyme (SACe-N-C) on the improvement of insulin resistance and to elucidate its underlying mechanisms using HFD/STZ-induced C57BL/6J mice and insulin-resistant HepG2 cells. The results indicate that SACe-N-C significantly improves hepatic glycogen synthesis and reduces oxidative stress, as well as pancreatic and liver injury. Specifically, compared to the T2DM model group, fasting blood glucose decreased by 29%, hepatic glycogen synthesis increased by 17.13%, and insulin secretion increased by 18.87%. The sod and GPx in the liver increased by 17.80% and 25.28%, respectively. In terms of mechanism, SACe-N-C modulated glycogen synthesis through the PI3K/AKT/GSK3β signaling pathway and activated the Keap1/Nrf2 pathway to alleviate oxidative stress. Collectively, this study suggests that SACe-N-C has the potential to treat T2DM. Full article

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20 pages, 2585 KiB

Open AccessReview

Significance of Necroptosis in Cartilage Degeneration

by Md Abdul Khaleque, Jea-Hoon Kim, Md Amit Hasan Tanvir, Jong-Beom Park and Young-Yul Kim

Biomolecules 2024, 14(9), 1192; https://doi.org/10.3390/biom14091192 - 21 Sep 2024

Abstract

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue [...] Read more.

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue damage. Key mediators such as receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3(RIPK3), and mixed lineage kinase domain-like (MLKL) are pivotal in this process. Studies reveal necroptosis contributes significantly to OA and RA pathophysiology, where elevated RIPK3 and associated proteins drive cartilage degradation. Targeting necroptotic pathways shows promise; inhibitors like Necrostatin-1 (Nec-1), GSK’872, and Necrosulfonamide (NSA) reduce necroptotic cell death, offering potential therapeutic avenues. Additionally, autophagy’s role in mitigating necroptosis-induced damage highlights the need for comprehensive strategies addressing multiple pathways. Despite these insights, further research is essential to fully understand necroptosis’ mechanisms and develop effective treatments. This review synthesizes current knowledge on necroptosis in cartilage degeneration, aiming to inform novel therapeutic approaches for OA, RA, and trauma. Full article

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20 pages, 6344 KiB

Open AccessArticle

USP18 Is Associated with PD-L1 Antitumor Immunity and Improved Prognosis in Colorectal Cancer

by Cili Jifu, Linxia Lu, Jiaxin Ding, Mengjun Lv, Jun Xia, Jingtao Wang and Peijun Wang

Biomolecules 2024, 14(9), 1191; https://doi.org/10.3390/biom14091191 - 21 Sep 2024

Abstract

Background: Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to [...] Read more.

Background: Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to targeted immunotherapy. The deubiquitinating enzyme USP18 is known to play an important role in various aspects of the immune response, but its role in tumor immunity in CRC remains unclear. Methods: In this study, multiple online datasets were used to systematically analyze the expression, prognosis, and immunomodulatory role of USP18 in CRC. The effect of USP18 on CRC was assessed via shRNA-mediated knockdown of USP18 expression in combination with CCK-8 and colony formation assays. Finally, molecular docking analysis of USP18/ISG15 and programmed death-ligand 1 (PD-L1) was performed via HDOCK, and an ELISA was used to verify the potential of USP18 to regulate PD-L1. Results: Our study revealed that USP18 expression was significantly elevated in CRC patients and closely related to clinicopathological characteristics. The experimental data indicated that silencing USP18 significantly promoted the proliferation and population-dependent growth of CRC cells. In addition, high USP18 expression was positively correlated with the CRC survival rate and closely associated with tumor-infiltrating CD8+ T cells and natural killer (NK) cells. Interestingly, USP18 was correlated with the expression of various chemokines and immune checkpoint genes. The results of molecular docking simulations suggest that USP18 may act as a novel regulator of PD-L1 and that its deficiency may potentiate the antitumor immune response to PD-L1 blockade immunotherapy in CRC. Conclusions: In summary, USP18 shows great promise for research and clinical application as a potential target for CRC immunotherapy. Full article

(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)

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Open AccessReview

Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets

by Elena Conte, Brigida Boccanegra, Giorgia Dinoi, Michael Pusch, Annamaria De Luca, Antonella Liantonio and Paola Imbrici

Biomolecules 2024, 14(9), 1190; https://doi.org/10.3390/biom14091190 - 21 Sep 2024

Abstract

Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, [...] Read more.

Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation, and is stimulated by various energy sources and hormonal signaling pathways. Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC. Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality. Even though several therapeutic options are available for the treatment of TSC, there is further need for a better understanding of the pathophysiological basis of the neurologic and other manifestations seen in TSC, and for novel therapeutic approaches. This review provides an overview of the main current therapies for TSC and discusses recent studies highlighting the repurposing of approved drugs and the emerging role of novel targets for future drug design. Full article

(This article belongs to the Special Issue Neurological Disorders: From Molecular Mechanisms to Therapy Strategies)

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