International Journal of Molecular Sciences

26 pages, 988 KiB

Open AccessReview

by Adrianna Winnicka, Joanna Brzeszczyńska, Joanna Saluk and Paulina Wigner-Jeziorska

Int. J. Mol. Sci. 2024, 25(19), 10388; https://doi.org/10.3390/ijms251910388 (registering DOI) - 26 Sep 2024

Bladder cancer (BC) is one of the most common malignant neoplasms of the genitourinary system. Traditional BC therapies include chemotherapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multidrug resistance pose serious challenges to the benefits of BC [...] Read more.

Bladder cancer (BC) is one of the most common malignant neoplasms of the genitourinary system. Traditional BC therapies include chemotherapy, targeted therapy, and immunotherapy. However, limitations such as lack of specificity, cytotoxicity, and multidrug resistance pose serious challenges to the benefits of BC therapies. Consequently, current studies focus on the search for new therapeutic solutions. In recent years, there has been a growing interest in using nanotechnology in the treatment of both non-invasive (NMIBC) and invasive bladder cancer (MIBC). Nanotechnology is based on the use of both organic molecules (chitosan, liposomes) and inorganic molecules (superparamagnetic iron oxide nanoparticles) as carriers of active substances. The main aim of such molecules is the targeted transport and prolonged retention of the drug in the target tissue, which increases the therapeutic efficacy of the active substance. This review discusses the numerous types of nanoparticles (including chitosan, polymeric nanoparticles, liposomes, and protein nanoparticles), targeting mechanisms, and approved nanotherapeutics with oncological implications in cancer treatment. We also present nanoformulation applications in phototherapy, gene therapy, and immunotherapy. Moreover, we summarise the current perspectives, advantages, and challenges in clinical translation. Full article

(This article belongs to the Section Molecular Oncology)

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21 pages, 779 KiB

Open AccessReview

The Comparative Oncology of Canine Malignant Melanoma in Targeted Therapy: A Systematic Review of In Vitro Experiments and Animal Model Reports

by Xiaohui He, Yu Gao, Yuqing Deng, Junying He, Ingo Nolte, Hugo Murua Escobar and Feng Yu

Int. J. Mol. Sci. 2024, 25(19), 10387; https://doi.org/10.3390/ijms251910387 (registering DOI) - 26 Sep 2024

Abstract

Canine malignant melanoma (CMM) is highly aggressive and mostly located in the oral cavity. CMM is the predominant type of canine oral malignancy and shows striking homologies with human mucosal melanoma. In comparative oncology, canine oral melanomas (COMs), as spontaneous tumor models, have [...] Read more.

Canine malignant melanoma (CMM) is highly aggressive and mostly located in the oral cavity. CMM is the predominant type of canine oral malignancy and shows striking homologies with human mucosal melanoma. In comparative oncology, canine oral melanomas (COMs), as spontaneous tumor models, have the potential to acquire a unique value as a translational model of rare human melanoma subtypes. This review aims to provide a comprehensive summary of targeted therapies for canine malignant melanoma and to enrich the field of comparative oncology. Following the PRISMA guidelines, a comprehensive literature search was conducted across databases for studies from 1976 to April 2024. Studies were selected based on their relevance to targeted treatments. A total of 30 studies met the inclusion criteria. Based on the treatment approaches, the studies were further categorized into immunotherapies, small molecule signaling inhibitors, indirect kinase inhibitors, and other alternative strategies. Some treatments have been shown to result in stable disease or partial response, accounting for 29% (monoclonal antibody) and 76.5% (micro-RNA therapies) in clinical trials. Moreover, in vitro experiments of small molecule inhibitors, including cell signaling inhibitors and indirect kinase inhibitors, have shown the potential to be an effective treatment option for the development of therapeutic strategies in canine malignant melanoma. The observed response in in vitro experiments of CMM (particularly the oral and certain cutaneous subtypes) to drugs used in the treatment of human melanoma underlines the resemblance to human melanoma, therefore supporting the notion that CMM may be a valuable model for understanding rare human melanoma subtypes and exploring potential therapeutic avenues in preclinical trials. Finally, this literature review serves as a valuable resource for the development of therapeutic strategies for CMM and highlights the potential for translating these findings to human cancer treatment. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)

32 pages, 1933 KiB

Open AccessReview

Biomaterials Mimicking Mechanobiology: A Specific Design for a Specific Biological Application

by Leonardo Donati, Maria Luisa Valicenti, Samuele Giannoni, Francesco Morena and Sabata Martino

Int. J. Mol. Sci. 2024, 25(19), 10386; https://doi.org/10.3390/ijms251910386 (registering DOI) - 26 Sep 2024

Abstract

Mechanosensing and mechanotransduction pathways between the Extracellular Matrix (ECM) and cells form the essential crosstalk that regulates cell homeostasis, tissue development, morphology, maintenance, and function. Understanding these mechanisms involves creating an appropriate cell support that elicits signals to guide cellular functions. In this [...] Read more.

Mechanosensing and mechanotransduction pathways between the Extracellular Matrix (ECM) and cells form the essential crosstalk that regulates cell homeostasis, tissue development, morphology, maintenance, and function. Understanding these mechanisms involves creating an appropriate cell support that elicits signals to guide cellular functions. In this context, polymers can serve as ideal molecules for producing biomaterials designed to mimic the characteristics of the ECM, thereby triggering responsive mechanisms that closely resemble those induced by a natural physiological system. The generated specific stimuli depend on the different natural or synthetic origins of the polymers, the chemical composition, the assembly structure, and the physical and surface properties of biomaterials. This review discusses the most widely used polymers and their customization to develop biomaterials with tailored properties. It examines how the characteristics of biomaterials-based polymers can be harnessed to replicate the functions of biological cells, making them suitable for biomedical and biotechnological applications. Full article

(This article belongs to the Section Materials Science)

21 pages, 4561 KiB

Open AccessArticle

Linoleic Acid Induces Metabolic Reprogramming and Inhibits Oxidative and Inflammatory Effects in Keratinocytes Exposed to UVB Radiation

by Carolina Manosalva, Claudio Bahamonde, Franco Soto, Vicente Leal, César Ojeda, Carmen Cortés, Pablo Alarcón and Rafael A. Burgos

Int. J. Mol. Sci. 2024, 25(19), 10385; https://doi.org/10.3390/ijms251910385 - 26 Sep 2024

Abstract

Linoleic acid (LA), the primary ω-6 polyunsaturated fatty acid (PUFA) found in the epidermis, plays a crucial role in preserving the integrity of the skin’s water permeability barrier. Additionally, vegetable oils rich in LA have been shown to notably mitigate ultraviolet (UV) radiation-induced [...] Read more.

Linoleic acid (LA), the primary ω-6 polyunsaturated fatty acid (PUFA) found in the epidermis, plays a crucial role in preserving the integrity of the skin’s water permeability barrier. Additionally, vegetable oils rich in LA have been shown to notably mitigate ultraviolet (UV) radiation-induced effects, including the production of reactive oxygen species (ROS), cellular damage, and skin photoaging. These beneficial effects are primarily ascribed to the LA in these oils. Nonetheless, the precise mechanisms through which LA confers protection against damage induced by exposure to UVB radiation remain unclear. This study aimed to examine whether LA can restore redox and metabolic equilibria and to assess its influence on the inflammatory response triggered by UVB radiation in keratinocytes. Flow cytometry analysis unveiled the capacity of LA to diminish UVB-induced ROS levels in HaCaT cells. GC/MS-based metabolomics highlighted significant metabolic changes, especially in carbohydrate, amino acid, and glutathione (GSH) metabolism, with LA restoring depleted GSH levels post-UVB exposure. LA also upregulated PI3K/Akt-dependent GCLC and GSS expression while downregulating COX-2 expression. These results suggest that LA induces metabolic reprogramming, protecting against UVB-induced oxidative damage by enhancing GSH biosynthesis via PI3K/Akt signaling. Moreover, it suppresses UVB-induced COX-2 expression in HaCaT cells, making LA treatment a promising strategy against UVB-induced oxidative and inflammatory damage. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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22 pages, 920 KiB

Open AccessArticle

Physiologically Achievable Concentration of 2-Deoxy-D-Glucose Stimulates IFN-γ Secretion in Activated T Cells In Vitro

by Jernej Repas, Tjaša Frlic, Tadeja Snedec, Andreja Nataša Kopitar, Harald Sourij, Andrej Janež and Mojca Pavlin

Int. J. Mol. Sci. 2024, 25(19), 10384; https://doi.org/10.3390/ijms251910384 - 26 Sep 2024

Abstract

2-deoxy-D-glucose (2DG) is a glycolysis and protein N-glycosylation inhibitor with promising anti-tumor and immunomodulatory effects. However, 2DG can also suppress T cell function, including IFN-γ secretion. Few human T cell studies have studied low-dose 2DG, which can increase IFN-γ in a Jurkat clone. [...] Read more.

2-deoxy-D-glucose (2DG) is a glycolysis and protein N-glycosylation inhibitor with promising anti-tumor and immunomodulatory effects. However, 2DG can also suppress T cell function, including IFN-γ secretion. Few human T cell studies have studied low-dose 2DG, which can increase IFN-γ in a Jurkat clone. We therefore investigated 2DG’s effect on IFN-γ in activated human T cells from PBMCs, with 2DG treatment commenced either concurrently with activation or 48 h after activation. Concurrent 2DG treatment decreased IFN-γ secretion in a dose-dependent manner. However, 2DG treatment of pre-activated T cells had a hormetic effect on IFN-γ, with 0.15–0.6 mM 2DG (achievable in vivo) increasing and >2.4 mM 2DG reducing its secretion. In contrast, IL-2 levels declined monotonously with increasing 2DG concentration. Lower 2DG concentrations reduced PD-1 and increased CD69 expression regardless of treatment timing. The absence of increased T-bet or Eomes expression or IFNG transcription suggests another downstream mechanism. 2DG dose-dependently induced the unfolded protein response, suggesting a possible role in increased IFN-γ secretion, possibly by increasing the ER folding capacity for IFN-γ via increased chaperone expression. Overall, low-dose, short-term 2DG exposure could potentially improve the T cell anti-tumor response. Full article

(This article belongs to the Special Issue Regulation and Activation of Immune Cells through the Mitochondria)

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19 pages, 729 KiB

Open AccessReview

Refractory Celiac Disease: What the Gastroenterologist Should Know

by Mariana Verdelho Machado

Int. J. Mol. Sci. 2024, 25(19), 10383; https://doi.org/10.3390/ijms251910383 (registering DOI) - 26 Sep 2024

Abstract

Fewer than 1% of patients with celiac disease (CD) will develop refractory CD (RCD). As such, most gastroenterologists might never need to manage patients with RCD. However, all gastroenterologists must be familiarized with the basic concepts of RCD and non-responsive CD (NRCD), since [...] Read more.

Fewer than 1% of patients with celiac disease (CD) will develop refractory CD (RCD). As such, most gastroenterologists might never need to manage patients with RCD. However, all gastroenterologists must be familiarized with the basic concepts of RCD and non-responsive CD (NRCD), since it can present as a severe disease with high mortality, not only due to intestinal failure, but also due to progression to enteropathy-associated T cell lymphoma (EATL) and a higher susceptibility to life-threatening infections. The diagnostic workup and differential diagnosis with other causes of gastrointestinal symptoms and villous atrophy, as well as the differentiation between type I and II RCD, are complex, and may require specialized laboratories and reference hospitals. Immunosuppression is efficient in the milder RCDI; however, the treatment of RCDII falls short, with current options probably only providing transient clinical improvement and delaying EATL development. This review summarizes the current diagnostic and therapeutic approach for patients with RCD that all doctors that manage patients with CD should know. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

16 pages, 1071 KiB

Open AccessArticle

Enhanced Photodynamic Therapy Efficacy through Solid Lipid Nanoparticle of Purpurin-18-N-Propylimide Methyl Ester for Cancer Treatment

by Sooho Yeo, Huiqiang Wu, Il Yoon, Hye-Soo Kim, Young Kyu Song and Woo Kyoung Lee

Int. J. Mol. Sci. 2024, 25(19), 10382; https://doi.org/10.3390/ijms251910382 (registering DOI) - 26 Sep 2024

Abstract

Photodynamic therapy (PDT) is an innovative cancer treatment that utilizes light. When light irradiates, purpurin-18-N-propylimide methyl ester (P18 N PI ME) generates reactive oxygen species that destroy cancer cells. The hydrophobic nature of P18 N PI ME presents challenges regarding its aggregation in [...] Read more.

Photodynamic therapy (PDT) is an innovative cancer treatment that utilizes light. When light irradiates, purpurin-18-N-propylimide methyl ester (P18 N PI ME) generates reactive oxygen species that destroy cancer cells. The hydrophobic nature of P18 N PI ME presents challenges regarding its aggregation in the body, which can affect its effectiveness. This study aimed to enhance the bioavailability and effectiveness of cancer treatment by synthesizing P18 N PI ME and formulating P18 N PI ME-loaded solid lipid nanoparticles (SLNs). The efficacy of PDT was estimated using the 1,3-diphenylisobenzofuran (DPBF) assay and photocytotoxicity tests on the HeLa (human cervical carcinoma) and A549 (human lung carcinoma) cell lines. The P18 N PI ME-loaded SLNs demonstrated particle sizes in the range of 158.59 nm to 248.43 nm and zeta potentials in the range of –15.97 mV to –28.73 mV. These SLNs exhibited sustained release of P18 N PI ME. DPBF analysis revealed enhanced PDT effects with SLNs containing P18 N PI ME compared with standalone P18 N PI MEs. Photocytotoxicity assays indicated toxicity under light irradiation but no toxicity in the dark. Furthermore, the smallest-sized formulation exhibited the most effective photodynamic activity. These findings indicate the potential of P18 N PI ME-loaded SLNs as promising strategies for PDT in cancer therapy. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products)

16 pages, 2817 KiB

Open AccessArticle

Blockade of mTORC1 via Rapamycin Suppresses 27-Hydroxycholestrol-Induced Inflammatory Responses

by Nakyung Kang, Jaesung Kim, Munju Kwon, Yonghae Son, Seong-Kug Eo, Ninib Baryawno, Byoung Soo Kim, Sik Yoon, Sae-Ock Oh, Dongjun Lee and Koanhoi Kim

Int. J. Mol. Sci. 2024, 25(19), 10381; https://doi.org/10.3390/ijms251910381 (registering DOI) - 26 Sep 2024

Abstract

Atherosclerosis is characterized by the deposition and accumulation of extracellular cholesterol and inflammatory cells in the arterial blood vessel walls, and 27-hydroxycholesterol (27OHChol) is the most abundant cholesterol metabolite. 27OHChol is an oxysterol that induces immune responses, including immune cell activation and chemokine [...] Read more.

Atherosclerosis is characterized by the deposition and accumulation of extracellular cholesterol and inflammatory cells in the arterial blood vessel walls, and 27-hydroxycholesterol (27OHChol) is the most abundant cholesterol metabolite. 27OHChol is an oxysterol that induces immune responses, including immune cell activation and chemokine secretion, although the underlying mechanisms are not fully understood. In this study, we investigated the roles of the mechanistic target of rapamycin (mTOR) in 27HChol-induced inflammation using rapamycin. Treating monocytic cells with rapamycin effectively reduced the expression of CCL2 and CD14, which was involved with the increased immune response by 27OHChol. Rapamycin also suppressed the phosphorylation of S6 and 4EBP1, which are downstream of mTORC1. Additionally, it also alleviates the increase in differentiation markers into macrophage. These results suggest that 27OHChol induces inflammation by activating the mTORC1 signaling pathway, and rapamycin may be useful for the treatment of atherosclerosis-related inflammation involving 27OHchol. Full article

(This article belongs to the Section Molecular Biology)

14 pages, 720 KiB

Open AccessReview

A Review of the Tear Film Biomarkers Used to Diagnose Sjogren’s Syndrome

by Jason Peng, David Feinstein, Salvatore DeSimone and Pietro Gentile

Int. J. Mol. Sci. 2024, 25(19), 10380; https://doi.org/10.3390/ijms251910380 (registering DOI) - 26 Sep 2024

Abstract

This literature review looks at Sjogren’s Syndrome (SS), a chronic autoimmune disorder affecting exocrine glands, particularly the lacrimal and salivary glands. SS manifests as ocular and oral dryness, with severe complications like visual dysfunction and corneal perforation, as well as systemic implications, such [...] Read more.

This literature review looks at Sjogren’s Syndrome (SS), a chronic autoimmune disorder affecting exocrine glands, particularly the lacrimal and salivary glands. SS manifests as ocular and oral dryness, with severe complications like visual dysfunction and corneal perforation, as well as systemic implications, such as interstitial lung disease and lymphoma. This review explores the use of tear film biomarkers to diagnose SS, emphasizing the significance of their identification in aiding clinical diagnosis and differentiation from other diseases. This study identified and analyzed 15 papers, encompassing 1142 patients and employing various tear sample collection methods. Tear biomarkers were categorized by function and explored in-depth. Categories include (1) antimicrobials, antivirals, and antifungals; (2) components of immune regulation; (3) components that regulate metabolic processes; and (4) inflammatory markers. Noteworthy findings include the potential diagnostic values of tear lysozyme, lactoferrin, dinucleoside polyphosphates, cathepsin, defensin, antibodies, epidermal fatty acid-binding protein, HLA-DR, ADAM10, aquaporin 5, and various miRNAs and mRNAs. Overall, our understanding of SS tear film composition is enhanced, providing valuable insights into the pathogenesis of SS and offering a foundation for future diagnostic and therapeutic advancements in autoimmune conditions affecting the ocular surface. Full article

(This article belongs to the Section Molecular Immunology)

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16 pages, 3001 KiB

Open AccessArticle

Diabetic Mice Spleen Vulnerability Contributes to Decreased Persistence of Antibody Production after SARS-CoV-2 Vaccine

by Yara Atef, Tomoya Ito, Akitsu Masuda, Yuri Kato, Akiyuki Nishimura, Yasunari Kanda, Jun Kunisawa, Takahiro Kusakabe and Motohiro Nishida

Int. J. Mol. Sci. 2024, 25(19), 10379; https://doi.org/10.3390/ijms251910379 (registering DOI) - 26 Sep 2024

Abstract

During the COVID-19 pandemic, diabetic and obese patients experienced higher rates of hospital admissions, severe illness, and mortality. However, vaccinations failed to provide those vulnerable populations the same level of protection against COVID-19 severity as those without diabetic and obese phenotypes. Our study [...] Read more.

During the COVID-19 pandemic, diabetic and obese patients experienced higher rates of hospital admissions, severe illness, and mortality. However, vaccinations failed to provide those vulnerable populations the same level of protection against COVID-19 severity as those without diabetic and obese phenotypes. Our study aimed to investigate how diabetes mellitus (DM) impacts the immune response following vaccination including the artificially designed trimeric SARS-CoV-2 spike (S)-protein. By using two diabetic mouse models, ob/ob mice (obese, hyperglycemic, and insulin-resistant) and STZ-treated mice (insulin-deficient and hyperglycemic), we observed a significant reduction in S-protein-specific IgG antibody titer post-vaccination in both diabetic models compared to wild-type (WT) mice. Both diabetic mouse models exhibited significant abnormalities in spleen tissue, including marked reductions in splenic weight and the size of the white pulp regions. Furthermore, the splenic T-cell and B-cell zones were notably diminished, suggesting an underlying immune dysfunction that could contribute to impaired antibody production. Notably, vaccination with the S-protein, when paired with an optimal adjuvant, did not exacerbate diabetic cardiomyopathy, blood glucose levels, or liver function, providing reassurance about the vaccine′s safety. These findings offer valuable insights into potential mechanisms responsible for the decreased persistence of antibody production in diabetic patients. Full article

(This article belongs to the Section Molecular Immunology)

19 pages, 4917 KiB

Open AccessArticle

Amino Acid-Based Protein-Mimic Hydrogel Incorporating Pro-Regenerative Lipid Mediator and Microvascular Fragments Promotes the Healing of Deep Burn Wounds

by Yan Lu, Shanchun Su, Chih-Chang Chu, Yuichi Kobayashi, Abdul-Razak Masoud, Hongying Peng, Nathan Lien, Mingyu He, Christopher Vuong, Ryan Tran and Song Hong

Int. J. Mol. Sci. 2024, 25(19), 10378; https://doi.org/10.3390/ijms251910378 (registering DOI) - 26 Sep 2024

Abstract

Pro-regenerative lipid mediator 1 (PreM1) is a specialized pro-resolving lipid mediator that promotes wound healing and regenerative functions of mesenchymal stem cells (MSCs), endothelial cells, and macrophages. The healing of third-degree (3°) burns and regenerative functions of MSCs are enhanced by ACgel1, an [...] Read more.

Pro-regenerative lipid mediator 1 (PreM1) is a specialized pro-resolving lipid mediator that promotes wound healing and regenerative functions of mesenchymal stem cells (MSCs), endothelial cells, and macrophages. The healing of third-degree (3°) burns and regenerative functions of MSCs are enhanced by ACgel1, an arginine-and-chitosan-based protein-mimic hybrid hydrogel. Adipose-tissue derived microvascular fragments (MVFs) are native vascularization units and a rich source of MSCs, endothelial cells, and perivascular cells for tissue regeneration. Here we describe an innovative PreM1-MVFs-ACgel1 construct that incorporated PreM1 and MVFs into ACgel1 via optimal design and fabrication. This construct delivered PreM1 to 3°-burn wounds at least up to 7 days-post-burn (dpb), and scaffolded and delivered MVFs. PreM1-MVFs-ACgel1 promoted the healing of 3°-burns in mice, including vascularization and collagen formation. The re-epithelization and closure of 3° burn wounds were promoted by ACgel1, MVFs, PreM1, MVFs-ACgel1, PreM1-ACgel1, or PreM1-MVFs-ACgel1 at certain time-point(s), while PreM1-MVFs-ACgel1 was most effective with 97% closure and 4.69% relative epithelial gap at 13 dpb compared to saline control. The PreM1-ACgel1 and MVFs-ACgel1 also promoted blood vessel regeneration of 3°-burns although PreM1-MVFs-ACgel1 is significantly more effective. These PreM1- and/or MVF-functionalized ACgel1 have nonexistent or minimal graft-donor requirements and are promising adjuvant therapeutic candidates for treating deep burns. Full article

(This article belongs to the Special Issue Recent Advances in Wound Healing: 2nd Edition)

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23 pages, 2408 KiB

Open AccessReview

Chitosan–Clay Mineral Nanocomposites with Antibacterial Activity for Biomedical Application: Advantages and Future Perspectives

by Danina Krajišnik, Snežana Uskoković-Marković and Aleksandra Daković

Int. J. Mol. Sci. 2024, 25(19), 10377; https://doi.org/10.3390/ijms251910377 (registering DOI) - 26 Sep 2024

Abstract

Polymers of natural origin, such as representatives of various polysaccharides (e.g., cellulose, dextran, hyaluronic acid, gellan gum, etc.), and their derivatives, have a long tradition in biomedical applications. Among them, the use of chitosan as a safe, biocompatible, and environmentally friendly heteropolysaccharide has [...] Read more.

Polymers of natural origin, such as representatives of various polysaccharides (e.g., cellulose, dextran, hyaluronic acid, gellan gum, etc.), and their derivatives, have a long tradition in biomedical applications. Among them, the use of chitosan as a safe, biocompatible, and environmentally friendly heteropolysaccharide has been particularly intensively researched over the last two decades. The potential of using chitosan for medical purposes is reflected in its unique cationic nature, viscosity-increasing and gel-forming ability, non-toxicity in living cells, antimicrobial activity, mucoadhesiveness, biodegradability, as well as the possibility of chemical modification. The intuitive use of clay minerals in the treatment of superficial wounds has been known in traditional medicine for thousands of years. To improve efficacy and overcome the ubiquitous bacterial resistance, the beneficial properties of chitosan have been utilized for the preparation of chitosan–clay mineral bionanocomposites. The focus of this review is on composites containing chitosan with montmorillonite and halloysite as representatives of clay minerals. This review highlights the antibacterial efficacy of chitosan–clay mineral bionanocomposites in drug delivery and in the treatment of topical skin infections and wound healing. Finally, an overview of the preparation, characterization, and possible future perspectives related to the use of these advancing composites for biomedical applications is presented. Full article

(This article belongs to the Special Issue Polymers, Polymer Blends, and Polymeric Drug Release Systems with Antiviral or Antibacterial Effect—2nd Edition)

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14 pages, 3336 KiB

Open AccessArticle

Integration Linkage Mapping and Comparative Transcriptome Analysis to Dissect the Genetic Basis of Rice Salt Tolerance Associated with the Germination Stage

by Leiyue Geng, Tuo Zou, Wei Zhang, Shuo Wang, Yutao Yao, Zhenyu Zheng, Qi Du and Longzhi Han

Int. J. Mol. Sci. 2024, 25(19), 10376; https://doi.org/10.3390/ijms251910376 (registering DOI) - 26 Sep 2024

Abstract

Soil salinity poses a serious threat to rice production. The salt tolerance of rice at the germination stage is one of the major determinants of stable stand establishment, which is very important for direct seeding in saline soil. The complexity and polygenic nature [...] Read more.

Soil salinity poses a serious threat to rice production. The salt tolerance of rice at the germination stage is one of the major determinants of stable stand establishment, which is very important for direct seeding in saline soil. The complexity and polygenic nature of salt tolerance have limited the efficiency of discovering and cloning key genes in rice. In this study, an RIL population with an ultra-high-density genetic map was employed to investigate the salt-tolerant genetic basis in rice, and a total of 20 QTLs were detected, including a major and stable QTL (qRCL3-1). Subsequently, salt-specific DEGs from a comparative transcriptome analysis were overlaid onto annotated genes located on a stable QTL interval, and eight putative candidate genes were further identified. Finally, from the sequence alignment and variant analysis, OsCam1-1 was confirmed to be the most promising candidate gene for regulating salinity tolerance in rice. This study provides important information for elucidating the genetic and molecular basis of rice salt tolerance at the germination stage, and the genes detected here will be useful for improvements in rice salt tolerance. Full article

(This article belongs to the Special Issue Advance in Plant Abiotic Stress: 2nd Edition)

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17 pages, 948 KiB

Open AccessReview

Molecular Mechanisms Affecting Statin Pharmacokinetics after Bariatric Surgery

by Matea Petrinović, Domagoj Majetić, Miro Bakula, Ivan Pećin, Daniela Fabris-Vitković, Marin Deškin, Deša Tešanović Perković, Maja Bakula, Marina Gradišer, Ines Bilić Ćurčić and Silvija Canecki-Varžić

Int. J. Mol. Sci. 2024, 25(19), 10375; https://doi.org/10.3390/ijms251910375 (registering DOI) - 26 Sep 2024

Abstract

According to recent data, one in eight people in the world struggle with obesity. Obesity management is increasingly dependent on bariatric surgical interventions, as the combination of lifestyle modifications and pharmacotherapy could have a modest long-term effect. Surgery is recommended only for individuals [...] Read more.

According to recent data, one in eight people in the world struggle with obesity. Obesity management is increasingly dependent on bariatric surgical interventions, as the combination of lifestyle modifications and pharmacotherapy could have a modest long-term effect. Surgery is recommended only for individuals whose body mass index (BMI) ≥ 40 kg/m² and ≥ 35 kg/m² in the presence of weight-related comorbidities. The most commonly performed procedures are sleeve gastrectomy and roux-en-Y gastric bypass. Pharmacokinetic and pharmacodynamic alterations occur as a result of the anatomical and physiological changes caused by surgery, which further differ depending on physicochemical drug factors and factors related to the dosage form. The following modifications are distinguished based on the type of bariatric surgery performed. Most bariatric patients have accompanying comorbidities, including dyslipidemia treated with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins. Significant improvements in the lipid profile are observed early in the postoperative period. The data reported in this review on statin pharmacokinetic alterations have demonstrated substantial inter- and intravariability, making it difficult to adopt clear guidelines. Based on the current literature review, reducing the statin dose to the lowest effective with continuous monitoring is considered an optimal approach in clinical practice. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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17 pages, 840 KiB

Open AccessArticle

Comprehensive Catalog of Variants Potentially Associated with Hidradenitis Suppurativa, Including Newly Identified Variants from a Cohort of 100 Patients

by Kévin Muret, Vincent Le Goff, Claire Dandine-Roulland, Claire Hotz, Francette Jean-Louis, Bertrand Boisson, Lilia Mesrob, Florian Sandron, Delphine Daian, Robert Olaso, Edith Le Floch, Vincent Meyer, Pierre Wolkenstein, Jean-Laurent Casanova, Yves Lévy, Eric Bonnet, Jean-François Deleuze and Sophie Hüe

Int. J. Mol. Sci. 2024, 25(19), 10374; https://doi.org/10.3390/ijms251910374 (registering DOI) - 26 Sep 2024

Abstract

Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome [...] Read more.

Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the γ-secretase complex that affect Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most reported HS cases do not follow a simple genetic pattern. In this article, we performed whole-exome sequencing (WES) on a cohort of 100 individuals with HS, and we provide a comprehensive review of the variants known to be described or associated with HS. 91 variants were associated with the γ-secretase complex, and 78 variants were associated with other genes involved in the Notch pathway, keratinization, or immune response. Through this new genetic analysis, we have added ten new variants to the existing catalogs. All variants are available in a .vcf file and are provided as a resource for future studies. Full article

(This article belongs to the Special Issue Hidradenitis Suppurativa and Related Disorders)

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11 pages, 1208 KiB

Open AccessArticle

Are BDNF and Stress Levels Related to Antidepressant Response?

by Mónica Flores-Ramos, Andrés Vega-Rosas, Nadia Palomera-Garfias, Ricardo Saracco-Alvarez and Gerardo Bernabé Ramírez-Rodríguez

Int. J. Mol. Sci. 2024, 25(19), 10373; https://doi.org/10.3390/ijms251910373 - 26 Sep 2024

Abstract

Antidepressant response is a multifactorial process related to biological and environmental factors, where brain-derived neurotrophic factor (BDNF) may play an important role in modulating depressive and anxious symptoms. We aimed to analyze how BDNF impacts antidepressant response, considering the levels of anxiety. Methods: [...] Read more.

Antidepressant response is a multifactorial process related to biological and environmental factors, where brain-derived neurotrophic factor (BDNF) may play an important role in modulating depressive and anxious symptoms. We aimed to analyze how BDNF impacts antidepressant response, considering the levels of anxiety. Methods: A total of 40 depressed adults were included. We evaluated initial serum BDNF, anxiety through the State–Trait Anxiety Inventory (STAI), and the severity of depressive symptoms by the Hamilton Depression Rating Scale (HDRS). Participants received antidepressant treatment for 8 weeks, and response to treatment was evaluated according to the final HDRS scores. Results: Basal BDNF was higher in responders compared to non-responder depressed patients, in addition to being inversely associated with the severity of anxiety and depression. Conclusions: Baseline BDNF serum is an adequate predictive factor for response to antidepressant treatment with SSRI, with lower pre-treatment levels of BDNF associated with higher anxiety symptoms after treatment. Stress levels could influence the response to treatment, but its association was not conclusive. Full article

(This article belongs to the Section Molecular Neurobiology)

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16 pages, 2553 KiB

Open AccessArticle

Targeting USP14/UCHL5: A Breakthrough Approach to Overcoming Treatment-Resistant FLT3-ITD-Positive AML

by Ayako Nogami, Hideki Jose Amemiya, Hiroki Fujiwara, Yoshihiro Umezawa, Shuji Tohda and Toshikage Nagao

Int. J. Mol. Sci. 2024, 25(19), 10372; https://doi.org/10.3390/ijms251910372 (registering DOI) - 26 Sep 2024

Abstract

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) are associated with poor prognosis and therapy resistance. This study aimed to demonstrate that inhibiting the deubiquitinating enzymes ubiquitin-specific peptidase 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5) [...] Read more.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in acute myeloid leukemia (AML) are associated with poor prognosis and therapy resistance. This study aimed to demonstrate that inhibiting the deubiquitinating enzymes ubiquitin-specific peptidase 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5) (USP14/UCHL5) with b-AP15 or the organogold compound auranofin (AUR) induces apoptosis in the ITD-transformed human leukemia cell line MV4-11 and mononuclear leukocytes derived from patients with FLT3-ITD-positive AML. This study included patients diagnosed with AML at Tokyo Medical and Dental University Hospital between January 2018 and July 2024. Both treatments blocked downstream FLT3 pathway events, with the effects potentiated by USP14 knockdown. Both treatments inhibited FLT3 deubiquitination via K48 and disrupted translation initiation via 4EBP1, a downstream FLT3 target. FLT3 was downregulated in the leukemic cells, with the associated activation of stress-related MAP kinase pathways and increased NF-E2-related factor 2. Furthermore, the overexpression of B-cell lymphoma-extra-large and myeloid cell leukemia-1 prevented the cell death caused by b-AP15 and AUR. These results suggest that inhibiting USP14/UCHL5, which involves multiple regulatory mechanisms, is a promising target for novel therapies for treatment-resistant FLT3-ITD-positive AML. Full article

(This article belongs to the Special Issue Molecular Mechanism of Leukemogenesis)

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16 pages, 1109 KiB

Open AccessArticle

Rapid and Direct Detection of the Stubby Root Nematode, Paratrichodorus allius, from Soil DNA Extracts Using Recombinase Polymerase Amplification Assay

by Mankanwal Goraya and Guiping Yan

Int. J. Mol. Sci. 2024, 25(19), 10371; https://doi.org/10.3390/ijms251910371 - 26 Sep 2024

Abstract

The stubby root nematode, Paratrichodorus allius, is one of the most important plant-parasitic nematodes. Besides root feeding, P. allius also transmits the Tobacco rattle virus in potatoes, which causes corky ringspot disease. Rapid detection of P. allius is key for efficient management. This [...] Read more.

The stubby root nematode, Paratrichodorus allius, is one of the most important plant-parasitic nematodes. Besides root feeding, P. allius also transmits the Tobacco rattle virus in potatoes, which causes corky ringspot disease. Rapid detection of P. allius is key for efficient management. This study was conducted to develop a real-time recombinase polymerase amplification (RPA) assay that is capable of detecting P. allius directly in DNA extracts from soil using a simple portable device in real time. A fluorophore-attached probe was designed to target the internal transcribed spacer (ITS)-rDNA of P. allius and was used along with primers designed previously. The real-time RPA assay had the ability to detect P. allius DNA extracted directly from infested soil with a sensitivity of one-sixteenth portion of a single nematode. This RPA assay was specific, as it did not produce positive signals from non-target nematodes tested. The real-time RPA was found to be rapid as it could even detect P. allius in as little as 7 min. Testing with 15 field soil samples validated the RPA assay developed in this study. This is the first report of P. allius detection directly from soil DNA using real-time RPA and is the fastest method for P. allius detection in soil to date. Full article

(This article belongs to the Special Issue Advances in the Molecular Diagnostics of Agriculture Pathogens and Pests)

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17 pages, 3465 KiB

Open AccessArticle

Hair Growth-Promoting Effect of Hydrangea serrata (Thunb.) Ser. Extract and Its Active Component Hydrangenol: In Vitro and In Vivo Study

by Soyoon Park, Hyunjae Kim, Hye Shin Ahn, Changseon Na and Yu-Kyong Shin

Int. J. Mol. Sci. 2024, 25(19), 10370; https://doi.org/10.3390/ijms251910370 - 26 Sep 2024

Abstract

With the escalating prevalence of hair loss, the demand for effective hair loss treatment has surged. This study evaluated the effects of hot water extract of Hydrangea serrata (Thunb.) Ser. leaf (WHS) on hair growth, employing cell cultures, mice, and human skin organoid [...] Read more.

With the escalating prevalence of hair loss, the demand for effective hair loss treatment has surged. This study evaluated the effects of hot water extract of Hydrangea serrata (Thunb.) Ser. leaf (WHS) on hair growth, employing cell cultures, mice, and human skin organoid models. Both WHS and hydrangenol were found to enhance 5α-reductase inhibitory activity. WHS and hydrangenol have been shown to stimulate dermal papilla cell (DPC) growth, potentially through factors like keratinocyte growth factor (KGF), fibroblast growth factor 10 (FGF10), and transforming growth factor-β1 (TGF-β1). They also elevated the expression levels of keratin genes (K31 and K85) and the ceramide synthase (CerS3) gene, crucial clinical indicators of hair health. Furthermore, they exhibited notable anti-inflammatory and anti-androgenic properties by reducing the levels of tumor necrosis factor-α (TNF-α) and androgen signaling molecules, including androgen receptor (AR) and dickkopf-1 (DKK-1) gene expression. Oral administration of WHS to C57BL/6 mice for 3 weeks confirmed its hair growth-promoting effects, improving hair growth parameters and gene expression without significant changes in hair weight. Additionally, in a human skin organoid model, WHS was found to stimulate hair formation and augment the expression of follicle markers. These findings position WHS as a promising nutraceutical for promoting hair health, as evidenced by its efficacy in both in vitro and in vivo models. Full article

(This article belongs to the Special Issue Plant Extracts and Bioactive Molecules with Potential Benefits for Human Health)

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21 pages, 4625 KiB

Open AccessArticle

Vinblastine Resistance Is Associated with Nephronophthisis 3-Mediated Primary Cilia via Intraflagellar Transport Protein 88 and Apoptosis-Antagonizing Transcription Factor

by Pham Xuan Thuy, Tae-Kyu Jang and Eun-Yi Moon

Int. J. Mol. Sci. 2024, 25(19), 10369; https://doi.org/10.3390/ijms251910369 - 26 Sep 2024

Abstract

Primary cilia (PC) are microtubule-based organelles that function as cellular antennae to sense and transduce extracellular signals. Nephronophthisis 3 (NPHP3) is localized in the inversin compartment of PC. Mutations in NPHP3 are associated with renal-hepatic-pancreatic dysplasia. In this study, we investigated whether vinblastine [...] Read more.

Primary cilia (PC) are microtubule-based organelles that function as cellular antennae to sense and transduce extracellular signals. Nephronophthisis 3 (NPHP3) is localized in the inversin compartment of PC. Mutations in NPHP3 are associated with renal-hepatic-pancreatic dysplasia. In this study, we investigated whether vinblastine (VBL), a microtubule destabilizer, induces anticancer drug resistance through NPHP3-associated PC formation in HeLa human cervical cancer cells. A considerable increase in PC frequency was observed in HeLa cells under serum-deprived (SD) conditions, which led to the inhibition of VBL-induced cell death. VBL-resistant cells were established by repetitive treatments with VBL and showed an increase in PC frequency. NPHP3 expression was also increased by VBL treatment under serum starvation as well as in VBL-resistant cells. NPHP3 expression and PC-associated resistance were positively correlated with apoptosis-antagonizing transcription factor (AATF) and negatively correlated with inhibition of NPHP3. In addition, AATF-mediated NPHP3 expression is associated with PC formation via the regulation of intraflagellar transport protein 88 (IFT88). VBL resistance ability was reduced by treating with ciliobrevin A, a well-known ciliogenesis inhibitor. Collectively, cancer cell survival following VBL treatment is regulated by PC formation via AATF-mediated expression of IFT88 and NPHP3. Our data suggest that the activation of AATF and IFT88 could be a novel regulator to induce anticancer drug resistance through NPHP3-associated PC formation. Full article

(This article belongs to the Section Molecular Biology)

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30 pages, 3753 KiB

Open AccessArticle

Spatial Transcriptomic Profiling of Human Saphenous Vein Exposed to Ex Vivo Arterial Haemodynamics—Implications for Coronary Artery Bypass Graft Patency and Vein Graft Disease

by Liam W. McQueen, Shameem S. Ladak, Georgia R. Layton, Marcin Wozniak, Charles Solomon, Zein El-Dean, Gavin J. Murphy and Mustafa Zakkar

Int. J. Mol. Sci. 2024, 25(19), 10368; https://doi.org/10.3390/ijms251910368 - 26 Sep 2024

Abstract

Vein graft disease is the process by which saphenous vein grafts, utilised for revascularisation during coronary artery bypass graft surgery, undergo an inflammation-driven intimal hyperplasia and accelerated atherosclerosis process in subsequent years after implantation. The role of the arterial circulation, particularly the haemodynamic [...] Read more.

Vein graft disease is the process by which saphenous vein grafts, utilised for revascularisation during coronary artery bypass graft surgery, undergo an inflammation-driven intimal hyperplasia and accelerated atherosclerosis process in subsequent years after implantation. The role of the arterial circulation, particularly the haemodynamic properties’ impact on graft patency, have been investigated but have not to date been explored in depth at the transcriptomic level. We have undertaken the first-in-man spatial transcriptomic analysis of the long saphenous vein in response to ex vivo acute arterial haemodynamic stimulation, utilising a combination of a custom 3D-printed perfusion bioreactor and the 10X Genomics Visium Spatial Gene Expression technology. We identify a total of 413 significant genes (372 upregulated and 41 downregulated) differentially expressed in response to arterial haemodynamic conditions. These genes were associated with pathways including NFkB, TNF, MAPK, and PI3K/Akt, among others. These are established pathways involved in the initiation of an early pro-inflammatory response, leukocyte activation and adhesion signalling, tissue remodelling, and cellular differentiation. Utilising unsupervised clustering analysis, we have been able to classify subsets of the expression based on cell type and with spatial resolution. These findings allow for further characterisation of the early saphenous vein graft transcriptional landscape during the earliest stage of implantation that contributes to vein graft disease, in particular validation of pathways and druggable targets that could contribute towards the therapeutic inhibition of processes underpinning vein graft disease. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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24 pages, 8654 KiB

Open AccessArticle

Transcriptome Profiling Associated with CARD11 Overexpression in Colorectal Cancer Implicates a Potential Role for Tumor Immune Microenvironment and Cancer Pathways Modulation via NF-κB

by Faisal Alhosani, Burcu Yener Ilce, Reem Sami Alhamidi, Poorna Manasa Bhamidimarri, Alaa Mohamed Hamad, Noura Alkhayyal, Axel Künstner, Cyrus Khandanpour, Hauke Busch, Basel Al-Ramadi, Kadria Sayed, Ali AlFazari, Riyad Bendardaf and Rifat Hamoudi

Int. J. Mol. Sci. 2024, 25(19), 10367; https://doi.org/10.3390/ijms251910367 - 26 Sep 2024

Abstract

The immune system plays a critical role in inflammation by initiating responses to infections or tissue damage. The nuclear factor-κB (NF-κB) pathway plays a key role in inflammation and innate immunity, as well as other cellular activities. Dysregulation of this well-choreographed pathway has [...] Read more.

The immune system plays a critical role in inflammation by initiating responses to infections or tissue damage. The nuclear factor-κB (NF-κB) pathway plays a key role in inflammation and innate immunity, as well as other cellular activities. Dysregulation of this well-choreographed pathway has been implicated in various diseases, including cancer. CARD11 is a key molecule in the BCL10-MALT1 complex, which is involved in transducing the signal downstream of the NF-κB pathway. This study aims to elucidate how CARD11 overexpression exacerbates the prognosis of colorectal cancer (CRC). To identify the cellular pathways influenced by CARD11, transcriptomic analysis in both CRC cell lines and patients was carried out on CARD11– overexpressed HCT-116 and HT-29 CRC cell lines alongside empty vector-transfected cell lines. Furthermore, a comparison of transcriptomic data from adenoma and carcinoma CRC patients with low- (CARD11–) and high-(CARD11+) CARD11 expression was carried out. Whole transcriptomics and bioinformatics analysis results indicate that CARD11 appears to play a key role in CRC progression. Absolute GSEA (absGSEA) on HCT-116 transcriptomics data revealed that CARD11 overexpression promotes cell growth and tissue remodeling and enhances immune response. Key genes co-expressed with CARD11, such as EP300, KDM5A, HIF1A, NFKBIZ, and DUSP1, were identified as mediators of these processes. In the HT-29 cell line, CARD11 overexpression activated pathways involved in chemotaxis and extracellular matrix (ECM) organization, marked by IL1RN, MDK, SPP1, and chemokines like CXCL1, CXCL3, and CCL22, which were shown to contribute to the more invasive stage of CRC. In patient samples, adenoma patients exhibited increased expression of genes associated with the tumor immune microenvironment, such as IL6ST, collagen family members, and CRC transition markers, such as GLI3 and PIEZO2, in CARD11+ adenoma patients. Carcinoma patients showed a dramatic increase in the expression of MAPK8IP2 in CARD11+ carcinoma patients alongside other cancer-related genes, including EMB, EPHB6, and CPEB4. Full article

(This article belongs to the Special Issue New Molecular Aspects of Colorectal Cancer)

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15 pages, 2798 KiB

Open AccessArticle

Betulonic Acid Inhibits Type-2 Porcine Reproductive and Respiratory Syndrome Virus Replication by Downregulating Cellular ATP Production

by Feixiang Long, Lizhan Su, Mingxin Zhang, Shuhua Wang, Qian Sun, Jinyi Liu, Weisan Chen, Haihong Wang and Jianxin Chen

Int. J. Mol. Sci. 2024, 25(19), 10366; https://doi.org/10.3390/ijms251910366 - 26 Sep 2024

Abstract

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV) infection, has been a serious threat to the pork industry worldwide and continues to bring significant economic loss. Current vaccination strategies offer limited protection against PRRSV transmission, highlighting the urgent need for [...] Read more.

Porcine reproductive and respiratory syndrome (PRRS), caused by PRRS virus (PRRSV) infection, has been a serious threat to the pork industry worldwide and continues to bring significant economic loss. Current vaccination strategies offer limited protection against PRRSV transmission, highlighting the urgent need for novel antiviral approaches. In the present study, we reported for the first time that betulonic acid (BA), a widely available pentacyclic triterpenoids throughout the plant kingdom, exhibited potent inhibition on PRRSV infections in both Marc-145 cells and primary porcine alveolar macrophages (PAMs), with IC₅₀ values ranging from 3.3 µM to 3.7 µM against three different type-2 PRRSV strains. Mechanistically, we showed that PRRSV replication relies on energy supply from cellular ATP production, and BA inhibits PRRSV infection by reducing cellular ATP production. Our findings indicate that controlling host ATP production could be a potential strategy to combat PRRSV infections, and that BA might be a promising therapeutic agent against PRRSV epidemics. Full article

(This article belongs to the Special Issue Anti-cancer, Anti-inflammatory, and Antioxidation Active Substances: 2nd Edition)

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22 pages, 1928 KiB

Open AccessReview

Revolutionizing CAR T-Cell Therapies: Innovations in Genetic Engineering and Manufacturing to Enhance Efficacy and Accessibility

by Lorenzo Giorgioni, Alessandra Ambrosone, Maria Francesca Cometa, Anna Laura Salvati, Robert Nisticò and Armando Magrelli

Int. J. Mol. Sci. 2024, 25(19), 10365; https://doi.org/10.3390/ijms251910365 - 26 Sep 2024

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has achieved notable success in treating hematological cancers but faces significant challenges in solid-tumor treatment and overall efficacy. Key limitations include T-cell exhaustion, tumor relapse, immunosuppressive tumor microenvironments (TME), immunogenicity, and antigen heterogeneity. To address these issues, [...] Read more.

Chimeric antigen receptor (CAR) T-cell therapy has achieved notable success in treating hematological cancers but faces significant challenges in solid-tumor treatment and overall efficacy. Key limitations include T-cell exhaustion, tumor relapse, immunosuppressive tumor microenvironments (TME), immunogenicity, and antigen heterogeneity. To address these issues, various genetic engineering strategies have been proposed. Approaches such as overexpression of transcription factors or metabolic armoring and dynamic CAR regulation are being explored to improve CAR T-cell function and safety. Other efforts to improve CAR T-cell efficacy in solid tumors include targeting novel antigens or developing alternative strategies to address antigen diversity. Despite the promising preclinical results of these solutions, challenges remain in translating CAR T-cell therapies to the clinic to enable economically viable access to these transformative medicines. The efficiency and scalability of autologous CAR T-cell therapy production are hindered by traditional, manual processes which are costly, time-consuming, and prone to variability and contamination. These high-cost, time-intensive processes have complex quality-control requirements. Recent advancements suggest that smaller, decentralized solutions such as microbioreactors and automated point-of-care systems could improve production efficiency, reduce costs, and shorten manufacturing timelines, especially when coupled with innovative manufacturing methods such as transposons and lipid nanoparticles. Future advancements may include harmonized consumables and AI-enabled technologies, which promise to streamline manufacturing, reduce costs, and enhance production quality. Full article

(This article belongs to the Special Issue State-of-the-Art Cancer Immunotherapies—2nd Edition)

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13 pages, 10262 KiB

Open AccessArticle

Enhancing Cryopreserved Sperm Quality in Chinese Rare Minnow Gobiocypris rarus: The Impact of Antifreeze Proteins

by Huan Ye, Xin Li, Li Shen, Hao Du, Qing Zhang, Yongfeng He and Jinming Wu

Int. J. Mol. Sci. 2024, 25(19), 10364; https://doi.org/10.3390/ijms251910364 - 26 Sep 2024

Abstract

The Chinese rare minnow (Gobiocypris rarus), an important model fish in China, faces endangerment in the wild. Sperm cryopreservation facilitates the development of new strains and germplasm conservation, but the quality of its cryopreserved sperm remains low. This study evaluates the [...] Read more.

The Chinese rare minnow (Gobiocypris rarus), an important model fish in China, faces endangerment in the wild. Sperm cryopreservation facilitates the development of new strains and germplasm conservation, but the quality of its cryopreserved sperm remains low. This study evaluates the protective effects of different concentrations of antifreeze proteins (AFP I and AFP III) on the cryopreservation of Chinese rare minnow sperm. Cryopreserved sperm showed significant declines in progressive motility, curvilinear velocity (VCL), average path velocity (VAP), and lifespan compared to fresh sperm, except for straight-line velocity (VSL). The cryomedium containing 10 μg/mL AFP I improved these parameters to their highest levels. However, no significant difference was found in progressive motility and kinetic parameters between cryopreserved sperm with and without AFPs. Cryopreserved sperm with 10 μg/mL AFP I showed the highest plasma membrane integrity, mitochondrial activity, and DNA integrity, significantly better than without AFPs; importantly, the fertilization rate of cryopreserved sperm with 10 μg/mL AFP I was not significantly different from that of fresh sperm. These results indicate that the addition of 10 μg/mL AFP I to the cryomedium for Chinese rare minnow sperm does not improve kinetic parameters but significantly enhances sperm quality, aiding in its new strain development and germplasm conservation. Full article

(This article belongs to the Special Issue Aquatic Biotechnology and Its Application in Genetic Breeding)

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4 pages, 170 KiB

Open AccessEditorial

Special Issue “Research Progress of Bioimaging Materials”

by Liangcan He

Int. J. Mol. Sci. 2024, 25(19), 10363; https://doi.org/10.3390/ijms251910363 - 26 Sep 2024

Abstract

In the context of increasingly diverse diseases, early diagnosis and prevention, particularly in cancer control, have become more important than ever [...] Full article

(This article belongs to the Special Issue Research Progress of Bioimaging Materials)

12 pages, 9170 KiB

Open AccessArticle

A Novel Prognostic Model of Hepatocellular Carcinoma per Two NAD+ Metabolic Synthesis-Associated Genes

by Luo Dai, Shiliu Lu, Linfeng Mao, Mingbei Zhong, Gangping Feng, Songqing He and Guandou Yuan

Int. J. Mol. Sci. 2024, 25(19), 10362; https://doi.org/10.3390/ijms251910362 - 26 Sep 2024

Abstract

Hepatocellular carcinoma (HCC) is a formidable challenge to global human health, while recent years have witnessed the important role of NAD+ in tumorigenesis and progression. However, the expression pattern and prognostic value of NAD+ in HCC still remain elusive. Gene expression files and [...] Read more.

Hepatocellular carcinoma (HCC) is a formidable challenge to global human health, while recent years have witnessed the important role of NAD+ in tumorigenesis and progression. However, the expression pattern and prognostic value of NAD+ in HCC still remain elusive. Gene expression files and corresponding clinical pathological files associated with HCC were obtained from the Cancer Genome Atlas (TCGA) database, and genes associated with NAD+ were retrieved from the GSEA and differentially analyzed in tumor and normal tissues. A consensus clustering analysis was conducted by breaking down TCGA patients into four distinct groups, while Kaplan–Meier curves were generated to investigate the disparity in clinical pathology and endurance between clusters. A prognostic model based on NAD+-associated genes was established and assessed by combining LASSO-Cox regression, uni- and multi-variate Cox regression, and ROC curve analyses. Investigations were conducted to determine the expression of distinct mRNAs and proteins in both HCC and non-tumor tissues. A novel two-gene signature including poly (ADP-Ribose) polymerase 2 (PARP2) and sirtuin 6 (SIRT6) was obtained through LASSO-Cox regression and was identified to have favorable prognostic performance in HCC patients from TCGA. Analyses of both single and multiple variables showed that the prognostic model was a distinct prognostic factor in the endurance of liver cancer patients in both the training and trial groups. The nomogram also exhibited clinical significance in the prognosis of HCC patients. Immunohistochemistry, qRT-PCR, and Western blotting revealed that HCC samples exhibited higher PARP2 and SIRT6 expression levels than those of normal controls. This study identified a robust prognostic model comprising two NAD+-associated genes using bioinformatic methods, which is accurate in predicting the survival outcome of HCC patients. This model might benefit the early diagnosis of HCC and further facilitate the management of individualized medical service and clinical decision-making. Full article

(This article belongs to the Section Molecular Oncology)

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17 pages, 4202 KiB

Open AccessArticle

Mycovirus-Containing Aspergillus flavus Alters Transcription Factors in Normal and Acute Lymphoblastic Leukemia Cells

by Cameron K. Tebbi, Jiyu Yan, Eva Sahakian, Melanie Mediavilla-Varela, Javier Pinilla-Ibarz, Saumil Patel, George E. Rottinghaus, Rachel Y. Liu and Clare Dennison

Int. J. Mol. Sci. 2024, 25(19), 10361; https://doi.org/10.3390/ijms251910361 - 26 Sep 2024

Abstract

Transcription factors control genes to maintain normal hemopoiesis, and dysregulation of some factors can lead to acute lymphoblastic leukemia (ALL). Mycoviruses are known to alter the genetics of their fungal host. The present study evaluates the effects of the products of a mycovirus-containing [...] Read more.

Transcription factors control genes to maintain normal hemopoiesis, and dysregulation of some factors can lead to acute lymphoblastic leukemia (ALL). Mycoviruses are known to alter the genetics of their fungal host. The present study evaluates the effects of the products of a mycovirus-containing Aspergillus flavus (MCAF), isolated from the home of a patient with ALL, on certain transcription factors of normal and ALL cell lines. Our published studies have shown that ALL patients have antibodies to MCAF, and that exposure of the mononuclear leukocytes of patients in complete remission to its products, unlike controls, results in the re-development of genetic and cell surface phenotypes characteristic of ALL. For the present study, normal, pre-B, and B-cell leukemia cell lines were exposed to the culture of MCAF. Pre- and post-exposure levels of PAX5, Ikaros, and NF-κB were assessed. Exposure to MCAF resulted in apoptosis, cell cycle changes, and complete downregulation of all transcription factors in normal cell lines. In acute leukemia cell lines, cellular apoptosis and alterations in the cell cycle were also noted; however, while there was downregulation of all tested transcription factors, residual levels were retained. The noted alterations in the transcription factors caused by MCAF are novel findings. The possible role of MCAF in leukemogenesis needs to be further investigated. Mycovirus-containing Aspergillus flavus was initially isolated from a leukemia patient’s home. Our prior published studies have illuminated intriguing associations of this organism with leukemia. Unlike controls, patients diagnosed with acute lymphoblastic leukemia (ALL) harbor antibodies to this organism. Furthermore, the exposure of mononuclear cells from patients with ALL in complete remission to the products of this organism reproduced genetic and cell phenotypes characteristic of ALL. These findings underscore the potential role of environmental factors in leukemogenesis and hint at novel avenues for therapeutic intervention and preventive strategies. Full article

(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)

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12 pages, 2934 KiB

Open AccessArticle

Effect of CFTR Modulators on Oxidative Stress and Autophagy in Non-CFTR-Expressing Cells

by Filippo Scialò, Gustavo Cernera, Lorenza Polise, Giuseppe Castaldo, Felice Amato and Valeria Rachela Villella

Int. J. Mol. Sci. 2024, 25(19), 10360; https://doi.org/10.3390/ijms251910360 - 26 Sep 2024

Abstract

The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the [...] Read more.

The triple combination therapy for cystic fibrosis (CF), including elexacaftor, tezacaftor and ivacaftor (ETI or Trikafta), has been shown to improve lung function and reduce pulmonary exacerbations, thereby enhancing the quality of life for most CF patients. Recent findings suggest that both the individual components and ETI may have potential off-target effects, highlighting the need to understand how these modulators impact cellular physiology, particularly in cells that do not express CF transmembrane conductance regulator (CFTR). We used HEK293 cells, as a cell model not expressing the CFTR protein, to evaluate the effect of ETI and each of its components on autophagic machinery and on the Rab5/7 components of the Rab pathway. We firstly demonstrate that the single modulators Teza and Iva, and the combinations ET and ETI, increased ROS production in the absence of their target while decreasing it in cells expressing the CFTR ∆F508del. This increase in cellular stress was followed by an increase in the total level of polyubiquitinated proteins as well as the p62 level and LC3II/LC3I ratio. Furthermore, we found that ETI had the opposite effect on Rabs by increasing Rab5 levels while decreasing Rab7. Interestingly, these changes were abolished by the expression of mutated CFTR. Overall, our data suggest that in the absence of their target, both the individual modulators and ETI increased ROS production and halted both autophagic flux and plasma membrane protein recycling. Full article

(This article belongs to the Special Issue Cystic Fibrosis: Molecular Pathogenesis, Diagnosis, and Treatment)

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19 pages, 4114 KiB

Open AccessArticle

The Antioxidant and Anti-Fatigue Effects of Rare Ginsenosides and γ-Aminobutyric Acid in Fermented Ginseng and Germinated Brown Rice Puree

by Shiwen Feng, Tao Li, Xinrui Wei, Yifei Zheng, Yumeng Zhang, Gao Li and Yuqing Zhao

Int. J. Mol. Sci. 2024, 25(19), 10359; https://doi.org/10.3390/ijms251910359 - 26 Sep 2024

Abstract

γ-aminobutyric acid (GABA) and rare ginsenosides are good antioxidant and anti-fatigue active components that can be enriched via probiotic fermentation. In this study, ginseng and germinated brown rice were used as raw materials to produce six fermented purees using fermentation and non-fermentation technology. [...] Read more.

γ-aminobutyric acid (GABA) and rare ginsenosides are good antioxidant and anti-fatigue active components that can be enriched via probiotic fermentation. In this study, ginseng and germinated brown rice were used as raw materials to produce six fermented purees using fermentation and non-fermentation technology. We tested the chemical composition of the purees and found that the content of GABA and rare ginsenoside (Rh₄, Rg₃, and CK) in the puree made of ginseng and germinated brown rice (FGB) increased significantly after fermentation. The antioxidant activity of the six purees was determined using cell-free experiments, and it was found that FGB had better ferric-ion-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radical scavenging rates, exhibiting better antioxidant effects. We then evaluated the antioxidant effect of FGB in HepG₂ cells induced by H₂O₂ and found that FGB can reduce the generation of reactive oxygen species (ROS) in HepG₂ cells and increase the membrane potential level, thereby improving oxidative damage in these cells. In vivo experiments also showed that FGB has good antioxidant and anti-fatigue activities, which can prolong the exhaustive swimming time of mice and reduce the accumulation of metabolites, and is accompanied by a corresponding increase in liver glycogen and muscle glycogen levels as well as superoxide dismutase and lactate dehydrogenase activities. Finally, we believe that the substances with good antioxidant and anti-fatigue activity found in FGB are derived from co-fermented enriched GABA and rare ginsenosides. Full article

(This article belongs to the Special Issue Effects of Functional Food Components in Health and Disease)

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Int. J. Mol. Sci., Volume 25, Issue 19 (October-1 2024) – 157 articles

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