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14 pages, 4547 KiB

Open AccessArticle

Inhibition of KDM2/7 Promotes Notochordal Differentiation of hiPSCs

by Martha E. Diaz-Hernandez, Kimihide Murakami, Shizumasa Murata, Nazir M. Khan, Sreekala P. V. Shenoy, Katrin Henke, Hiroshi Yamada and Hicham Drissi

Cells 2024, 13(17), 1482; https://doi.org/10.3390/cells13171482 (registering DOI) - 4 Sep 2024

Abstract

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal [...] Read more.

Intervertebral disc disease (IDD) is a debilitating spine condition that can be caused by intervertebral disc (IVD) damage which progresses towards IVD degeneration and dysfunction. Recently, human pluripotent stem cells (hPSCs) were recognized as a valuable resource for cell-based regenerative medicine in skeletal diseases. Therefore, adult somatic cells reprogrammed into human induced pluripotent stem cells (hiPSCs) represent an attractive cell source for the derivation of notochordal-like cells (NCs) as a first step towards the development of a regenerative therapy for IDD. Utilizing a differentiation method involving treatment with a four-factor cocktail targeting the BMP, FGF, retinoic acid, and Wnt signaling pathways, we differentiate CRISPR/Cas9-generated mCherry-reporter knock-in hiPSCs into notochordal-like cells. Comprehensive analysis of transcriptomic changes throughout the differentiation process identified regulation of histone methylation as a pivotal driver facilitating the differentiation of hiPSCs into notochordal-like cells. We further provide evidence that specific inhibition of histone demethylases KDM2A and KDM7A/B enhanced the lineage commitment of hiPSCs towards notochordal-like cells. Our results suggest that inhibition of KDMs could be leveraged to alter the epigenetic landscape of hiPSCs to control notochord-specific gene expression. Thus, our study highlights the importance of epigenetic regulators in stem cell-based regenerative approaches for the treatment of disc degeneration. Full article

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20 pages, 9382 KiB

Open AccessArticle

Enhancing the Antibody Production Efficiency of Chinese Hamster Ovary Cells through Improvement of Disulfide Bond Folding Ability and Apoptosis Resistance

by Chen Zhang, Yunhui Fu, Wenyun Zheng, Feng Chang, Yue Shen, Jinping Niu, Yangmin Wang and Xingyuan Ma

Cells 2024, 13(17), 1481; https://doi.org/10.3390/cells13171481 (registering DOI) - 4 Sep 2024

Abstract

The complex structure of monoclonal antibodies (mAbs) expressed in Chinese hamster ovary (CHO) cells may result in the accumulation of unfolded proteins, triggering endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). If the protein folding ability cannot maintain ER homeostasis, the [...] Read more.

The complex structure of monoclonal antibodies (mAbs) expressed in Chinese hamster ovary (CHO) cells may result in the accumulation of unfolded proteins, triggering endoplasmic reticulum (ER) stress and an unfolded protein response (UPR). If the protein folding ability cannot maintain ER homeostasis, the cell will shut down protein translation and ultimately induce apoptosis. We co-overexpressed HsQSOX1b and survivin proteins in the antibody-producing cell line CHO-PAb to obtain a new cell line, CHO-PAb-QS. Compared with CHO-PAb cells, the survival time of CHO-PAb-QS cells in batch culture was extended by 2 days, and the antibody accumulation and productivity were increased by 52% and 45%, respectively. The proportion of (HC-LC)₂ was approximately doubled in the CHO-PAb-QS cells, which adapted to the accelerated disulfide bond folding capacity by upregulating the UPR’s strength and increasing the ER content. The results of the apoptosis assays indicated that the CHO-PAb-QS cell line exhibited more excellent resistance to apoptosis induced by ER stress. Finally, CHO-PAb-QS cells exhibited mild oxidative stress but did not significantly alter the redox status. This study demonstrated that strategies based on HsQSOX1b and survivin co-overexpression could facilitate protein disulfide bond folding and anti-apoptosis ability, enhancing antibody production efficiency in CHO cell lines. Full article

(This article belongs to the Collection Advances in Cell Culture and Tissue Engineering)

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18 pages, 994 KiB

Open AccessReview

Pre-Clinical Models for CAR T-Cell Therapy for Glioma

by Gust Vandecandelaere, Rishab Ramapriyan, Matthew Gaffey, Leland Geoffrey Richardson, Samuel Jeffrey Steuart, Masih Tazhibi, Adrian Kalaw, Eric P. Grewal, Jing Sun, William T. Curry and Bryan D. Choi

Cells 2024, 13(17), 1480; https://doi.org/10.3390/cells13171480 (registering DOI) - 4 Sep 2024

Abstract

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR [...] Read more.

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors. Full article

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34 pages, 13933 KiB

Open AccessArticle

by Michael V. Zaragoza, Thuy-Anh Bui, Halida P. Widyastuti, Mehrsa Mehrabi, Zixuan Cang, Yutong Sha, Anna Grosberg and Qing Nie

Cells 2024, 13(17), 1479; https://doi.org/10.3390/cells13171479 - 3 Sep 2024

Abstract

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins [...] Read more.

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. The molecular mechanisms of the disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of LMNA-related DCM using induced pluripotent stem cells derived from a family with a heterozygous LMNA c.357-2A>G splice-site mutation. We differentiated one LMNA-mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (four from Patients and eight from Controls) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for cardiac progenitors to cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Data integration and comparative analyses of Patient and Control cells found cell type and lineage-specific differentially expressed genes (DEGs) with enrichment, supporting pathway dysregulation. Top DEGs and enriched pathways included 10 ZNF genes and RNA polymerase II transcription in pluripotent cells (PP); BMP4 and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, CDH2 and EMT in CMs; LMNA and epigenetic regulation, as well as DDIT4 and mTORC1 signaling in EPDCs. Top DEGs also included XIST and other X-linked genes, six imprinted genes (SNRPN, PWAR6, NDN, PEG10, MEG3, MEG8), and enriched gene sets related to metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs, as proposed in other LMNA disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model. Full article

(This article belongs to the Collection Lamins and Laminopathies)

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18 pages, 3854 KiB

Open AccessArticle

An Abscopal Effect on Lung Metastases in Canine Mammary Cancer Patients Induced by Neoadjuvant Intratumoral Immunotherapy with Cowpea Mosaic Virus Nanoparticles and Anti-Canine PD-1

by Petra Sergent, Juan Carlos Pinto-Cárdenas, Adhara Jaciel Arreguin Carrillo, Daniel Luna Dávalos, Marisa Daniela González Pérez, Dora Alicia Mendoza Lechuga, Daniel Alonso-Miguel, Evelien Schaafsma, Abigail Jiménez Cuarenta, Diana Cárdenas Muñoz, Yuliana Zarabanda, Scott M. Palisoul, Petra J. Lewis, Fred W. Kolling IV, Jessica Fernanda Affonso de Oliveira, Nicole F. Steinmetz, Jay L. Rothstein, Louise Lines, Randolph J. Noelle, Steven Fiering and Hugo Arias-Pulido Show full author list Hide full author list

Cells 2024, 13(17), 1478; https://doi.org/10.3390/cells13171478 - 3 Sep 2024

Abstract

Neoadjuvant intratumoral (IT) therapy could amplify the weak responses to checkpoint blockade therapy observed in breast cancer (BC). In this study, we administered neoadjuvant IT anti-canine PD-1 therapy (IT acPD-1) alone or combined with IT cowpea mosaic virus therapy (IT CPMV/acPD-1) to companion [...] Read more.

Neoadjuvant intratumoral (IT) therapy could amplify the weak responses to checkpoint blockade therapy observed in breast cancer (BC). In this study, we administered neoadjuvant IT anti-canine PD-1 therapy (IT acPD-1) alone or combined with IT cowpea mosaic virus therapy (IT CPMV/acPD-1) to companion dogs diagnosed with canine mammary cancer (CMC), a spontaneous tumor resembling human BC. CMC patients treated weekly with acPD-1 (n = 3) or CPMV/acPD-1 (n = 3) for four weeks or with CPMV/acPD-1 (n = 3 patients not candidates for surgery) for up to 11 weeks did not experience immune-related adverse events. We found that acPD-1 and CPMV/acPD-1 injections resulted in tumor control and a reduction in injected tumors in all patients and in noninjected tumors located in the ipsilateral and contralateral mammary chains of treated dogs. In two metastatic CMC patients, CPMV/acPD-1 treatments resulted in the control and reduction of established lung metastases. CPMV/acPD-1 treatments were associated with altered gene expression related to TLR1–4 signaling and complement pathways. These novel therapies could be effective for CMC patients. Owing to the extensive similarities between CMC and human BC, IT CPMV combined with approved anti-PD-1 therapies could be a novel and effective immunotherapy to treat local BC and suppress metastatic BC. Full article

(This article belongs to the Special Issue Cancer Immunotherapy Harnessing Innate and Adaptive Immune Effector Cells and PD-1 Immune Checkpoint Inhibitors)

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27 pages, 11038 KiB

Open AccessArticle

The Effect of Synthetic Polyamine BPA-C8 on the Fertilization Process of Intact and Denuded Sea Urchin Eggs

by Nunzia Limatola, Jong Tai Chun, Jean-Louis Schmitt, Jean-Marie Lehn and Luigia Santella

Cells 2024, 13(17), 1477; https://doi.org/10.3390/cells13171477 - 2 Sep 2024

Abstract

Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs’ JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote [...] Read more.

Sea urchin eggs are covered with layers of extracellular matrix, namely, the vitelline layer (VL) and jelly coat (JC). It has been shown that sea urchin eggs’ JC components serve as chemoattractants or ligands for the receptor on the fertilizing sperm to promote the acrosome reaction. Moreover, the egg’s VL provides receptors for conspecific sperm to bind, and, to date, at least two sperm receptors have been identified on the surface of sea urchin eggs. Interestingly, however, according to our previous work, denuded sea urchin eggs devoid of the JC and VL do not fail to become fertilized by sperm. Instead, they are bound and penetratedby multiple sperm, raising the possibility that an alternative pathway independent of the VL-residing sperm receptor may be at work. In this research, we studied the roles of the JC and VL using intact and denuded eggs and the synthetic polyamine BPA-C8. BPA-C8 is known to bind to the negatively charged macromolecular complexes in the cells, such as the JC, VL, and the plasma membrane of echinoderm eggs, as well as to the actin filaments in fibroblasts. Our results showed that, when added to seawater, BPA-C8 significantly repressed the Ca²⁺ wave in the intact P. lividus eggs at fertilization. In eggs deprived of the VL and JC, BPA-C8 binds to the plasma membrane and increases fibrous structures connecting microvilli, thereby allowing the denuded eggs to revert towards monospermy at fertilization. However, the reduced Ca²⁺ signal in denuded eggs was nullified compared to the intact eggs because removing the JC and VL already decreased the Ca²⁺ wave. BPA-C8 does not cross the VL and the cell membrane of unfertilized sea urchin eggs to diffuse into the cytoplasm at variance with the fibroblasts. Indeed, the jasplakinolide-induced polymerization of subplasmalemmal actin filaments was inhibited in the eggs microinjected with BPA-C8, but not in the ones bath-incubated with the same dose of BPA-C8. Full article

(This article belongs to the Special Issue The Cell Biology of Fertilization)

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22 pages, 2712 KiB

Open AccessArticle

Antibody-Mediated Protein Knockdown Reveals Distal-Less Functions for Eyespots and Parafocal Elements in Butterfly Wing Color Pattern Development

by Yugo Nakazato and Joji M. Otaki

Cells 2024, 13(17), 1476; https://doi.org/10.3390/cells13171476 - 2 Sep 2024

Abstract

One of the important genes for eyespot development in butterfly wings is Distal-less. Its function has been evaluated via several methods, including CRISPR/Cas9 genome editing. However, functional inhibition may be performed at the right time at the right place using a different [...] Read more.

One of the important genes for eyespot development in butterfly wings is Distal-less. Its function has been evaluated via several methods, including CRISPR/Cas9 genome editing. However, functional inhibition may be performed at the right time at the right place using a different method. Here, we used a novel protein delivery method for pupal wing tissues in vivo to inactivate a target protein, Distal-less, with a polyclonal anti-Distal-less antibody using the blue pansy butterfly Junonia orithya. We first demonstrated that various antibodies including the anti-Distal-less antibody were delivered to wing epithelial cells in vivo in this species. Treatment with the anti-Distal-less antibody reduced eyespot size, confirming the positive role of Distal-less in eyespot development. The treatment eliminated or deformed a parafocal element, suggesting a positive role of Distal-less in the development of the parafocal element. This result also suggested the integrity of an eyespot and its corresponding parafocal element as the border symmetry system. Taken together, these findings demonstrate that the antibody-mediated protein knockdown method is a useful tool for functional assays of proteins, such as Distal-less, expressed in pupal wing tissues, and that Distal-less functions for eyespots and parafocal elements in butterfly wing color pattern development. Full article

(This article belongs to the Section Reproductive Cells and Development)

19 pages, 6046 KiB

Open AccessArticle

Activation of Yes-Associated Protein Is Indispensable for Transformation of Kidney Fibroblasts into Myofibroblasts during Repeated Administration of Cisplatin

by Jia-Bin Yu, Babu J. Padanilam and Jinu Kim

Cells 2024, 13(17), 1475; https://doi.org/10.3390/cells13171475 - 2 Sep 2024

Abstract

Cisplatin is a potent chemotherapy medication that is used to treat various types of cancer. However, it can cause nephrotoxic side effects, which lead to acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). Although a clinically relevant in vitro model of [...] Read more.

Cisplatin is a potent chemotherapy medication that is used to treat various types of cancer. However, it can cause nephrotoxic side effects, which lead to acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). Although a clinically relevant in vitro model of CKD induced by repeated administration of low-dose cisplatin (RAC) has been established, its underlying mechanisms remain poorly understood. Here, we compared single administration of high-dose cisplatin (SAC) to repeated administration of low-dose cisplatin (RAC) in myofibroblast transformation and cellular morphology in a normal rat kidney fibroblast NRK-49F cell line. RAC instead of SAC transformed the fibroblasts into myofibroblasts as determined by α-smooth muscle actin, enlarged cell size as represented by F-actin staining, and increased cell flattening as expressed by the semidiameter ratio of attached cells to floated cells. Those phenomena, as well as cellular senescence, were significantly detected from the time right before the second administration of cisplatin. Interestingly, inhibition of the interaction between Yes-associated protein (YAP) and the transcriptional enhanced associated domain (TEAD) using Verteporfin remarkedly reduced cell size, cellular senescence, and myofibroblast transformation during RAC. These findings collectively suggest that YAP activation is indispensable for cellular hypertrophy, senescence, and myofibroblast transformation during RAC in kidney fibroblasts. Full article

(This article belongs to the Special Issue Recent Advances in the Development and Progression of Kidney Diseases (Volume II))

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22 pages, 13640 KiB

Open AccessReview

Unraveling the Mystery of Energy-Sensing Enzymes and Signaling Pathways in Tumorigenesis and Their Potential as Therapeutic Targets for Cancer

by Zeenat Mirza and Sajjad Karim

Cells 2024, 13(17), 1474; https://doi.org/10.3390/cells13171474 - 2 Sep 2024

Abstract

Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated [...] Read more.

Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways. Full article

(This article belongs to the Special Issue Kinase Signaling and Kinase-Targeted Therapies on Cancer: Advances, Challenges, and Future Directions—Second Edition)

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27 pages, 23298 KiB

Open AccessArticle

Keratin 8/18a.1 Expression Influences Embryonic Neural Crest Cell Dynamics and Contributes to Postnatal Corneal Regeneration in Zebrafish

by Antionette L. Williams and Brenda L. Bohnsack

Cells 2024, 13(17), 1473; https://doi.org/10.3390/cells13171473 - 2 Sep 2024

Abstract

A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development [...] Read more.

A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development revealed keratin intermediate filament genes krt8 and krt18a.1 as additional factors expressed during anterior segment development. In situ hybridization and immunofluorescence microscopy confirmed krt8 and krt18a.1 expression in the early neural plate border and migrating cranial neural crest cells. Morpholino oligonucleotide (MO)-mediated knockdown of K8 and K18a.1 markedly disrupted the migration of neural crest cell subpopulations and decreased neural crest cell marker gene expression in the craniofacial region and eye at 48 h postfertilization (hpf), resulting in severe phenotypic defects reminiscent of neurocristopathies. Interestingly, the expression of K18a.1, but not K8, is regulated by retinoic acid (RA) during early-stage development. Further, both keratin proteins were detected during postnatal corneal regeneration in adult zebrafish. Altogether, we demonstrated that both K8 and K18a.1 contribute to the early development and postnatal repair of neural crest cell-derived ocular tissues. Full article

(This article belongs to the Special Issue Molecular and Clinical Advances in Understanding Early Embryo Development—Volume II)

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10 pages, 1499 KiB

Open AccessArticle

Maternal Dietary Deficiency in Choline Reduced Levels of MMP-2 Levels in Blood and Brain Tissue of Male Offspring Mice

by Mitra Esfandiarei, Shawn G. U. Strash, Amanda Covaleski, Sharadyn Ille, Weidang Li and Nafisa M. Jadavji

Cells 2024, 13(17), 1472; https://doi.org/10.3390/cells13171472 - 2 Sep 2024

Abstract

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, [...] Read more.

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in the blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. When offspring were 3 months of age, ischemic stroke was induced. One and a half months later, blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and reported reduced levels of MMP-2 in ChDD male offspring in both tissue types. No changes were observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke. Full article

(This article belongs to the Section Cells of the Nervous System)

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71 pages, 6125 KiB

Open AccessReview

A Comprehensive Review of Cardiovascular Disease Management: Cardiac Biomarkers, Imaging Modalities, Pharmacotherapy, Surgical Interventions, and Herbal Remedies

by Vasudeva Reddy Netala, Sireesh Kumar Teertam, Huizhen Li and Zhijun Zhang

Cells 2024, 13(17), 1471; https://doi.org/10.3390/cells13171471 - 1 Sep 2024

Abstract

Cardiovascular diseases (CVDs) continue to be a major global health concern, representing a leading cause of morbidity and mortality. This review provides a comprehensive examination of CVDs, encompassing their pathophysiology, diagnostic biomarkers, advanced imaging techniques, pharmacological treatments, surgical interventions, and the emerging role [...] Read more.

Cardiovascular diseases (CVDs) continue to be a major global health concern, representing a leading cause of morbidity and mortality. This review provides a comprehensive examination of CVDs, encompassing their pathophysiology, diagnostic biomarkers, advanced imaging techniques, pharmacological treatments, surgical interventions, and the emerging role of herbal remedies. The review covers various cardiovascular conditions such as coronary artery disease, atherosclerosis, peripheral artery disease, deep vein thrombosis, pulmonary embolism, cardiomyopathy, rheumatic heart disease, hypertension, ischemic heart disease, heart failure, cerebrovascular diseases, and congenital heart defects. The review presents a wide range of cardiac biomarkers such as troponins, C-reactive protein, CKMB, BNP, NT-proBNP, galectin, adiponectin, IL-6, TNF-α, miRNAs, and oxylipins. Advanced molecular imaging techniques, including chest X-ray, ECG, ultrasound, CT, SPECT, PET, and MRI, have significantly enhanced our ability to visualize myocardial perfusion, plaque characterization, and cardiac function. Various synthetic drugs including statins, ACE inhibitors, ARBs, β-blockers, calcium channel blockers, antihypertensives, anticoagulants, and antiarrhythmics are fundamental in managing CVDs. Nonetheless, their side effects such as hepatic dysfunction, renal impairment, and bleeding risks necessitate careful monitoring and personalized treatment strategies. In addition to conventional therapies, herbal remedies have garnered attention for their potential cardiovascular benefits. Plant extracts and their bioactive compounds, such as flavonoids, phenolic acids, saponins, and alkaloids, offer promising cardioprotective effects and enhanced cardiovascular health. This review underscores the value of combining traditional and modern therapeutic approaches to improve cardiovascular outcomes. This review serves as a vital resource for researchers by integrating a broad spectrum of information on CVDs, diagnostic tools, imaging techniques, pharmacological treatments and their side effects, and the potential of herbal remedies. Full article

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13 pages, 1690 KiB

Open AccessArticle

Curcumin Inhibits TORC1 and Prolongs the Lifespan of Cells with Mitochondrial Dysfunction

by Arshia Naaz, Yizhong Zhang, Nashrul Afiq Faidzinn, Sonia Yogasundaram, Rajkumar Dorajoo and Mohammad Alfatah

Cells 2024, 13(17), 1470; https://doi.org/10.3390/cells13171470 - 1 Sep 2024

Abstract

Aging is an inevitable biological process that contributes to the onset of age-related diseases, often as a result of mitochondrial dysfunction. Understanding the mechanisms behind aging is crucial for developing therapeutic interventions. This study investigates the effects of curcumin on postmitotic cellular lifespan [...] Read more.

Aging is an inevitable biological process that contributes to the onset of age-related diseases, often as a result of mitochondrial dysfunction. Understanding the mechanisms behind aging is crucial for developing therapeutic interventions. This study investigates the effects of curcumin on postmitotic cellular lifespan (PoMiCL) during chronological aging in yeast, a widely used model for human postmitotic cellular aging. Our findings reveal that curcumin significantly prolongs the PoMiCL of wildtype yeast cells, with the most pronounced effects observed at lower concentrations, indicating a hormetic response. Importantly, curcumin also extends the lifespan of postmitotic cells with mitochondrial deficiencies, although the hormetic effect is absent in these defective cells. Mechanistically, curcumin inhibits TORC1 activity, enhances ATP levels, and induces oxidative stress. These results suggest that curcumin has the potential to modulate aging and offer therapeutic insights into age-related diseases, highlighting the importance of context in its effects. Full article

(This article belongs to the Special Issue Understanding Aging Mechanisms to Prevent Age-Related Diseases)

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17 pages, 1063 KiB

Open AccessReview

The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update

by Roberto Campagna, Laura Mazzanti, Veronica Pompei, Sonila Alia, Arianna Vignini and Monica Emanuelli

Cells 2024, 13(17), 1469; https://doi.org/10.3390/cells13171469 - 1 Sep 2024

Abstract

NAD⁺-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such [...] Read more.

NAD⁺-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging. Full article

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15 pages, 3889 KiB

Open AccessArticle

Understanding Macrophage Interaction with Antimony-Doped Tin Oxide Plasmonic Nanoparticles

by Olexiy Balitskii, Viktoriya Ivasiv, Maria Porteiro-Figueiras, Phattadon Yajan, Mira Witzig, Aura Maria Moreno-Echeverri, José Muñetón Díaz, Barbara Rothen-Rutishauser, Alke Petri-Fink and Sandeep Keshavan

Cells 2024, 13(17), 1468; https://doi.org/10.3390/cells13171468 (registering DOI) - 1 Sep 2024

Abstract

Antimony-doped tin oxide nanoparticles (ATO NPs) have emerged as a promising tool in biomedical applications, namely robust photothermal effects upon near-infrared (NIR) light exposure, enabling controlled thermal dynamics to induce spatial cell death. This study investigated the interplay between ATO NPs and macrophages, [...] Read more.

Antimony-doped tin oxide nanoparticles (ATO NPs) have emerged as a promising tool in biomedical applications, namely robust photothermal effects upon near-infrared (NIR) light exposure, enabling controlled thermal dynamics to induce spatial cell death. This study investigated the interplay between ATO NPs and macrophages, understanding cellular uptake and cytokine release. ATO NPs demonstrated biocompatibility with no impact on macrophage viability and cytokine secretion. These findings highlight the potential of ATO NPs for inducing targeted cell death in cancer treatments, leveraging their feasibility, unique NIR properties, and safe interactions with immune cells. ATO NPs offer a transformative platform with significant potential for future biomedical applications by combining photothermal capabilities and biocompatibility. Full article

(This article belongs to the Special Issue New Advances and Perspectives in Nanotechnology for the Treatment of Cancer Cells)

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14 pages, 1700 KiB

Open AccessReview

The Nuclear NF-κB Regulator IκBζ: Updates on Its Molecular Functions and Pathophysiological Roles

by Soh Yamazaki

Cells 2024, 13(17), 1467; https://doi.org/10.3390/cells13171467 - 31 Aug 2024

Abstract

More than a decade after the discovery of the classical cytoplasmic IκB proteins, IκBζ was identified as an additional member of the IκB family. Unlike cytoplasmic IκB proteins, IκBζ has distinct features, including its nuclear localization, preferential binding to NF-κB subunits, unique expression [...] Read more.

More than a decade after the discovery of the classical cytoplasmic IκB proteins, IκBζ was identified as an additional member of the IκB family. Unlike cytoplasmic IκB proteins, IκBζ has distinct features, including its nuclear localization, preferential binding to NF-κB subunits, unique expression properties, and specialized role in NF-κB regulation. While the activation of NF-κB is primarily controlled by cytoplasmic IκB members at the level of nuclear entry, IκBζ provides an additional layer of NF-κB regulation in the nucleus, enabling selective gene activation. Human genome-wide association studies (GWAS) and gene knockout experiments in mice have elucidated the physiological and pathological roles of IκBζ. Despite the initial focus to its role in activated macrophages, IκBζ has since been recognized as a key player in the IL-17-triggered production of immune molecules in epithelial cells, which has garnered significant clinical interest. Recent research has also unveiled a novel molecular function of IκBζ, linking NF-κB and the POU transcription factors through its N-terminal region, whose role had remained elusive for many years. Full article

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26 pages, 7315 KiB

Open AccessArticle

Breast Cancer Stem Cells Upregulate IRF6 in Stromal Fibroblasts to Induce Stromagenesis

by Harshini Muralidharan, Thomas Hansen, Anja Steinle, David Schumacher, Elmar Stickeler and Jochen Maurer

Cells 2024, 13(17), 1466; https://doi.org/10.3390/cells13171466 - 31 Aug 2024

Abstract

The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with [...] Read more.

The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with specific seeding ratios, we identified stromal fibroblast aggregation at the BCSC cluster periphery, and, on closer observation, the aggregated fibroblasts was found to encircle BCSC clusters in nematic organization. In addition, collagen type I and fibronectin accumulation were also found at the BCSC–stromal periphery. MACE-Seq analysis of BCSC-encapsulating fibroblasts displayed the transformation of stromal fibroblasts to CAFs and the upregulation of fibrosis regulating genes of which the Interferon Regulatory Factor 6 (IRF6) gene was identified. Loss of function experiments with the IRF6 gene decreased fibroblast encapsulation around BCSC clusters in 2D co-cultures. In BCSC xenografts, fibroblast IRF6 expression led to an increase in the stromal area and fibroblast density in tumors, in addition to a reduction in necrotic growth. Based on our findings, we propose that fibroblast IRF6 function is an important factor in the development of the stromal microenvironment and in sustaining the BCSC tumor niche. Full article

(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Challenges and Directions)

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22 pages, 5355 KiB

Open AccessArticle

1,25-Dihydroxyvitamin D Enhances the Regenerative Function of Lgr5⁺ Intestinal Stem Cells In Vitro and In Vivo

by Nisar Ali Shaikh, Chenfan Liu, Yue Yin, David J. Baylink and Xiaolei Tang

Cells 2024, 13(17), 1465; https://doi.org/10.3390/cells13171465 - 31 Aug 2024

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestines without a cure. Current therapies suppress inflammation to prevent further intestinal damage. However, healing already damaged intestinal epithelia is still an unmet medical need. Under physiological conditions, Lgr5⁺ intestinal stem [...] Read more.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestines without a cure. Current therapies suppress inflammation to prevent further intestinal damage. However, healing already damaged intestinal epithelia is still an unmet medical need. Under physiological conditions, Lgr5⁺ intestinal stem cells (ISCs) in the intestinal crypts replenish the epithelia every 3–5 days. Therefore, understanding the regulation of Lgr5⁺ ISCs is essential. Previous data suggest vitamin D signaling is essential to maintain normal Lgr5⁺ ISC function in vivo. Our recent data indicate that to execute its functions in the intestines optimally, 1,25(OH)₂D requires high concentrations that, if present systemically, can cause hypercalcemia (i.e., blood calcium levels significantly higher than physiological levels), leading to severe consequences. Using 5-bromo-2′-deoxyuridine (BrdU) to label the actively proliferating ISCs, our previous data suggested that de novo synthesized locally high 1,25(OH)₂D concentrations effectively enhanced the migration and differentiation of ISCs without causing hypercalcemia. However, although sparse in the crypts, other proliferating cells other than Lgr5⁺ ISCs could also be labeled with BrdU. This current study used high-purity Lgr5⁺ ISC lines and a mouse strain, in which Lgr5⁺ ISCs and their progeny could be specifically tracked, to investigate the effects of de novo synthesized locally high 1,25(OH)₂D concentrations on Lgr5⁺ ISC function. Our data showed that 1,25(OH)₂D at concentrations significantly higher than physiological levels augmented Lgr5⁺ ISC differentiation in vitro. In vivo, de novo synthesized locally high 1,25(OH)₂D concentrations significantly elevated local 1α-hydroxylase expression, robustly suppressed experimental colitis, and promoted Lgr5⁺ ISC differentiation. For the first time, this study definitively demonstrated 1,25(OH)₂D’s role in Lgr5⁺ ISCs, underpinning 1,25(OH)₂D’s promise in IBD therapy. Full article

(This article belongs to the Special Issue Vitamin D in Intestinal Health and Diseases)

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16 pages, 1532 KiB

Open AccessReview

Maintaining the Balance: Regulation of NK Cell Activity

by Vanna Imširović, Felix M. Wensveen, Bojan Polić and Vedrana Jelenčić

Cells 2024, 13(17), 1464; https://doi.org/10.3390/cells13171464 - 31 Aug 2024

Abstract

Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather [...] Read more.

Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather than depending on the engagement of a single activating receptor, their activation involves a delicate balance between inhibitory and activating signals mediated through an array of surface molecules. Only when this cumulative balance surpasses a specific threshold do NK cells initiate their activity. Remarkably, the activation threshold of NK cells remains robust even when cells express vastly different repertoires of inhibitory and activating receptors. These threshold values seem to be influenced by NK cell interactions with their environment during development and after release from the bone marrow. Understanding how NK cells integrate this intricate pattern of stimuli is an ongoing area of research, particularly relevant for cellular therapies seeking to harness the anti-cancer potential of these cells by modifying surface receptor expression. In this review, we will explore some of the current dogmas regarding NK cell activation and discuss recent literature addressing advances in our understanding of this field. Full article

(This article belongs to the Special Issue Advances in the Study of Natural Killer (NK) Cells)

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