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15 pages, 683 KiB

Open AccessArticle

The Potential Contribution of MyomiRs miR-133a-3p, -133b, and -206 Dysregulation in Cardiovascular Disease Risk

by Paolina Crocco, Alberto Montesanto, Rossella La Grotta, Ersilia Paparazzo, Luca Soraci, Serena Dato, Giuseppe Passarino and Giuseppina Rose

Int. J. Mol. Sci. 2024, 25(23), 12772; https://doi.org/10.3390/ijms252312772 - 27 Nov 2024

Abstract

Cardiovascular disease (CVD) is a major global health concern. The number of people with CVD is expected to rise due to aging populations and increasing risk factors such as obesity and diabetes. Identifying new molecular markers is crucial for early diagnosis and treatment. [...] Read more.

Cardiovascular disease (CVD) is a major global health concern. The number of people with CVD is expected to rise due to aging populations and increasing risk factors such as obesity and diabetes. Identifying new molecular markers is crucial for early diagnosis and treatment. Among these, plasma levels of some miRNAs, specifically expressed in cardiac and skeletal muscle, known as myomiRs, have gained attention for their roles in cardiovascular health. This study analyzed the plasma levels of miR-133a-3p, -133b, and -206 in the pathogenesis of cardiovascular diseases. Using a case–control study design with patients recruited from several nursing homes from Calabria (southern Italy) characterized by different types of CVD compared with non-CVD controls, we found downregulation of miR-133a-3p in heart failure and miR-133b in stroke, along with the overall decreased expression of miR-133b and miR-206 in CVD patients, although they showed low specificity as biomarkers of CVD (as based on ROC analysis). In silico functional characterization of their targets and signaling pathways revealed their involvement in critical cardiovascular processes. Although further research is necessary to fully elucidate their mechanisms and clinical utility, the findings reported here may provide insight into the potential contribution of myomiRs in the cardiovascular injury framework, also offering indications for new research directions. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Determinants of Age-Related Traits: New Challenges and Insights)

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13 pages, 2298 KiB

Open AccessArticle

Qualitative Transcriptional Signature for Predicting the Pathological Response of Colorectal Cancer to FOLFIRI Therapy

by Jun He, Mengyao Wang, Dandan Wu, Hao Fu and Xiaopei Shen

Int. J. Mol. Sci. 2024, 25(23), 12771; https://doi.org/10.3390/ijms252312771 - 27 Nov 2024

Abstract

FOLFIRI (5-FU, leucovorin, irinotecan) is the first-line chemotherapy for metastatic colorectal cancer (mCRC), but response rates are under 50%. This study aimed to develop a predictive signature for FOLFIRI response in mCRC patients. Firstly, Spearman’s rank correlation and Wilcoxon rank-sum test were used [...] Read more.

FOLFIRI (5-FU, leucovorin, irinotecan) is the first-line chemotherapy for metastatic colorectal cancer (mCRC), but response rates are under 50%. This study aimed to develop a predictive signature for FOLFIRI response in mCRC patients. Firstly, Spearman’s rank correlation and Wilcoxon rank-sum test were used to select chemotherapy response genes and gene pairs, respectively. Then, an optimization procedure was used to determine the final signature. A predictive signature consisting of three gene pairs (3-GPS) was identified. In the training set, 3-GPS achieved an accuracy of 0.94. In a validation set of 60 samples, predicted responders had significantly better progression-free survival than the predicted non-responders (HR = 0.47, p = 0.01). A comparable result was observed in an additional validation set of 27 samples (HR = 0.06, p = 0.02). The co-expressed genes of the signature were enriched in pathways associated with the immunotherapy response, and they interacted extensively with FOLFIRI-related genes. Notably, the expression of signature genes significantly correlated with various immune cell types, including plasma cells and memory-resting CD4+ T cells. In conclusion, the REO-based signature effectively identifies mCRC patients likely to benefit from FOLFIRI. Furthermore, these signature genes may play a crucial role in the chemotherapy. Full article

(This article belongs to the Topic Advances in Colorectal Cancer Therapy)

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25 pages, 1588 KiB

Open AccessArticle

Improved Skin Barrier Function Along with Hydration Benefits of Viola yedoensis Extract, Aesculin, and Schaftoside and LC-HRMS/MS Dereplication of Its Bio-Active Components

by Sreelatha Thonthula, Sandra De Sousa, Alexis Dubuis, Samia Boudah, Richa Mehta, Akanksha Singh, Joan Eilstein, Jean-Claude Tabet, Sherluck John, Dhimoy Roy and Steve Thomas Pannakal

Int. J. Mol. Sci. 2024, 25(23), 12770; https://doi.org/10.3390/ijms252312770 - 27 Nov 2024

Abstract

The skin hydration level is a key factor that influences the physical and mechanical properties of the skin. The stratum corneum (SC), the outermost layer of the epidermis, is responsible for the skin’s barrier function. In this study, we investigated the role of [...] Read more.

The skin hydration level is a key factor that influences the physical and mechanical properties of the skin. The stratum corneum (SC), the outermost layer of the epidermis, is responsible for the skin’s barrier function. In this study, we investigated the role of a unique composition of Viola yedoensis extract for its ability to activate CD44, a cell-surface receptor of hyaluronic acid, and aquaporin-3, a water-transporting protein, in human keratinocytes (HaCaT). An ELISA assay evaluating the protein expression levels of CD44, aquaporin-3 (AQP3), filaggrin, and keratin-10 revealed that V. yedoensis extract upregulated the levels of CD44 and AQP3 by 15% and 78%, respectively. Additionally, V. yedoensis extract demonstrated a comparative effect on water vapor flux in TEWL and lipid perturbation in DSC versus the reference, glycerin. In light of this new biological efficacy, a detailed phytochemical characterization was undertaken using an integrated LC-HRMS/MS-based metabolomics approach, which provided further insights on the chemistry of V. yedoensis. This led to the identification of 29 secondary metabolites, 14 of which are reported here for the first time, including esculetin, aesculin, apigenin and kaempferol C-glycosides, megastigmane glycosides, roseoside, platanionoside B, and an eriojaposide B isomer, along with the rare, calenduloside F and esculetin diglucoside, which are reported for the first time from the genus, Viola. Notably, two active components identified in the V. yedoensis extract, namely, aesculin and schaftoside, showed an upregulation of the protein expression of CD44 in HaCaT cells by 123% and 193% within 24 h of treatment, respectively, while aesculin increased AQP3 levels by 46%. Aesculin and schaftoside also significantly upregulated the expression of K-10 levels by 299% and 116%, which was considerably higher than sodium hyaluronate, the positive control. The rationale used to characterize the new structures is outlined along with the related biosynthetic pathways envisioned to generate roseoside and Eriojaposide B. These findings provide new molecular insights to deepen the understanding of how V. yedoensis extract, along with the biomarkers aesculin and schaftoside, restores the skin barrier and skin hydration benefits. Full article

(This article belongs to the Special Issue Recent Advances in Medicinal Plants and Natural Products)

15 pages, 1676 KiB

Open AccessArticle

The Therapeutic Effects of SP-8356, a Verbenone Derivative, with Multimodal Cytoprotective Mechanisms in an Ischemic Stroke Rat Model

by Hwa Young Song, Sejong Jin, Sekwang Lee, Angela Melinda Anthony Jalin, Kyung-Hye Roh and Won-Ki Kim

Int. J. Mol. Sci. 2024, 25(23), 12769; https://doi.org/10.3390/ijms252312769 - 27 Nov 2024

Abstract

An ischemic cerebral stroke results from the interruption of blood flow to the brain, triggering rapid and complex cascades of excitotoxicity, oxidative stress, and inflammation. Current reperfusion therapies, including intravenous thrombolysis and mechanical thrombectomy, cause further brain injury due to reperfusion-induced cytotoxicity. To [...] Read more.

An ischemic cerebral stroke results from the interruption of blood flow to the brain, triggering rapid and complex cascades of excitotoxicity, oxidative stress, and inflammation. Current reperfusion therapies, including intravenous thrombolysis and mechanical thrombectomy, cause further brain injury due to reperfusion-induced cytotoxicity. To date, novel cytoprotective therapies that could address these challenges have yet to be developed, likely due to the limitations of targeting a single pathologic mechanism. To address these unmet clinical needs, we investigated a synthetic verbenone derivative, SP-8356, as a potential multi-target cytoprotective agent for acute ischemic strokes. In transient middle cerebral artery occlusion (MCAO) rats, SP-8356 significantly reduced brain infarct and edema volumes while improving acute neurological deficits in a dose-dependent manner. Furthermore, SP-8356 improved long-term outcomes, particularly by reducing mortality. These potent cytoprotective effects of SP-8356 were achieved by suppressing the excessive production of free radicals and pro-inflammatory cytokines, reducing the infiltration of inflammatory cells, and mitigating increases in blood–brain barrier permeability. Additional research is needed to determine whether co-administration of SP-8356 can extend the therapeutic time window of reperfusion therapies by mitigating ischemia/reperfusion injury. Full article

(This article belongs to the Section Molecular Biology)

30 pages, 3897 KiB

Open AccessArticle

Efficient Genome Editing Using ‘NanoMEDIC’ AsCas12a-VLPs Produced with Pol II-Transcribed crRNA

by Sofiia E. Borovikova, Mikhail V. Shepelev, Dmitriy V. Mazurov and Natalia A. Kruglova

Int. J. Mol. Sci. 2024, 25(23), 12768; https://doi.org/10.3390/ijms252312768 - 27 Nov 2024

Abstract

Virus-like particles (VLPs) are an attractive vehicle for the delivery of Cas nuclease and guide RNA ribonucleoprotein complexes (RNPs). Most VLPs are produced by packaging SpCas9 and its sgRNA, which is expressed from the RNA polymerase III (Pol III)-transcribed U6 promoter. VLPs assemble [...] Read more.

Virus-like particles (VLPs) are an attractive vehicle for the delivery of Cas nuclease and guide RNA ribonucleoprotein complexes (RNPs). Most VLPs are produced by packaging SpCas9 and its sgRNA, which is expressed from the RNA polymerase III (Pol III)-transcribed U6 promoter. VLPs assemble in the cytoplasm, but U6-driven sgRNA is localized in the nucleus, which hinders the efficient formation and packaging of RNPs into VLPs. In this study, using the nuclease packaging mechanism of ‘NanoMEDIC’ VLPs, we produced VLPs with AsCas12a and exploited its ability to process pre-crRNA. This allowed us to direct crRNA in the cytoplasm as part of a Pol II-driven transcript where AsCas12a excised mature crRNA, thus boosting RNP incorporation into VLPs. CMV-driven crRNA increased Venus and CCR5 transgene knockout levels in 293 cells from 30% to 50–90% and raised the level of endogenous CXCR4 knockout in Jurkat T cells from 1% to 20%. Changing a single crRNA to an array of three or six identical crRNAs improved CXCR4 knockout rates by up to 60–70%. Compared to SpCas9-VLPs, the editing efficiencies of AsCas12a-VLPs were higher, regardless of promoter usage. Thus, we showed that AsCas12a and CMV-driven crRNA could be efficiently packaged into VLPs and mediate high levels of gene editing. AsCas12a-VLPs are a new and promising tool for the delivery of RNPs into mammalian cells that will allow efficient target genome editing and may be useful for gene therapy applications. Full article

(This article belongs to the Special Issue CRISPR-Cas Systems and Genome Editing—2nd Edition)

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45 pages, 1847 KiB

Open AccessReview

Redefining Roles: A Paradigm Shift in Tryptophan–Kynurenine Metabolism for Innovative Clinical Applications

by Masaru Tanaka, Ágnes Szabó and László Vécsei

Int. J. Mol. Sci. 2024, 25(23), 12767; https://doi.org/10.3390/ijms252312767 - 27 Nov 2024

Abstract

The tryptophan–kynurenine (KYN) pathway has long been recognized for its essential role in generating metabolites that influence various physiological processes. Traditionally, these metabolites have been categorized into distinct, often opposing groups, such as pro-oxidant versus antioxidant, excitotoxic/neurotoxic versus neuroprotective. This dichotomous framework has [...] Read more.

The tryptophan–kynurenine (KYN) pathway has long been recognized for its essential role in generating metabolites that influence various physiological processes. Traditionally, these metabolites have been categorized into distinct, often opposing groups, such as pro-oxidant versus antioxidant, excitotoxic/neurotoxic versus neuroprotective. This dichotomous framework has shaped much of the research on conditions like neurodegenerative and neuropsychiatric disorders, as well as cancer, where metabolic imbalances are a key feature. The effects are significantly influenced by various factors, including the concentration of metabolites and the particular cellular milieu in which they are generated. A molecule that acts as neuroprotective at low concentrations may exhibit neurotoxic effects at elevated levels. The oxidative equilibrium of the surrounding environment can alter the function of KYN from an antioxidant to a pro-oxidant. This narrative review offers a comprehensive examination and analysis of the contemporary understanding of KYN metabolites, emphasizing their multifaceted biological functions and their relevance in numerous physiological and pathological processes. This underscores the pressing necessity for a paradigm shift in the comprehension of KYN metabolism. Understanding the context-dependent roles of KYN metabolites is vital for novel therapies in conditions like Alzheimer’s disease, multiple sclerosis, and cancer. Comprehensive pathway modulation, including balancing inflammatory signals and enzyme regulation, offers promising avenues for targeted, effective treatments. Full article

(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)

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29 pages, 1311 KiB

Open AccessReview

The Future of Bone Repair: Emerging Technologies and Biomaterials in Bone Regeneration

by Julia Weronika Łuczak, Małgorzata Palusińska, Damian Matak, Damian Pietrzak, Paweł Nakielski, Sławomir Lewicki, Marta Grodzik and Łukasz Szymański

Int. J. Mol. Sci. 2024, 25(23), 12766; https://doi.org/10.3390/ijms252312766 - 27 Nov 2024

Abstract

Bone defects and fractures present significant clinical challenges, particularly in orthopedic and maxillofacial applications. While minor bone defects may be capable of healing naturally, those of a critical size necessitate intervention through the use of implants or grafts. The utilization of traditional methodologies, [...] Read more.

Bone defects and fractures present significant clinical challenges, particularly in orthopedic and maxillofacial applications. While minor bone defects may be capable of healing naturally, those of a critical size necessitate intervention through the use of implants or grafts. The utilization of traditional methodologies, encompassing autografts and allografts, is constrained by several factors. These include the potential for donor site morbidity, the restricted availability of suitable donors, and the possibility of immune rejection. This has prompted extensive research in the field of bone tissue engineering to develop advanced synthetic and bio-derived materials that can support bone regeneration. The optimal bone substitute must achieve a balance between biocompatibility, bioresorbability, osteoconductivity, and osteoinductivity while simultaneously providing mechanical support during the healing process. Recent innovations include the utilization of three-dimensional printing, nanotechnology, and bioactive coatings to create scaffolds that mimic the structure of natural bone and enhance cell proliferation and differentiation. Notwithstanding the advancements above, challenges remain in optimizing the controlled release of growth factors and adapting materials to various clinical contexts. This review provides a comprehensive overview of the current advancements in bone substitute materials, focusing on their biological mechanisms, design considerations, and clinical applications. It explores the role of emerging technologies, such as additive manufacturing and stem cell-based therapies, in advancing the field. Future research highlights the need for multidisciplinary collaboration and rigorous testing to develop advanced bone graft substitutes, improving outcomes and quality of life for patients with complex defects. Full article

(This article belongs to the Special Issue Regenerative Medicine: Biomaterials and Stem Cell Research)

22 pages, 468 KiB

Open AccessArticle

Association of Sympathovagal Imbalance with Increased Inflammation and Impaired Adaptive Immunity in Bladder Cancer Patients

by Iveta Mikolaskova, Milan Zvarik, Kinga Szaboova, Elena Tibenska, Vladimira Durmanova, Magda Suchankova, Boris Kollarik, Patrik Hesko, Patrik Palacka, Maria Bucova and Luba Hunakova

Int. J. Mol. Sci. 2024, 25(23), 12765; https://doi.org/10.3390/ijms252312765 - 27 Nov 2024

Abstract

Stress responses can impact bladder cancer (BC) outcomes via immune–inflammatory pathway modulation. This study explores heart rate variability (HRV) associations with serum immune–inflammatory biomarkers, blood count inflammatory markers, and psychosocial self-report measures in patients versus healthy controls. The TREM-1 and TREM-2 expressions on [...] Read more.

Stress responses can impact bladder cancer (BC) outcomes via immune–inflammatory pathway modulation. This study explores heart rate variability (HRV) associations with serum immune–inflammatory biomarkers, blood count inflammatory markers, and psychosocial self-report measures in patients versus healthy controls. The TREM-1 and TREM-2 expressions on peripheral blood monocytes were analysed via flow cytometry; serum inflammatory biomarkers by ELISA; HRV (5-min ECG) pre-tumour resection; blood counts by haematology analyser; and psychosocial factors by validated questionnaires. Patients exhibited altered immune–inflammatory profiles with increased TREM-1/TREM-2, sTREM-1, sTREM-1/sTREM-2 ratio, BDNF, MCP-1, and NLR, and reduced IFN-γ, IL-10, LMR, and PMR. HRV analysis indicated sympathetic dominance (SNS, Stress indices, ACmod) and reduced parasympathetic modulation (PNS index, SDNN, RMSSD, 2UV%, DCmod, SD1). Sympathetic HRV indices correlated positively with sTREM-1, sTREM-1/sTREM-2 ratio, fractalkine, and inflammatory markers (SII, NLR, PLR) and negatively with parasympathetic HRV indices—correlations absent in controls. Only in patients, reduced physical function and social support, and higher anxiety, depression, and fatigue, associated positively with sympathetic HRV indices and inflammatory markers. This study links immune–inflammatory markers, HRV parameters, and psychosocial factors in BC, suggesting that immune and autonomic variations may relate to unfavourable outcomes. Incorporating these assessments could help tailor more personalised treatment strategies for BC patients. Full article

(This article belongs to the Special Issue Towards Complex Molecular Cancer Therapies)

10 pages, 422 KiB

Open AccessArticle

Frequencies of an IFNL4 Variant in an Admixed Population from Amazonia and Its Influence on Hepatitis C Infection

by Carolina Cabral Angelim, Álesson Adam Fonseca Andrade, Renata Santos de Sousa, Raissa Lima Correa, Amanda Roberta Vieira Sacramento, Letícia Dias Martins, Simone Regina Souza da Silva Conde, Antonio Carlos Rosário Vallinoto, Rosimar Neris Martins Feitosa and Greice de Lemos Cardoso Costa

Int. J. Mol. Sci. 2024, 25(23), 12764; https://doi.org/10.3390/ijms252312764 - 27 Nov 2024

Abstract

The rs12979860 polymorphism, related to the IFNL4 gene, is suggested as a factor that impacts fibrosis progression in hepatitis C virus (HCV) infection and exhibits a wide distribution pattern across global populations. In this retrospective cross-sectional study, we aimed to investigate the frequency [...] Read more.

The rs12979860 polymorphism, related to the IFNL4 gene, is suggested as a factor that impacts fibrosis progression in hepatitis C virus (HCV) infection and exhibits a wide distribution pattern across global populations. In this retrospective cross-sectional study, we aimed to investigate the frequency of this variant in an Amazonian population from Brazil, as well as its association with liver fibrosis development and its staging in HCV carriers. Our results show a significant association of the TT genotype in the sample of patients with HCV (OR = 2.291; 95% CI = 1.088–4.826; p = 0.033) and the greater frequency of the T allele (62.1%), which is similar to the those of African populational groups. Populational genetics analysis showed significant differences in allele frequencies on global levels. The frequency of the C allele in the study population (37.8%) was like that of the African population (39.7%), and differed from all other populations, which ranged from 62.5% to 92.9%. These findings suggest that rs12979860 plays a role in susceptibility to hepatitis C. Additionally, they allow us to propose that the response to hepatitis C infection in this group may resemble that of the African population. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

13 pages, 4843 KiB

Open AccessArticle

Analysis of CD1a-Positive Monocyte-Derived Cells in the Regional Lymph Nodes of Patients with Gallbladder Cancer

by Sachiko Maeda, Keita Kai, Kanako Kawasaki, Tomokazu Tanaka, Takao Ide and Hirokazu Noshiro

Int. J. Mol. Sci. 2024, 25(23), 12763; https://doi.org/10.3390/ijms252312763 - 27 Nov 2024

Abstract

Dendritic cells (DCs) are known to be major antigen-presenting cells, and lymph nodes (LNs) play an important role in DC-mediated immune response. CD1a is known as a marker of monocyte-derived DCs. The present study focused on the infiltration of CD1a-positive DCs (CD1a-DCs) into [...] Read more.

Dendritic cells (DCs) are known to be major antigen-presenting cells, and lymph nodes (LNs) play an important role in DC-mediated immune response. CD1a is known as a marker of monocyte-derived DCs. The present study focused on the infiltration of CD1a-positive DCs (CD1a-DCs) into regional LNs in 70 cases of gallbladder cancer (GBC). After univariate analyses, the results showed that LN infiltration by CD1a-DCs was associated with unfavorable clinical outcomes in patients with GBC, with all cases categorized in the CD1a-DCs high group had nodal metastasis. LN infiltration by CD1a-DCs was not an independent prognostic factor identified by multivariate analyses. After subgroup analyses of cases with LN metastasis (n = 32), no significant impacts of CD1a-DCs infiltration into metastatic LNs were observed. In contrast, CD1a-DCs infiltration into primary tumors had a significant impact on surgical outcomes. The results of strong confounding between CD1a-DCs and LN metastasis support the theory that CD1a-DCs are developed from monocytes at tumor sites. As the results of previous research focused on CD1a-DCs infiltration into regional LNs of other organs varied, the role and significance of CD1a-DCs infiltration in regional LNs may be different according to the tumor histology or its primary site. Thus, further studies are needed to clarify the role and significance of CD1a-DCs infiltration into regional LNs of solid cancers. Full article

(This article belongs to the Special Issue New Insights in Tumor Immunity)

15 pages, 611 KiB

Open AccessArticle

Non-Susceptibility Gene Variants in Head and Neck Paragangliomas

by Anastasiya V. Snezhkina, Vladislav S. Pavlov, George S. Krasnov, Dmitry V. Kalinin, Elena A. Pudova, Olga V. Stolbovskaya, Anastasiya V. Dunshina, Maria S. Fedorova and Anna V. Kudryavtseva

Int. J. Mol. Sci. 2024, 25(23), 12762; https://doi.org/10.3390/ijms252312762 (registering DOI) - 27 Nov 2024

Abstract

Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale [...] Read more.

Head and neck paragangliomas (HNPGLs) are rare neoplasms that, along with pheochromocytomas and extra-adrenal paragangliomas, are associated with inherited mutations in at least 12 susceptibility genes in approximately 40% of cases. However, due to the rarity of HNPGLs, only a series of small-scale studies and individual cases have reported mutations in additional genes that may be involved in tumorigenesis. Consequently, numerous disease-causing mutations and genes responsible for the pathogenesis of HNPGLs remain poorly investigated. The aim of this study was to gain a deeper understanding of the genetic basis of HNPGLs by focusing on variants in genes that were not previously identified as well-known drivers. A whole-exome data analysis was conducted on a representative set of 152 HNPGLs. In 30% of the tumors examined, 53 potentially deleterious variants were identified in 36 different genes. The analysis identified pathogenic or likely pathogenic variants in the ARNT, IDH2, L2HGDH, MYH3, PIK3CA, and TERT genes. A functional network analysis of the mutated genes revealed numerous associations and a list of metabolic pathways (e.g., the TCA cycle, carbon metabolism, pyruvate metabolism, etc.) and signaling pathways (e.g., HIF1, PI3K-Akt, FoxO, AMPK, MAPK, etc.) that may play an important role in the development of HNPGLs. The identified range of genetic alterations affecting multiple genes and, potentially, influencing diverse cellular pathways provides an enhanced molecular genetic characterization of HNPGLs. Full article

(This article belongs to the Special Issue Genetic Mutations in Health and Disease)

10 pages, 738 KiB

Open AccessArticle

Degradation and/or Dissociation of Neurodegenerative Disease-Related Factor Amyloid-β by a Suspension Containing Calcium Hydrogen Carbonate Mesoscopic Crystals

by Nodoka Iwaya, Akikazu Sakudo, Takuya Kanda, Koichi Furusaki, Rumiko Onishi, Takashi Onodera and Yasuhiro Yoshikawa

Int. J. Mol. Sci. 2024, 25(23), 12761; https://doi.org/10.3390/ijms252312761 - 27 Nov 2024

Abstract

Amyloid-β (Aβ) aggregates accumulate in the brains of individuals with Alzheimer’s disease and are thought to potentially act as prions, promoting further aggregation. Consequently, the biochemistry of Aβ has emerged as a promising target for Alzheimer’s disease. CAC-717, a suspension of calcium bicarbonate [...] Read more.

Amyloid-β (Aβ) aggregates accumulate in the brains of individuals with Alzheimer’s disease and are thought to potentially act as prions, promoting further aggregation. Consequently, the biochemistry of Aβ has emerged as a promising target for Alzheimer’s disease. CAC-717, a suspension of calcium bicarbonate mesoscopic structures derived from natural sources, has been shown to inactivate various pathogens, including prions. This study examined the effects of CAC-717 on both the formation and degradation/dissociation of Aβ aggregates using thioflavin T fluorescence and enzyme-linked immunosorbent assays. Aggregates of Aβ(1–42) peptide were generated by incubation at 37 °C for 24 h, and the effect of introducing CAC-717 on the aggregates was evaluated after further incubation at 25 °C for 30 min. Moreover, CAC-717 was also tested for its ability to inhibit the initial aggregation of Aβ. The results showed that CAC-717 significantly degraded and/or dissociated Aβ aggregates in a concentration-dependent manner. Specifically, CAC-717 treatment for 5 min disrupted Aβ aggregates to give Aβ monomer and oligomer concentrations as high as 130 nM compared to ~10 nM for the water control. In addition, CAC-717 degraded and/or dissociated aggregates within 10 s at 37 °C, and pre-treatment with CAC-717 significantly inhibited aggregation. These results suggest that CAC-717 not only degrades and/or dissociates Aβ aggregates but also inhibits their formation, highlighting its potential as a disinfectant for Alzheimer’s disease. Full article

(This article belongs to the Collection Feature Papers in Materials Science)

21 pages, 5787 KiB

Open AccessArticle

Only Infant MLL-Rearranged Leukemia Is Susceptible to an Inhibition of Polo-like Kinase 1 (PLK-1) by Volasertib

by Jacqueline Fischer, Estelle Erkner, Pia Radszuweit, Thomas Hentrich, Hildegard Keppeler, Fulya Korkmaz, Julia Schulze-Hentrich, Rahel Fitzel, Claudia Lengerke, Dominik Schneidawind and Corina Schneidawind

Int. J. Mol. Sci. 2024, 25(23), 12760; https://doi.org/10.3390/ijms252312760 - 27 Nov 2024

Abstract

MLL-rearranged (MLLr) leukemia is characterized by a poor prognosis. Depending on the cell of origin, it differs in the aggressiveness and therapy response. For instance, in adults, volasertib blocking Polo-like kinase 1 (PLK-1) exhibited limited success. Otherwise, PLK-1 characterizes an [...] Read more.

MLL-rearranged (MLLr) leukemia is characterized by a poor prognosis. Depending on the cell of origin, it differs in the aggressiveness and therapy response. For instance, in adults, volasertib blocking Polo-like kinase 1 (PLK-1) exhibited limited success. Otherwise, PLK-1 characterizes an infant MLLr signature, indicating potential sensitivity. By using our CRISPR/Cas9 MLLr model in CD34+ cells from human cord blood (huCB) and bone marrow (huBM) mimicking the infant and adult patient diseases, we were able to shed light on this phenomenon. The PLK-1 mRNA level was significantly increased in our huCB compared to the huBM model, which was underpinned by analyzing infant and adult MLLr leukemia patients. Importantly, the expression levels correlated with a functional response. Volasertib induced a significant dose-dependent decrease in proliferation and cell cycle arrest, most pronounced in the infant model. Mechanistically, upon volasertib treatment, we uncovered negative feedback only in the huBM model by compensatory upregulation of PLK-1 and related genes like AURKA involved in mitosis. Importantly, the poor response could be overcome by a combinatorial strategy with alisertib, an Aurora kinase A inhibitor. Our study emphasizes the importance of considering the cell of origin in therapeutic decision-making and provides the rationale for evaluating volasertib and alisertib in MLLr leukemia. Full article

(This article belongs to the Special Issue Hallmarks of Cancer: Emerging Insights and Innovations)

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21 pages, 14775 KiB

Open AccessReview

Multifaceted Role of Apolipoprotein C3 in Cardiovascular Disease Risk and Metabolic Disorder in Diabetes

by Bo-Yi Pan, Chen-Sheng Chen, Fang-Yu Chen and Ming-Yi Shen

Int. J. Mol. Sci. 2024, 25(23), 12759; https://doi.org/10.3390/ijms252312759 - 27 Nov 2024

Abstract

Apolipoprotein C3 (APOC3) plays a critical role in regulating triglyceride levels and serves as a key predictor of cardiovascular disease (CVD) risk, particularly in patients with diabetes. While APOC3 is known to inhibit lipoprotein lipase, recent findings reveal its broader influence across lipoprotein [...] Read more.

Apolipoprotein C3 (APOC3) plays a critical role in regulating triglyceride levels and serves as a key predictor of cardiovascular disease (CVD) risk, particularly in patients with diabetes. While APOC3 is known to inhibit lipoprotein lipase, recent findings reveal its broader influence across lipoprotein metabolism, where it modulates the structure and function of various lipoproteins. Therefore, this review examines the complex metabolic cycle of APOC3, emphasizing the impact of APOC3-containing lipoproteins on human metabolism, particularly in patients with diabetes. Notably, APOC3 affects triglyceride-rich lipoproteins and causes structural changes in high-, very low-, intermediate-, and low-density lipoproteins, thereby increasing CVD risk. Evidence suggests that elevated APOC3 levels—above the proposed safe range of 10–15 mg/dL—correlate with clinically significant CVD outcomes. Recognizing APOC3 as a promising biomarker for CVD, this review underscores the urgent need for high-throughput, clinically feasible methods to further investigate its role in lipoprotein physiology in both animal models and human studies. Additionally, we analyze the relationship between APOC3-related genes and lipoproteins, reinforcing the value of large-population studies to understand the impact of APOC3 on metabolic diseases. Ultimately, this review supports the development of therapeutic strategies targeting APOC3 reduction as a preventive approach for diabetes-related CVD. Full article

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

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13 pages, 1069 KiB

Open AccessCommunication

Highly Efficient Methods with a Generalized Linear Mixed Model for the Quantitative Trait Locus Mapping of Resistance to Columnaris Disease in Rainbow Trout (Oncorhynchus mykiss)

by Yuxin Song, Zhongyu Chang, Ao Chen, Yunfeng Zhao, Yanliang Jiang and Li Jiang

Int. J. Mol. Sci. 2024, 25(23), 12758; https://doi.org/10.3390/ijms252312758 - 27 Nov 2024

Abstract

Linear mixed models (LMMs) are commonly used in genome-wide association studies (GWASs) to evaluate population structures and relatedness. However, LMMs have been shown to be ineffective in controlling false positive errors for the analysis of resistance to Columnaris disease in Rainbow Trout. To [...] Read more.

Linear mixed models (LMMs) are commonly used in genome-wide association studies (GWASs) to evaluate population structures and relatedness. However, LMMs have been shown to be ineffective in controlling false positive errors for the analysis of resistance to Columnaris disease in Rainbow Trout. To solve this problem, we conducted a series of studies using generalized linear mixed-model association software such as GMMAT (v1.4.0) (generalized linear mixed-model association tests), SAIGE (v1.4.0) (Scalable and Accurate Implementation of Generalized mixed model), and Optim-GRAMMAR for scanning a total of 25,853 SNPs. Seven different SNPs (single-nucleotide polymorphisms) associated with the trait of resistance to Columnaris were detected by Optim-GRAMMAR, four SNPs were detected by GMMAT, and three SNPs were detected by SAIGE, and all of these SNPs can explain 8.87% of the genetic variance of the trait of resistance to Columnaris disease. The heritability of the trait of resistance to Columnaris re-evaluated by GMMAT was calibrated and was found to amount to a total of 0.71 other than 0.35, which was seriously underestimated in previous research. The identification of LOC110520307, LOC110520314, and LOC110520317 associated with the resistance to Columnaris disease will provide us more genes to improve the genetic breeding by molecular markers. Finally, we continued the haplotype and gene-based analysis and successfully identified some haplotypes and a gene (TTf-2) associated with resistance to Columnaris disease. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

26 pages, 6053 KiB

Open AccessArticle

Pancreastatin Inhibition Alters the Colonic Epithelial Cells Profile in a Sex-Dependent Manner

by Diane M. Tshikudi, Hannah Hutchison and Jean-Eric Ghia

Int. J. Mol. Sci. 2024, 25(23), 12757; https://doi.org/10.3390/ijms252312757 - 27 Nov 2024

Abstract

The impaired mucosal barrier is a hallmark of ulcerative colitis (UC), an inflammatory colonic disorder with epidemiological and pathophysiology sex bias. UC Patients overexpress the colonic epithelial cells (CECs)-derived peptide pancreastatin (PST). Pancreastatin inhibitor 8 (PSTi8), an inhibitor of PST, has shown promising [...] Read more.

The impaired mucosal barrier is a hallmark of ulcerative colitis (UC), an inflammatory colonic disorder with epidemiological and pathophysiology sex bias. UC Patients overexpress the colonic epithelial cells (CECs)-derived peptide pancreastatin (PST). Pancreastatin inhibitor 8 (PSTi8), an inhibitor of PST, has shown promising anti-inflammatory effects on UC. However, no data exist in the context of CEC barrier function and integrity. We investigated the impact of PSTi8 treatment on CECs in homeostatic and colitic conditions. PSTi8 (2.5 mg/mL/kg, i.r.) or PBS treatment started one day before colitis induction (5% dextran sodium sulfate for five days) in male and female C57BL/6 mice. The disease activity score was assessed daily. Epithelial-associated cytokines, markers specific to differentiation, proliferation, differentiated CECs, stem cells, CECs regulators, and the PSTi8 G-protein coupled receptor 78 (GPR78) signaling pathway, were evaluated using ELISA, immunofluorescence and qRT-PCR. PSTi8 treatment reduced the epithelial-associated cytokines and differentiated CECs while promoting CEC proliferation and self-renewal in females at a steady state through the GRP78 signaling pathway. PSTi8 treatment exacerbated colitis severity and increased CEC differentiation while reducing proliferation in colitic females. Conversely, PSTi8 treatment reduced males’ susceptibility to colitis by preserving stem cells and differentiated CECs. PST regulated colonic mucosal maintenance in a sex- and disease-dependent manner. Full article

(This article belongs to the Section Molecular Immunology)

12 pages, 1467 KiB

Open AccessArticle

Paraoxonase-1 Is a Pivotal Regulator Responsible for Suppressing Allergic Airway Inflammation Through Adipose Stem Cell-Derived Extracellular Vesicles

by Jae Hoon Jung, Shin Ae Kang, Ji-Hwan Park, Sung-Dong Kim, Hak Sun Yu, Sue Jean Mun and Kyu-Sup Cho

Int. J. Mol. Sci. 2024, 25(23), 12756; https://doi.org/10.3390/ijms252312756 - 27 Nov 2024

Abstract

Although adipose stem cell (ASC)-derived extracellular vesicles (EVs) are as effective as ASCs in the suppression of Th2 cell-mediated eosinophilic inflammation, the role of identified pulmonary genes has not been well documented. Thus, we assessed the immunomodulatory effects of paraoxonase-1 (PON1) on allergic [...] Read more.

Although adipose stem cell (ASC)-derived extracellular vesicles (EVs) are as effective as ASCs in the suppression of Th2 cell-mediated eosinophilic inflammation, the role of identified pulmonary genes has not been well documented. Thus, we assessed the immunomodulatory effects of paraoxonase-1 (PON1) on allergic airway inflammation in a mouse model of asthma. Five-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of PON1 on allergic airway inflammation, the intranasal and intraperitoneal injections of recombinant mouse serum PON1 (5 μg/50 μL) were performed before the OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, and eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), cytokine profiles of BALF and lung draining lymph nodes (LLNs), the expression of interleukin (IL)-25 and transforming growth factor (TGF)-β in mouse lung epithelial cell (MLE-12 cell), and dendritic cell (DC) differentiation. The intraperitoneal and intranasal administration of PON1 significantly decreased AHR, total inflammatory cells and eosinophils in BALF, eosinophilic airway inflammation, serum total, and OVA-specific IgE. PON1 treatment, which marked reduced IL-4, IL-5, and IL-13 in the BALF and LLN but significantly increased interferon-γ and TGF-β. Furthermore, PON1 treatment significantly decreased the expression of IL-25 and increased TGF-β in MLE-12 cells. The expressions of CD40, CD80, and CD86 in immature DCs were significantly increased by PON1 treatment. The administration of PON1 ameliorated allergic airway inflammation and improved AHR through the downregulation of IL-4, IL-5, and IL-13 and upregulation of TGF-β in asthmatic mice. Furthermore, PON1 treatment decreased Th2-mediated inflammation induced by Aspergillus protease antigen by decreasing IL-25 and increasing TGF-β. Full article

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

16 pages, 4485 KiB

Open AccessArticle

Isolation, Characterization, and Unlocking the Potential of Mimir124 Phage for Personalized Treatment of Difficult, Multidrug-Resistant Uropathogenic E. coli Strain

by Alla Golomidova, Yuriy Kupriyanov, Ruslan Gabdrakhmanov, Marina Gurkova, Eugene Kulikov, Ilya Belalov, Viktoria Uskevich, Dmitry Bespiatykh, Maria Letarova, Alexander Efimov, Alexander Kuznetsov, Egor Shitikov, Dmitry Pushkar, Andrey Letarov and Fedor Zurabov

Int. J. Mol. Sci. 2024, 25(23), 12755; https://doi.org/10.3390/ijms252312755 - 27 Nov 2024

Abstract

Escherichia coli and its bacteriophages are among the most studied model microorganisms. Bacteriophages for various E. coli strains can typically be easily isolated from environmental sources, and many of these viruses can be harnessed to combat E. coli infections in humans and animals. [...] Read more.

Escherichia coli and its bacteriophages are among the most studied model microorganisms. Bacteriophages for various E. coli strains can typically be easily isolated from environmental sources, and many of these viruses can be harnessed to combat E. coli infections in humans and animals. However, some relatively rare E. coli strains pose significant challenges in finding suitable phages. The uropathogenic strain E. coli UPEC124, isolated from a patient suffering from neurogenic bladder dysfunction, was found to be resistant to all coliphages in our collections, and initial attempts to isolate new phages failed. Using an improved procedure for phage enrichment, we isolated the N4-related phage Mimir124, belonging to the Gamaleyavirus genus, which was able to lyse this “difficult” E. coli strain. Although Mimir124 is a narrow-spectrum phage, it was effective in the individualized treatment of the patient, leading to pathogen eradication. The primary receptor of Mimir124 was the O antigen of the O101 type; consequently, Mimir124-resistant clones were rough (having lost the O antigen). These clones, however, gained sensitivity to some phages that recognize outer membrane proteins as receptors. Despite the presence of nine potential antiviral systems in the genome of the UPEC124 strain, the difficulty in finding effective phages was largely due to the efficient, non-specific cell surface protection provided by the O antigen. These results highlight the importance of an individualized approach to phage therapy, where narrow host-range phages—typically avoided in pre-fabricated phage cocktails—may be instrumental. Furthermore, this study illustrates how integrating genomic, structural, and functional insights can guide the development of innovative therapeutic strategies, paving the way for broader applications of phage therapy in combating multidrug-resistant bacterial pathogens. Full article

(This article belongs to the Special Issue Molecular Research of Microbial Infection and Phage Therapy)

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20 pages, 1759 KiB

Open AccessArticle

Genome-Wide Identification of the Lectin Receptor-Like Kinase Gene Family in Avena sativa and Its Role in Salt Stress Tolerance

by Gui Xiong, Dongli Cui, Yaqi Tian, Trude Schwarzacher, John Seymour Heslop-Harrison and Qing Liu

Int. J. Mol. Sci. 2024, 25(23), 12754; https://doi.org/10.3390/ijms252312754 - 27 Nov 2024

Abstract

Lectin receptor-like kinases (LecRLKs) are membrane-bound receptor genes found in many plant species. They are involved in perceiving stresses and responding to the environment. Oat (Avena sativa; 2n = 6x = 42) are an important food and forage crop [...] Read more.

Lectin receptor-like kinases (LecRLKs) are membrane-bound receptor genes found in many plant species. They are involved in perceiving stresses and responding to the environment. Oat (Avena sativa; 2n = 6x = 42) are an important food and forage crop with potential in drought, saline, or alkaline soils. Here, we present a comprehensive genome-wide analysis of the LecRLK gene family in A. sativa and the crop’s wild relatives A. insularis (4x) and A. longiglumis (2x), unveiling a rich diversity with a total of 390 LecRLK genes identified, comprising 219 G-types, 168 L-types, and 3 C-types in oats. Genes were unevenly distributed across the oat chromosomes. GFP constructs show that family members were predominantly located in the plasma membrane. Expression under salt stress demonstrated functional redundancy and differential expression of LecRLK gene family members in oats: 173 members of this family were involved in the response to salt stress, and the expression levels of three C-type genes in the root and leaf were significantly increased under salt stress. The results show the diversity, evolutionary dynamics, and functional implications of the LecRLK gene family in A. sativa, setting a foundation for defining its roles in plant development and stress resilience, and suggesting its potential agricultural application for crop improvement. Full article

(This article belongs to the Special Issue Genetic Engineering of Plants for Stress Tolerance)

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