Current Issues in Molecular Biology

19 pages, 6970 KiB

Open AccessArticle

Wound Healing, Metabolite Profiling, and In Silico Studies of Aspergillus terreus

by Amal A. Al Mousa, Mohamed E. Abouelela, Ahmed Mansour, Mohamed Nasr, Yasser H. Ali, Nadaa S. Al Ghamidi, Youssef Abo-Dahab, Hassan Mohamed, Nageh F. Abo-Dahab and Abdallah M. A. Hassane

Curr. Issues Mol. Biol. 2024, 46(10), 11681-11699; https://doi.org/10.3390/cimb46100694 (registering DOI) - 19 Oct 2024

Abstract

Burn injuries, which significantly affect global public health, require effective treatment strategies tailored to varying severity. Fungi are considered a sustainable, easily propagated source for lead therapeutic discovery. In this study, we explored the burn wound healing potential of Aspergillus terreus through a [...] Read more.

Burn injuries, which significantly affect global public health, require effective treatment strategies tailored to varying severity. Fungi are considered a sustainable, easily propagated source for lead therapeutic discovery. In this study, we explored the burn wound healing potential of Aspergillus terreus through a combination of in vitro, in vivo, metabolite profiling, and in silico analysis. The in vitro scratch assays performed with human skin fibroblast cells showed promising wound healing activity. Furthermore, the burn-induced rats model showed a marked improvement in cutaneous wound healing, evidenced by an accelerated rate of wound closure and better skin regeneration after A. terreus extract treatment at 14 days. The results of this study demonstrated significant enhancements in wound closure and tissue regeneration in the treated rat model, surpassing the outcomes of standard treatments. This controlled healing process, evidenced by superior collagen synthesis and angiogenesis and confirmed by histopathological studies, suggests that A. terreus has potential beyond the traditionally studied fungal metabolites. The metabolite profiling of 27 bioactive compounds was further investigated by docking analysis for the potential inhibition of the NF-κB pathway, which has an important function in inflammation and wound repair. The compounds eurobenzophenone A (7), aspernolide D (16), asperphenalenone A (23), aspergilate D (15), kodaistatin A (18), and versicolactone A (14) showed the highest binding affinity to the target protein with a pose score of −16.86, −14.65, −12.65, −12.45, −12.19, and −12.08 kcal/mol, respectively. Drug-likeness properties were also conducted. The findings suggest the potential wound healing properties of A. terreus as a source for lead therapeutic candidate discovery. Full article

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

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13 pages, 812 KiB

Open AccessArticle

Exploring the Gene Expression and Plasma Protein Levels of HSP90, HSP60, and GDNF in Multiple Sclerosis Patients and Healthy Controls

by Igor Sokolowski, Aleksandra Kucharska-Lusina, Elzbieta Miller, Tomasz Poplawski and Ireneusz Majsterek

Curr. Issues Mol. Biol. 2024, 46(10), 11668-11680; https://doi.org/10.3390/cimb46100693 (registering DOI) - 19 Oct 2024

Abstract

Abstract: Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by immune-mediated inflammation and neurodegeneration in the central nervous system (CNS). In this study; we aimed to investigate the gene expression and plasma protein levels of three neuroprotective genes—heat shock proteins (HSP90 and [...] Read more.

Abstract: Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by immune-mediated inflammation and neurodegeneration in the central nervous system (CNS). In this study; we aimed to investigate the gene expression and plasma protein levels of three neuroprotective genes—heat shock proteins (HSP90 and HSP60) and glial cell line-derived neurotrophic factor (GDNF)—in MS patients compared to healthy controls. Forty patients with relapsing-remitting MS and 40 healthy volunteers participated in this study. Gene expression was measured using reverse transcription quantitative real-time PCR, and protein levels were assessed via ELISA. The results showed a significant increase in HSP90 (1.7-fold) and HSP60 (2-fold) gene expression in MS patients compared to controls, along with corresponding increases in protein levels (1.5-fold for both HSP90 and HSP60). In contrast, GDNF gene expression and protein levels were significantly reduced in MS patients, with a 7-fold decrease in gene expression and a 1.6-fold reduction in protein levels. Notably, a non-linear relationship between GDNF gene expression and protein concentration was observed in MS patients, suggesting complex regulatory mechanisms influencing GDNF in the disease. The upregulation of HSP90 and HSP60 in MS highlights their roles in immune regulation and stress responses, while the reduction in GDNF indicates impaired neuroprotection. These findings suggest that HSP90, HSP60, and GDNF could serve as biomarkers for disease progression and as potential therapeutic targets in MS, offering promising avenues for future research and treatment development. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Demyelinating Disorders and Remyelination Strategies of the CNS)

3 pages, 178 KiB

Open AccessEditorial

Exploring the Frontiers of Neuroinflammation: New Horizons in Research and Treatment

by Giovanna Rigillo and Silvia Alboni

Curr. Issues Mol. Biol. 2024, 46(10), 11665-11667; https://doi.org/10.3390/cimb46100692 (registering DOI) - 19 Oct 2024

Abstract

The Special Issue “Advanced Research in Neuroinflammation” offers a rich and diverse collection of studies that deepen our understanding of how inflammatory mediators are involved in various neurological conditions [...] Full article

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

19 pages, 2028 KiB

Open AccessReview

Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches

by Jinuk Kim and Chulwon Choi

Curr. Issues Mol. Biol. 2024, 46(10), 11646-11664; https://doi.org/10.3390/cimb46100691 (registering DOI) - 19 Oct 2024

Abstract

Neurodegenerative disorders, particularly Alzheimer’s and Parkinson’s diseases, continue to challenge modern medicine despite therapeutic advances. Orphan G-protein-coupled receptors (GPCRs) have emerged as promising targets in the central nervous system, offering new avenues for drug development. This review focuses on the structural biology of [...] Read more.

Neurodegenerative disorders, particularly Alzheimer’s and Parkinson’s diseases, continue to challenge modern medicine despite therapeutic advances. Orphan G-protein-coupled receptors (GPCRs) have emerged as promising targets in the central nervous system, offering new avenues for drug development. This review focuses on the structural biology of orphan GPCRs implicated in these disorders, providing a comprehensive analysis of their molecular architecture and functional mechanisms. We examine recent breakthroughs in structural determination techniques, such as cryo-electron microscopy and X-ray crystallography, which have elucidated the intricate conformations of these receptors. The review highlights how structural insights inform our understanding of orphan GPCR activation, ligand binding and signaling pathways. By integrating structural data with molecular pharmacology, we explore the potential of structure-guided approaches in developing targeted therapeutics toward orphan GPCRs. This structural-biology-centered perspective aims to deepen our comprehension of orphan GPCRs and guide future drug discovery efforts in neurodegenerative disorders. Full article

(This article belongs to the Special Issue Network Pharmacology, Multi-targets and Receptor–Receptor Interactions in the CNS)

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16 pages, 2086 KiB

Open AccessArticle

Homosalate and ERK Knockdown in the Modulation of Aurelia coerulea Metamorphosis by Regulating the PI3K Pathway and ERK Pathway

by Jinhong Chen, Xiaoyu Geng, Bingbing Li, Jinyao Xie, Jieying Ma, Zhen Qin, Mingke Wang and Jishun Yang

Curr. Issues Mol. Biol. 2024, 46(10), 11630-11645; https://doi.org/10.3390/cimb46100690 - 18 Oct 2024

Viewed by 180

Abstract

Metamorphosis control is pivotal in preventing the outbreak of jellyfish, and it is often studied using common model organisms. The widespread use of the ultraviolet blocking agent homosalate in cosmetics poses a threat to marine ecosystems. Although the impact of homosalate on marine [...] Read more.

Metamorphosis control is pivotal in preventing the outbreak of jellyfish, and it is often studied using common model organisms. The widespread use of the ultraviolet blocking agent homosalate in cosmetics poses a threat to marine ecosystems. Although the impact of homosalate on marine organisms has been extensively examined, there is a notable absence of research on its effects on jellyfish metamorphosis and the underlying mechanisms, warranting further investigation. In this study, we first established a study model by using 5-methoxy-2-methylindole to induce Aurelia coerulea metamorphosis, and selected homosalate as a PI3K agonist and an ERK agonist, while we used YS-49 as a specific PI3K agonist, as well as ERK knockdown, to observe their effect on the metamorphosis of Aurelia coerulea. The results showed that an Aurelia coerulea metamorphosis model was established successfully, and the PI3K agonist homosalate, YS-49, and the knockdown of ERK molecules could significantly delay the metamorphosis development of Aurelia coerulea. We propose that activating PI3K/Akt and inhibiting the ERK pathway are involved in the delayed development of Aurelia coerulea, which provides a new strategy for the prevention and control of jellyfish blooms. Full article

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

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17 pages, 1815 KiB

Open AccessArticle

Decoding the Genetic Basis of Mast Cell Hypersensitivity and Infection Risk in Hypermobile Ehlers-Danlos Syndrome

by Purusha Shirvani, Arash Shirvani and Michael F. Holick

Curr. Issues Mol. Biol. 2024, 46(10), 11613-11629; https://doi.org/10.3390/cimb46100689 - 17 Oct 2024

Viewed by 347

Abstract

Hypermobile Ehlers-Danlos syndrome (hEDS) is a connective tissue disorder marked by joint hypermobility, skin hyperextensibility, and tissue fragility. Recent studies have linked hEDS with mast cell activation syndrome (MCAS), suggesting a genetic interplay affecting immune regulation and infection susceptibility. This study aims to [...] Read more.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a connective tissue disorder marked by joint hypermobility, skin hyperextensibility, and tissue fragility. Recent studies have linked hEDS with mast cell activation syndrome (MCAS), suggesting a genetic interplay affecting immune regulation and infection susceptibility. This study aims to decode the genetic basis of mast cell hypersensitivity and increased infection risk in hEDS by identifying specific genetic variants associated with these conditions. We conducted whole-genome sequencing (WGS) on 18 hEDS participants and 7 first-degree relatives as controls, focusing on identifying genetic variants associated with mast cell dysregulation. Participants underwent clinical assessments to document hEDS symptoms and mast cell hypersensitivity, with particular attention to past infections and antihistamine response. Our analysis identified specific genetic variants in MT-CYB, HTT, MUC3A, HLA-B and HLA-DRB1, which are implicated in hEDS and MCAS. Protein–protein interaction (PPI) network analysis revealed significant interactions among identified variants, highlighting their involvement in pathways related to antigen processing, mucosal protection, and collagen synthesis. Notably, 61.1% of the hEDS cohort reported recurrent infections compared to 28.5% in controls, and 72.2% had documented mast cell hypersensitivity versus 14.2% in controls. These findings provide a plausible explanation for the complex interplay between connective tissue abnormalities and immune dysregulation in hEDS. The identified genetic variants offer insights into potential therapeutic targets for modulating mast cell activity and improving patient outcomes. Future research should validate these findings in larger cohorts and explore the functional implications of these variants to develop effective treatment strategies for hEDS and related mast cell disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Allergy and Immune Diseases, Immunodeficiencies, 2nd Edition)

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20 pages, 5135 KiB

Open AccessArticle

Whole-Genome Sequencing of the Entomopathogenic Fungus Fusarium solani KMZW-1 and Its Efficacy Against Bactrocera dorsalis

by Junfu Yu, Mehboob Hussain, Mingqi Wu, Chunlan Shi, Shini Li, Yuanxia Ji, Sikandar Hussain, Deqiang Qin, Chun Xiao and Guoxing Wu

Curr. Issues Mol. Biol. 2024, 46(10), 11593-11612; https://doi.org/10.3390/cimb46100688 - 17 Oct 2024

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Abstract

Fusarium solani KMZW-1 is recognized for its potential as a biocontrol agent against agricultural and forestry pests, particularly due to its compatibility with integrated pest management (IPM) strategies. This study aimed to investigate the complete genome of F. solani KMZW-1 and assess its pathogenicity [...] Read more.

Fusarium solani KMZW-1 is recognized for its potential as a biocontrol agent against agricultural and forestry pests, particularly due to its compatibility with integrated pest management (IPM) strategies. This study aimed to investigate the complete genome of F. solani KMZW-1 and assess its pathogenicity against Bactrocera dorsalis. Whole-genome sequencing revealed a genome size of 47,239,278 bp, comprising 27 contigs, with a GC content of 51.16% and fungus identified as F. solani KMZW-1. The genome completeness was assessed as 97.93% using BUSCO analysis, the DFVF sequence identifier was Fusarium 0G092560.1, and AntiSMASH analysis identified 35 gene clusters associated with secondary metabolite biosynthesis, providing insights into the genetic basis of its pathogenic mechanisms and biocontrol potential. Comparative genomic analysis found 269 unique genes for F. solani KMZW-1, and collinearity analysis exhibited a high degree of synteny with Fusarium solani-melongenae. The pathogenicity of F. solani KMZW-1 was assessed using concentrations ranging from 1 × 10⁴ to 1 × 10¹¹ conidia/mL. Higher concentrations (1 × 10¹⁰ to 1 × 10¹¹ conidia/mL) resulted in significantly increased cumulative mortality rates of B. dorsalis adults compared to the control group. Notably, the pathogenicity was higher in male adults than in females. Probit analysis yielded LC₅₀ (50% lethal concentration) values of 5.662 for female and 4.486 for male B. dorsalis adults. In summary, F. solani, KMZW-1 exhibits strong insecticidal activity against B. dorsalis and shows potential as a biocontrol agent with IPM strategies. These findings provide robust genomic evidence supporting the use of F. solani KMZW-1 in managing against B. dorsalis populations. Full article

(This article belongs to the Section Molecular Plant Sciences)

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13 pages, 2109 KiB

Open AccessArticle

The Effects of Warm Acupuncture on the Expression of AMPK in High-Fat Diet-Induced MAFLD Rats

by Yumi Lee, Donghee Choi, Junghye Park, Jae Gwan Kim, Taejin Choi and Daehwan Youn

Curr. Issues Mol. Biol. 2024, 46(10), 11580-11592; https://doi.org/10.3390/cimb46100687 - 17 Oct 2024

Viewed by 157

Abstract

This study investigated the effects of acupuncture and warm acupuncture on the expression and mechanism of the AMP-activated protein kinase (AMPK) signalling pathway associated with lipid accumulation in the liver tissue of rats with metabolic dysfunction-associated fatty liver disease (MAFLD) induced [...] Read more.

This study investigated the effects of acupuncture and warm acupuncture on the expression and mechanism of the AMP-activated protein kinase (AMPK) signalling pathway associated with lipid accumulation in the liver tissue of rats with metabolic dysfunction-associated fatty liver disease (MAFLD) induced by a high-fat diet. Sprague–Dawley rats were categorised into four groups: control (CON), untreated MAFLD (MAFLD), and two MAFLD groups treated with acupuncture (ACU) and warm acupuncture (WA). The treatment groups underwent 16 application sessions over 8 weeks at the SP9 and BL18 acupoints. We measured the expression levels of AMPK, sterol regulatory element-binding protein1 (SREBP1), acetyl-coenzyme A carboxylase (ACC), peroxisome proliferator-activated receptorα (PPARα), carnitine palmitoyltransferase1 (CPT1), and CPT2. AMPK was activated in both ACU and WA groups. WA downregulated both SREBP1 and ACC expression at the protein level, whereas the acupuncture treatment downregulated SREBP1 expression. Additionally, WA selectively induced the activation of signalling pathways related to AMPK, PPARα, CPT1, and CPT2 at the mRNA level. Histological observations confirmed that fat accumulation was reduced in both the ACU and the WA groups compared to the MAFLD group. The WA treatment-promoted amelioration of HFD-induced MAFLD may be related to the activation of the AMPK/SREBP1/ACC pathway in the liver. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Fatty Liver Disease: From Pathogenesis to Treatment)

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32 pages, 910 KiB

Open AccessReview

Interleukin-12 Delivery Strategies and Advances in Tumor Immunotherapy

by Chunyan Dong, Dejiang Tan, Huimin Sun, Zhuang Li, Linyu Zhang, Yiyang Zheng, Sihan Liu, Yu Zhang and Qing He

Curr. Issues Mol. Biol. 2024, 46(10), 11548-11579; https://doi.org/10.3390/cimb46100686 - 16 Oct 2024

Viewed by 465

Abstract

Interleukin-12 (IL-12) is considered to be a promising cytokine for enhancing an antitumor immune response; however, recombinant IL-12 has shown significant toxicity and limited efficacy in early clinical trials. Recently, many strategies for delivering IL-12 to tumor tissues have been developed, such as [...] Read more.

Interleukin-12 (IL-12) is considered to be a promising cytokine for enhancing an antitumor immune response; however, recombinant IL-12 has shown significant toxicity and limited efficacy in early clinical trials. Recently, many strategies for delivering IL-12 to tumor tissues have been developed, such as modifying IL-12, utilizing viral vectors, non-viral vectors, and cellular vectors. Previous studies have found that the fusion of IL-12 with extracellular matrix proteins, collagen, and immune factors is a way to enhance its therapeutic potential. In addition, studies have demonstrated that viral vectors are a good platform, and a variety of viruses such as oncolytic viruses, adenoviruses, and poxviruses have been used to deliver IL-12—with testing previously conducted in various cancer models. The local expression of IL-12 in tumors based on viral delivery avoids systemic toxicity while inducing effective antitumor immunity and acting synergistically with other therapies without compromising safety. In addition, lipid nanoparticles are currently considered to be the most mature drug delivery system. Moreover, cells are also considered to be drug carriers because they can effectively deliver therapeutic substances to tumors. In this article, we will systematically discuss the anti-tumor effects of IL-12 on its own or in combination with other therapies based on different delivery strategies. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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11 pages, 584 KiB

Open AccessArticle

Association of SLC19A1 Gene Polymorphisms and Its Regulatory miRNAs with Methotrexate Toxicity in Children with Acute Lymphoblastic Leukemia

by Vasiliki Karpa, Kallirhoe Kalinderi, Eleni Gavriilaki, Vasiliki Antari, Emmanuil Hatzipantelis, Theodora Katopodi, Liana Fidani and Athanasios Tragiannidis

Curr. Issues Mol. Biol. 2024, 46(10), 11537-11547; https://doi.org/10.3390/cimb46100685 - 16 Oct 2024

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Abstract

Methotrexate (MTX) is an anti-folate chemotherapeutic agent that is considered to be a gold standard in Acute Lymphoblastic Leukemia (ALL) therapy. Nevertheless, toxicities induced mainly due to high doses of MTX are still a challenge for clinical practice. MTX pharmacogenetics implicate various genes [...] Read more.

Methotrexate (MTX) is an anti-folate chemotherapeutic agent that is considered to be a gold standard in Acute Lymphoblastic Leukemia (ALL) therapy. Nevertheless, toxicities induced mainly due to high doses of MTX are still a challenge for clinical practice. MTX pharmacogenetics implicate various genes as predictors of MTX toxicity, especially those that participate in MTX intake like solute carrier family 19 member 1 (SLC19A1). The aim of the present study was to evaluate the association between SLC19A1 polymorphisms and its regulatory miRNAs with MTX toxicity in children with ALL. A total of 86 children with ALL were included in this study and were all genotyped for rs2838958, rs1051266 and rs1131596 SLC19A1 polymorphisms as well as the rs56292801 polymorphism of miR-5189. Patients were followed up (48, 72 and 96 h) after treatment with MTX in order to evaluate the presence of MTX-associated adverse events. Our results indicate that there is a statistically significant correlation between the rs1131596 SLC19A1 polymorphism and the development of MTX-induced hepatotoxicity (p = 0.03), but there is no significant association between any of the studied polymorphisms and mucositis or other side effects, such as nausea, emesis, diarrhea, neutropenia, skin rash and infections. In addition, when genotype TT of rs1131596 and genotype AA of rs56292801 are both present in a patient then there is a higher risk of developing severe hepatotoxicity (p = 0.0104). Full article

(This article belongs to the Special Issue Molecular Insights and Therapeutic Advances in Hematological Disorders)

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18 pages, 2545 KiB

Open AccessReview

Cardiac Amyloidosis: State-of-the-Art Review in Molecular Pathology

by Cecilia Salzillo, Renato Franco, Andrea Ronchi, Andrea Quaranta and Andrea Marzullo

Curr. Issues Mol. Biol. 2024, 46(10), 11519-11536; https://doi.org/10.3390/cimb46100684 - 16 Oct 2024

Viewed by 218

Abstract

Amyloidosis refers to a group of diseases caused by extracellular deposits of misfolded proteins, which alter tissue function and structure, potentially affecting any organ. The term “amyloid” was introduced in the 19th century and later associated with pathological protein deposits. Amyloid fibrils, which [...] Read more.

Amyloidosis refers to a group of diseases caused by extracellular deposits of misfolded proteins, which alter tissue function and structure, potentially affecting any organ. The term “amyloid” was introduced in the 19th century and later associated with pathological protein deposits. Amyloid fibrils, which are insoluble and resistant to degradation, originate from soluble proteins that undergo misfolding. This process can be triggered by several factors, such as aging, elevated protein concentrations, or pathogenic variants. Amyloid deposits damage organs both by disrupting tissue architecture and through direct cytotoxic effects, leading to conditions such as heart failure. Amyloidosis can be classified into acquired or inherited forms and can be systemic or localized. Diagnosing cardiac amyloidosis is complex and often requires tissue biopsies, which are supported by Congo Red dye staining. In some cases, bisphosphonate bone scans may provide a less invasive diagnostic option. In this state-of-the-art review, we focus on the most common forms of cardiac amyloidosis, from epidemiology to therapy, emphasizing the differences in molecular mechanisms and the importance of pathological diagnosis for appropriate treatment using a multidisciplinary approach. Full article

(This article belongs to the Special Issue A Focus on the Molecular Basis of Cardiovascular Diseases)

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16 pages, 2065 KiB

Open AccessArticle

Investigating the Inhibitory Potential of Flavonoids against Aldose Reductase: Insights from Molecular Docking, Dynamics Simulations, and gmx_MMPBSA Analysis

by Muhammad Yasir, Jinyoung Park, Eun-Taek Han, Jin-Hee Han, Won Sun Park and Wanjoo Chun

Curr. Issues Mol. Biol. 2024, 46(10), 11503-11518; https://doi.org/10.3390/cimb46100683 - 16 Oct 2024

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Abstract

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, with aldose reductase playing a critical role in the pathophysiology of diabetic complications. This study aimed to investigate the efficacy of flavonoid compounds as potential aldose reductase inhibitors using a combination [...] Read more.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, with aldose reductase playing a critical role in the pathophysiology of diabetic complications. This study aimed to investigate the efficacy of flavonoid compounds as potential aldose reductase inhibitors using a combination of molecular docking and molecular dynamics (MD) simulations. The three-dimensional structures of representative flavonoid compounds were obtained from PubChem, minimized, and docked against aldose reductase using Discovery Studio’s CDocker module. The top 10 compounds Daidzein, Quercetin, Kaempferol, Butin, Genistein, Sterubin, Baicalein, Pulchellidin, Wogonin, and Biochanin_A were selected based on their lowest docking energy values for further analysis. Subsequent MD simulations over 100 ns revealed that Daidzein and Quercetin maintained the highest stability, forming multiple conventional hydrogen bonds and strong hydrophobic interactions, consistent with their favorable interaction energies and stable RMSD values. Comparative analysis of hydrogen bond interactions and RMSD profiles underscored the ligand stability. MMPBSA analysis further confirmed the significant binding affinities of Daidzein and Quercetin, highlighting their potential as aldose reductase inhibitors. This study highlights the potential of flavonoids as aldose reductase inhibitors, offering insights into their binding interactions and stability, which could contribute to developing novel therapeutics for DM complications. Full article

(This article belongs to the Special Issue Innovative Strategies and Applications for Drug Discovery)

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43 pages, 1049 KiB

Open AccessReview

A Scoping Review on Hepatoprotective Mechanism of Herbal Preparations through Gut Microbiota Modulation

by Chin Long Poo, Mei Siu Lau, Nur Liana Md Nasir, Nik Aina Syazana Nik Zainuddin, Mohd Rahimi Ashraf Abd Rahman, Siti Khadijah Mustapha Kamal, Norizah Awang and Hussin Muhammad

Curr. Issues Mol. Biol. 2024, 46(10), 11460-11502; https://doi.org/10.3390/cimb46100682 - 16 Oct 2024

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Abstract

Liver diseases cause millions of deaths globally. Current treatments are often limited in effectiveness and availability, driving the search for alternatives. Herbal preparations offer potential hepatoprotective properties. Disrupted gut microbiota is linked to liver disorders. This scoping review aims to explore the effects [...] Read more.

Liver diseases cause millions of deaths globally. Current treatments are often limited in effectiveness and availability, driving the search for alternatives. Herbal preparations offer potential hepatoprotective properties. Disrupted gut microbiota is linked to liver disorders. This scoping review aims to explore the effects of herbal preparations on hepatoprotective mechanisms, particularly in the context of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatic steatosis, with a focus on gut microbiota modulation. A systematic search was performed using predetermined keywords in four electronic databases (PubMed, Scopus, EMBASE, and Web of Science). A total of 55 studies were included for descriptive analysis, covering study characteristics such as disease model, dietary model, animal model, intervention details, comparators, and study outcomes. The findings of this review suggest that the hepatoprotective effects of herbal preparations are closely related to their interactions with the gut microbiota. The hepatoprotective mechanisms of herbal preparations are shown through their effects on the gut microbiota composition, intestinal barrier, and microbial metabolites, which resulted in decreased serum levels of liver enzymes and lipids, improved liver pathology, inhibition of hepatic fatty acid accumulation, suppression of inflammation and oxidative stress, reduced insulin resistance, and altered bile acid metabolism. Full article

(This article belongs to the Special Issue Advances in Molecular Biology Methods in Hepatology Research)

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22 pages, 2160 KiB

Open AccessArticle

A Study of Hydroelectrolytic and Acid–Base Disturbances in MIS-C Patients: A Perspective on Antidiuretic Hormone Secretion

by Carmen Loredana Petrea (Cliveți), Diana-Andreea Ciortea, Iuliana-Laura Candussi, Gabriela Gurău, Nicoleta Mădălina Matei, Simona-Elena Bergheș, Sergiu Ioachim Chirila and Sorin Ion Berbece

Curr. Issues Mol. Biol. 2024, 46(10), 11438-11459; https://doi.org/10.3390/cimb46100681 - 16 Oct 2024

Viewed by 230

Abstract

COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) is a rare autoimmune disorder characterized by a range of polymorphic manifestations, similar to but distinct from other well-known inflammatory syndromes in children. We conducted a retrospective–descriptive study in which we summarized the clinical presentation of, [...] Read more.

COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) is a rare autoimmune disorder characterized by a range of polymorphic manifestations, similar to but distinct from other well-known inflammatory syndromes in children. We conducted a retrospective–descriptive study in which we summarized the clinical presentation of, biomarker variations in, and complications occurring in patients diagnosed with MIS-C, admitted to the Emergency Clinical Hospital for Children “Sf. Ioan”, Galati, between July 2020 and June 2024. A total of 36 children met the MIS-C classification criteria according to the WHO-approved case definitions. A total of 41.7% (n = 15) were male and 58.3% (n = 21) were female. The median age of the study group was 4 years (IQR: 1.75–9.25 years). Surgical involvement was suspected in 16.7% (n = 6) of the patients, while 52.8% (n = 19) required intensive care. Clinically, fever was the most common symptom present in 89% (n = 32) of the cases. Gastrointestinal disorders were also common, with 50% (n = 18) presenting with inappetence, 42% (n = 15) with vomiting, and 39% (n = 14) with abdominal pain from admission, which worsened over time. Paraclinically, all patients exhibited signs of inflammation, and 86.1% (n = 31) had hydroelectrolytic and acid–base imbalances. The median hospital stay was 10 days (IQR: 7–12 days), with a stagnant clinical course in most cases. The inflammatory mechanisms in MIS-C, which can affect the secretion of antidiuretic hormone (ADH), were correlated with hydroelectrolytic disturbances and may lead to severe complications. For this reason, it is imperative to evaluate hydroelectrolytic disorders in the context of MIS-C and use diagnostic and prognostic biomarkers to develop effective therapeutic management strategies, ultimately improving the quality of life of affected children. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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13 pages, 1651 KiB

Open AccessArticle

Impact of Dupilumab on Skin Surface Lipid-RNA Profile in Severe Asthmatic Patients

by Yoshihiko Sato, Hitoshi Sasano, Sumiko Abe, Yuuki Sandhu, Shoko Ueda, Sonoko Harada, Yuki Tanabe, Kyoko Shima, Tetsuya Kuwano, Yuya Uehara, Takayoshi Inoue, Ko Okumura, Kazuhisa Takahashi and Norihiro Harada

Curr. Issues Mol. Biol. 2024, 46(10), 11425-11437; https://doi.org/10.3390/cimb46100680 - 15 Oct 2024

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Abstract

The analysis of skin surface lipid-RNAs (SSL-RNAs) provides a non-invasive method for understanding the molecular pathology of atopic dermatitis (AD), but its relevance to asthma remains uncertain. Although dupilumab, a biologic drug approved for both asthma and AD, has shown efficacy in improving [...] Read more.

The analysis of skin surface lipid-RNAs (SSL-RNAs) provides a non-invasive method for understanding the molecular pathology of atopic dermatitis (AD), but its relevance to asthma remains uncertain. Although dupilumab, a biologic drug approved for both asthma and AD, has shown efficacy in improving symptoms for both conditions, its impact on SSL-RNAs is unclear. This study aimed to investigate the impact of dupilumab treatment on SSL-RNA profiles in patients with severe asthma. An SSL-RNA analysis was performed before and after administering dupilumab to asthma patients requiring this intervention. Skin samples were collected non-invasively from patients before and after one year of dupilumab treatment. Although 26 patients were enrolled, an SSL-RNA analysis was feasible in only 7 due to collection challenges. After dupilumab treatment, improvements were observed in asthma symptoms, exacerbation rates, and lung function parameters. Serum levels of total IgE and periostin decreased. The SSL-RNA analysis revealed the differential expression of 218 genes, indicating significant down-regulation of immune responses, particularly those associated with type 2 inflammation, suggesting potential improvement in epithelial barrier function. Dupilumab treatment may not only impact type 2 inflammation but also facilitate the normalization of the skin. Further studies are necessary to fully explore the potential of SSL-RNA analysis as a non-invasive biomarker for evaluating treatment response in asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Allergy and Immune Diseases, Immunodeficiencies, 2nd Edition)

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31 pages, 2431 KiB

Open AccessArticle

Sympathetic Innervation of Interscapular Brown Adipose Tissue Is Not a Predominant Mediator of Oxytocin-Induced Brown Adipose Tissue Thermogenesis in Female High Fat Diet-Fed Rats

by Andrew D. Dodson, Adam J. Herbertson, Mackenzie K. Honeycutt, Ron Vered, Jared D. Slattery, Matvey Goldberg, Edison Tsui, Tami Wolden-Hanson, James L. Graham, Tomasz A. Wietecha, Kevin D. O’Brien, Peter J. Havel, Carl L. Sikkema, Elaine R. Peskind, Thomas O. Mundinger, Gerald J. Taborsky, Jr. and James E. Blevins

Curr. Issues Mol. Biol. 2024, 46(10), 11394-11424; https://doi.org/10.3390/cimb46100679 - 15 Oct 2024

Viewed by 286

Abstract

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (T_IBAT) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic [...] Read more.

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (T_IBAT) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of T_IBAT and reduction of body weight in DIO rats. We first measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg ≈ 0.5, 0.99, and 4.96 nmol) to stimulate T_IBAT in female HFD-fed rats. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) stimulated T_IBAT similarly between sham rats and denervated rats (p = NS). We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day ≈ 16.1 μg/day) or vehicle infusion to reduce body weight, adiposity and energy intake in female HFD-fed rats (N = 7–8/group). Chronic 4V OT reduced body weight gain (sham: −18.0 ± 4.9 g; denervation: −15.9 ± 3.7 g) and adiposity (sham: −13.9 ± 3.7 g; denervation: −13.6 ± 2.4 g) relative to vehicle treatment (p < 0.05) and these effects were similar between groups (p = NS). These effects were attributed, in part, to reduced energy intake evident during weeks 2 (p < 0.05) and 3 (p < 0.05). To test whether these results translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice (p < 0.05 vs. vehicle). Together, these findings suggest that (1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and (2) the effects of OT to reduce weight gain and adiposity translate to other female mouse models of diet-induced obesity (DIO). Full article

(This article belongs to the Special Issue Current Advances in Oxytocin Research)

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19 pages, 3497 KiB

Open AccessArticle

Genome-Wide Identification and Expression Analysis of the HSF Gene Family in Ammopiptanthus mongolicus

by Shuai Zhao, Jun Qing, Zhiguo Yang, Tian Tian, Yanqiu Yan, Hui Li and Yu’e Bai

Curr. Issues Mol. Biol. 2024, 46(10), 11375-11393; https://doi.org/10.3390/cimb46100678 - 14 Oct 2024

Viewed by 279

Abstract

Ammopiptanthus mongolicus is an ancient remnant species from the Mediterranean displaying characteristics such as high-temperature tolerance, drought resistance, cold resistance, and adaptability to impoverished soil. In the case of high-temperature tolerance, heat shock transcription factors (HSFs) are integral transcriptional regulatory proteins exerting a [...] Read more.

Ammopiptanthus mongolicus is an ancient remnant species from the Mediterranean displaying characteristics such as high-temperature tolerance, drought resistance, cold resistance, and adaptability to impoverished soil. In the case of high-temperature tolerance, heat shock transcription factors (HSFs) are integral transcriptional regulatory proteins exerting a critical role in cellular processes. Despite extensive research on the HSF family across various species, there has been no analysis specifically focused on A. mongolicus. In this study, we identified 24 members of the AmHSF gene family based on the genome database of A. mongolicus, which were unevenly distributed over 9 chromosomes. Phylogenetic analysis showed that these 24 members can be categorized into 5 primary classes consisting of a total of 13 subgroups. Analysis of the physical and chemical properties revealed significant diversity among these proteins. With the exception of the AmHSFB3 protein, which is localized in the cytoplasm, all other AmHSF proteins were found to be situated in the nucleus. Comparison of amino acid sequences revealed that all AmHSF proteins contain a conserved DNA-binding domains structure, and the DNA-binding domains and oligomerization domains of the AmHSF gene exhibit conservation with counterparts across diverse species; we investigated the collinearity of AmHSF genes in relation to those of three other representative species. Through GO enrichment analysis, evidence emerged that AmHSF genes are involved in heat stress responses and may be involved in multiple transcriptional regulatory pathways that coordinate plant growth and stress responses. Finally, through a comprehensive analysis using transcriptome data, we examined the expression levels of 24 AmHSFs under 45 °C. The results revealed significant differences in the expression profiles of AmHSFs at different time intervals during exposure to high temperatures, highlighting their crucial role in responding to heat stress. In summary, these results provide a better understanding of the role and regulatory mechanisms of HSF in the heat stress response of A. mongolicus, meanwhile also establishing a foundation for further exploration of the biological functions of AmHSF in the adversity response of A. mongolicus. Full article

(This article belongs to the Section Molecular Plant Sciences)

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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 - 13 Oct 2024

Viewed by 496

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 - 13 Oct 2024

Viewed by 291

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 - 12 Oct 2024

Viewed by 284

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 - 12 Oct 2024

Viewed by 391

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

Viewed by 381

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

Viewed by 469

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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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

Viewed by 455

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

Viewed by 440

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

Viewed by 418

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

Viewed by 362

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

Viewed by 476

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

Viewed by 657

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

Viewed by 426

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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