Cells

19 pages, 4912 KiB

Open AccessArticle

Enhancement of Tendon Repair Using Tendon-Derived Stem Cells in Small Intestinal Submucosa via M2 Macrophage Polarization

by Xufeng Mao, Liwei Yao, Mei Li, Xiqian Zhang, Bowen Weng, Weilai Zhu, Renhao Ni, Kanan Chen, Linhua Yi, Jiyuan Zhao and Haijiao Mao

Cells 2022, 11(17), 2770; https://doi.org/10.3390/cells11172770 - 05 Sep 2022

Cited by 14 | Viewed by 2389

Abstract

(1) Background: Reconstruction of Achilles tendon defects and prevention of postoperative tendon adhesions were two serious clinical problems. In the treatment of Achilles tendon defects, decellularized matrix materials and mesenchymal stem cells (MSCs) were thought to address both problems. (2) Methods: In vitro, [...] Read more.

(1) Background: Reconstruction of Achilles tendon defects and prevention of postoperative tendon adhesions were two serious clinical problems. In the treatment of Achilles tendon defects, decellularized matrix materials and mesenchymal stem cells (MSCs) were thought to address both problems. (2) Methods: In vitro, cell adhesion, proliferation, and tenogenic differentiation of tendon-derived stem cells (TDSCs) on small intestinal submucosa (SIS) were evaluated. RAW264.7 was induced by culture medium of TDSCs and TDSCs–SIS scaffold groups. A rat Achilles tendon defect model was used to assess effects on tendon regeneration and antiadhesion in vivo. (3) Results: SIS scaffold facilitated cell adhesion and tenogenic differentiation of TDSCs, while SIS hydrogel coating promoted proliferation of TDSCs. The expression of TGF-β and ARG-1 in the TDSCs-SIS scaffold group were higher than that in the TDSCs group on day 3 and 7. In vivo, the tendon regeneration and antiadhesion capacity of the implanted TDSCs–SIS scaffold was significantly enhanced. The expression of CD163 was significantly highest in the TDSCs–SIS scaffold group; meanwhile, the expression of CD68 decreased more significantly in the TDSCs–SIS scaffold group than the other two groups. (4) Conclusion: This study showed that biologically prepared SIS scaffolds synergistically promote tendon regeneration with TDSCs and achieve antiadhesion through M2 polarization of macrophages. Full article

(This article belongs to the Topic Stem Cell Differentiation and Applications)

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19 pages, 4767 KiB

Open AccessArticle

Differentiation Capacity of Bone Marrow-Derived Rat Mesenchymal Stem Cells from DsRed and Cre Transgenic Cre/loxP Models

by Hsiang-Ching Tseng, Menq-Rong Wu, Chia-Hsun Lee and Jong-Kai Hsiao

Cells 2022, 11(17), 2769; https://doi.org/10.3390/cells11172769 - 05 Sep 2022

Cited by 4 | Viewed by 1875

Abstract

Cre/loxP recombination is a well-established technique increasingly used for modifying DNA both in vitro and in vivo. Nucleotide alterations can be edited in the genomes of mammalian cells, and genetic switches can be designed to target the expression or excision of a [...] Read more.

Cre/loxP recombination is a well-established technique increasingly used for modifying DNA both in vitro and in vivo. Nucleotide alterations can be edited in the genomes of mammalian cells, and genetic switches can be designed to target the expression or excision of a gene in any tissue at any time in animal models. In this study, we propose a system which worked via the Cre/loxP switch gene and DsRed/emGFP dual-color fluorescence imaging. Mesenchymal stem cells (MSCs) can be used to regenerate damaged tissue because of their differentiation capacity. Although previous studies have presented evidence of fusion of transplanted MSCs with recipient cells, the possibility of fusion in such cases remains debated. Moreover, the effects and biological implications of the fusion of MSCs at the tissue and organ level have not yet been elucidated. Thus, the method for determining this issue is significant and the models we proposed can illustrate the question. However, the transgenic rats exhibited growth slower than that of wild-type rats over several weeks. The effects on the stemness, proliferation, cell cycle, and differentiation ability of bone marrow–derived rat MSCs (BM-rMSCs) from the models were examined to ensure our design was appropriate for the in vivo application. We demonstrated that MSC surface markers were maintained in DsRed and Cre transgenic rMSCs (DsRed-rMSCs and Cre-rMSCs, respectively). A WST-8 assay revealed decreased proliferative activity in these DsRed-rMSCs and Cre-rMSCs; this result was validated through cell counting. Furthermore, cell cycle analysis indicated a decrease in the proportion of G1-phase cells and a concomitant increase in the proportion of S-phase cells. The levels of cell cycle–related proteins also decreased in the DsRed-rMSCs and Cre-rMSCs, implying decelerated phase transition. However, the BM-rMSCs collected from the transgenic rats did not exhibit altered adipogenesis, osteogenesis, or chondrogenesis. The specific markers of these types of differentiation were upregulated after induction. Therefore, BM-rMSCs from DsRed and Cre transgenic models can be used to investigate the behavior of MSCs and related mechanisms. Such application may further the development of stem cell therapy for tissue damage and other diseases. Full article

(This article belongs to the Special Issue Regeneration of Tissue with Mesenchymal Stem Cells)

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13 pages, 2686 KiB

Open AccessArticle

The Dynamic Changes of Alternative Electron Flows upon Transition from Low to High Light in the Fern Cyrtomium fortune and the Gymnosperm Nageia nagi

by Jun-Bin Cheng, Shi-Bao Zhang, Jin-Song Wu and Wei Huang

Cells 2022, 11(17), 2768; https://doi.org/10.3390/cells11172768 - 05 Sep 2022

Cited by 1 | Viewed by 1349

Abstract

In photosynthetic organisms except angiosperms, an alternative electron sink that is mediated by flavodiiron proteins (FLVs) plays the major role in preventing PSI photoinhibition while cyclic electron flow (CEF) is also essential for normal growth under fluctuating light. However, the dynamic changes of [...] Read more.

In photosynthetic organisms except angiosperms, an alternative electron sink that is mediated by flavodiiron proteins (FLVs) plays the major role in preventing PSI photoinhibition while cyclic electron flow (CEF) is also essential for normal growth under fluctuating light. However, the dynamic changes of FLVs and CEF has not yet been well clarified. In this study, we measured the P700 signal, chlorophyll fluorescence, and electrochromic shift spectra in the fern Cyrtomium fortune and the gymnosperm Nageia nagi. We found that both species could not build up a sufficient proton gradient (∆pH) within the first 30 s after light abruptly increased. During this period, FLVs-dependent alternative electron flow was functional to avoid PSI over-reduction. This functional time of FLVs was much longer than previously thought. By comparison, CEF was highly activated within the first 10 s after transition from low to high light, which favored energy balancing rather than the regulation of a PSI redox state. When FLVs were inactivated during steady-state photosynthesis, CEF was re-activated to favor photoprotection and to sustain photosynthesis. These results provide new insight into how FLVs and CEF interact to regulate photosynthesis in non-angiosperms. Full article

(This article belongs to the Special Issue Research on Photosynthesis under Stress)

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22 pages, 856 KiB

Open AccessReview

Pathophysiology and Therapy of Associated Features of Migraine

by Maria Dolores Villar-Martinez and Peter J. Goadsby

Cells 2022, 11(17), 2767; https://doi.org/10.3390/cells11172767 - 05 Sep 2022

Cited by 14 | Viewed by 5171

Abstract

Migraine is a complex and debilitating disorder that is broadly recognised by its characteristic headache. However, given the wide array of clinical presentations in migraineurs, the headache might not represent the main troublesome symptom and it can even go unnoticed. Understanding migraines exclusively [...] Read more.

Migraine is a complex and debilitating disorder that is broadly recognised by its characteristic headache. However, given the wide array of clinical presentations in migraineurs, the headache might not represent the main troublesome symptom and it can even go unnoticed. Understanding migraines exclusively as a pain process is simplistic and certainly hinders management. We describe the mechanisms behind some of the most disabling associated symptoms of migraine, including the relationship between the central and peripheral processes that take part in nausea, osmophobia, phonophobia, vertigo and allodynia. The rationale for the efficacy of the current therapeutic arsenal is also depicted in this article. The associated symptoms to migraine, apart from the painful component, are frequent, under-recognised and can be more deleterious than the headache itself. The clinical anamnesis of a headache patient should enquire about the associated symptoms, and treatment should be considered and individualised. Acknowledging the associated symptoms as a fundamental part of migraine has permitted a deeper and more coherent comprehension of the pathophysiology of migraine. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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31 pages, 5830 KiB

Open AccessArticle

Extracellular Vesicle-Mediated miR-150-3p Delivery in Joint Homeostasis: A Potential Treatment for Osteoarthritis?

by Huan Wang, Jun Shu, Chengfei Zhang, Yang Wang, Rongxing Shi, Fan Yang and Xuezhang Tang

Cells 2022, 11(17), 2766; https://doi.org/10.3390/cells11172766 - 05 Sep 2022

Cited by 6 | Viewed by 2196

Abstract

Background: The disruption of joint homeostasis is a critical event during the process of joint injury in osteoarthritis (OA). As regulatory molecules, microRNAs (miRNAs) can be released from secretory cells and delivered to recipient cells through extracellular vesicles (EVs), thereby playing an important [...] Read more.

Background: The disruption of joint homeostasis is a critical event during the process of joint injury in osteoarthritis (OA). As regulatory molecules, microRNAs (miRNAs) can be released from secretory cells and delivered to recipient cells through extracellular vesicles (EVs), thereby playing an important role in regulating joint homeostasis. We hypothesized that the fibroblast-like synoviocytes (FLSs) in healthy joints could release EVs enriched in miRNAs that can maintain joint homeostasis by regulating the signal transduction pathways in the joints, whereby the articular cartilage (AC) is protected from degeneration, and OA progression is delayed. Methods: Via high-throughput sequencing and qPCR, we found that miR-150-3p was enriched in the circulating EVs in healthy rats. Next, we established an in vitro cell model in which chondrocytes were cultured with (i) FLSs transfected with miR-150-3p mimics or (ii) EVs released by FLSs (FLS–EVs) inside the healthy synovial membrane (SM). The transportation mechanism from FLSs to chondrocytes was studied using the EV inhibitor GW4869, and the FLSs were transfected with a miR-150-3p mimic or inhibitor. To assess the therapeutic effect of miR-150-3p-carrying EVs (EVs-150) in vivo, healthy FLS-derived EVs (H-FLS–EVs) were injected into the tail vein of rats with OA at various stages of the pathogenesis and evaluated for the progression of OA. Results: The chondrocytes could uptake fluorescent-labeled miR-150-3p mimics and FLS–EVs, and GW4869 suppressed this uptake. The overexpression of miR-150-3p could significantly reduce the concentrations of pro-inflammatory cytokines in the cell culture medium and the expression of the miR-150-3p target T cell receptor-interacting molecule 14 (Trim14), as well as the innate immune-related factors, including nuclear factor kappa B (NF-κB) and interferon-β (IFN-β). Similarly to the in vitro findings, the miR-150-3p level in the serum EVs was significantly upregulated among the EV-treated rats. In the AC of the OA rat model injected with H-FLS–EVs, the joint degeneration was suppressed, and Type II collagen (COLII) and aggrecan (ACAN) were significantly upregulated, whereas the innate immune-related factors Trim14, NF-κB, and IFN-β were downregulated compared with the levels in the untreated OA rats. Notably, the suppression of joint degeneration was more significant when H-FLS–EVs were administered at the early stages of OA rather than the late stages. Conclusion: H-FLS–EVs protect chondrocyte function and maintain joint homeostasis by modulating the innate immune response by suppressing the Trim14/NF-κB/IFNβ axis. These effects are achieved through the EV-mediated transport of miR-150-3p from the FLSs to the chondrocytes. Our findings show that EV-mediated miR-150-3p can be used to suppress OA, thus providing a novel therapeutic strategy. Additionally, the EV-mediated miR-150-3p transport may also serve as a potential biomarker in the diagnosis, treatment, and prognosis of OA. Full article

(This article belongs to the Collection microRNAs in Health and Diseases)

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18 pages, 8959 KiB

Open AccessArticle

Transplantation of Human Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Promotes Forelimb Functional Recovery after Cervical Spinal Cord Injury

by Yiyan Zheng, Chrystine M. Gallegos, Haipeng Xue, Shenglan Li, Dong H. Kim, Hongxia Zhou, Xugang Xia, Ying Liu and Qilin Cao

Cells 2022, 11(17), 2765; https://doi.org/10.3390/cells11172765 - 05 Sep 2022

Cited by 5 | Viewed by 2130

Abstract

Locomotor function after spinal cord injury (SCI) is critical for assessing recovery. Currently, available means to improve locomotor function include surgery, physical therapy rehabilitation and exoskeleton. Stem cell therapy with neural progenitor cells (NPCs) transplantation is a promising reparative strategy. Along this line, [...] Read more.

Locomotor function after spinal cord injury (SCI) is critical for assessing recovery. Currently, available means to improve locomotor function include surgery, physical therapy rehabilitation and exoskeleton. Stem cell therapy with neural progenitor cells (NPCs) transplantation is a promising reparative strategy. Along this line, patient-specific induced pluripotent stem cells (iPSCs) are a remarkable autologous cell source, which offer many advantages including: great potential to generate isografts avoiding immunosuppression; the availability of a variety of somatic cells without ethical controversy related to embryo use; and vast differentiation. In this current work, to realize the therapeutic potential of iPSC-NPCs for the treatment of SCI, we transplanted purified iPSCs-derived NPCs into a cervical contusion SCI rat model. Our results showed that the iPSC-NPCs were able to survive and differentiate into both neurons and astrocytes and, importantly, improve forelimb locomotor function as assessed by the grooming task and horizontal ladder test. Purified iPSC-NPCs represent a promising cell type that could be further tested and developed into a clinically useful cell source for targeted cell therapy for cervical SCI patients. Full article

(This article belongs to the Collection Cell Biology of Spinal Cord Injury and Repair)

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17 pages, 1325 KiB

Open AccessReview

Current Understanding of Asthma Pathogenesis and Biomarkers

by Nazia Habib, Muhammad Asghar Pasha and Dale D. Tang

Cells 2022, 11(17), 2764; https://doi.org/10.3390/cells11172764 - 05 Sep 2022

Cited by 51 | Viewed by 11316

Abstract

Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most [...] Read more.

Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most important pathological process for asthma, which is mediated by Th2 cytokines, such as interleukin (IL)-5, IL-4, and IL-13. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2-low asthma can be mediated by non-Th2 cytokines, including IL-17 and tumor necrosis factor-α. There is emerging evidence to demonstrate that inflammation-independent processes also contribute to asthma pathogenesis. Protein kinases, adapter protein, microRNAs, ORMDL3, and gasdermin B are newly identified molecules that drive asthma progression, independent of inflammation. Eosinophils, IgE, fractional exhaled nitric oxide, and periostin are practical biomarkers for Th2-high asthma. Sputum neutrophils are easily used to diagnose Th2-low asthma. Despite progress, more studies are needed to delineate complex endotypes of asthma and to identify new and practical biomarkers for better diagnosis, classification, and treatment. Full article

(This article belongs to the Special Issue Airway Smooth Muscle and Asthma)

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15 pages, 1035 KiB

Open AccessReview

A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation

by Marc Micó-Carnero, Mohamed Amine Zaouali, Carlos Rojano-Alfonso, Cristina Maroto-Serrat, Hassen Ben Abdennebi and Carmen Peralta

Cells 2022, 11(17), 2763; https://doi.org/10.3390/cells11172763 - 05 Sep 2022

Cited by 6 | Viewed by 2519

Abstract

The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context [...] Read more.

The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today’s more vulnerable organs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Ischemia-Reperfusion Injury and Hepatoprotection)

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16 pages, 3875 KiB

Open AccessArticle

Pharmacological Inhibition of S100A4 Attenuates Fibroblast Activation and Renal Fibrosis

by Jia Wen, Baihai Jiao, Melanie Tran and Yanlin Wang

Cells 2022, 11(17), 2762; https://doi.org/10.3390/cells11172762 - 05 Sep 2022

Cited by 11 | Viewed by 2413

Abstract

The TGF-β/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-β/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 [...] Read more.

The TGF-β/Smad3 signaling pathway is an important process in the pathogenesis of kidney fibrosis. However, the molecular mechanisms are not completely elucidated. The current study examined the functional role of S100A4 in regulating TGF-β/Smad3 signaling in fibroblast activation and kidney fibrosis development. S100A4 was upregulated in the kidney in a murine model of renal fibrosis induced by folic acid nephropathy. Further, S100A4 was predominant in the tubulointerstitial cells of the kidney. Pharmacological inhibition of S100A4 with niclosamide significantly attenuated fibroblast activation, decreased collagen content, and reduced extracellular matrix protein expression in folic acid nephropathy. Overexpression of S100A4 in cultured renal fibroblasts significantly facilitated TGF-β1-induced activation of fibroblasts by increasing the expression of α-SMA, collagen-1 and fibronectin. In contrast, S100A4 knockdown prevented TGF-β1-induced activation of fibroblast and transcriptional activity of Smad3. Mechanistically, S100A4 interacts with Smad3 to stabilize the Smad3/Smad4 complex and promotes their translocation to the nucleus. In conclusion, S100A4 facilitates TGF-β signaling via interaction with Smad3 and promotes kidney fibrosis development. Manipulating S100A4 may provide a beneficial therapeutic strategy for chronic kidney disease. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Fibrosis)

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15 pages, 1327 KiB

Open AccessReview

Roles of Auxin in the Growth, Development, and Stress Tolerance of Horticultural Plants

by Qiongdan Zhang, Min Gong, Xin Xu, Honghai Li and Wei Deng

Cells 2022, 11(17), 2761; https://doi.org/10.3390/cells11172761 - 05 Sep 2022

Cited by 21 | Viewed by 6361

Abstract

Auxin, a plant hormone, regulates virtually every aspect of plant growth and development. Many current studies on auxin focus on the model plant Arabidopsis thaliana, or on field crops, such as rice and wheat. There are relatively few studies on what role auxin [...] Read more.

Auxin, a plant hormone, regulates virtually every aspect of plant growth and development. Many current studies on auxin focus on the model plant Arabidopsis thaliana, or on field crops, such as rice and wheat. There are relatively few studies on what role auxin plays in various physiological processes of a range of horticultural plants. In this paper, recent studies on the role of auxin in horticultural plant growth, development, and stress response are reviewed to provide novel insights for horticultural researchers and cultivators to improve the quality and application of horticultural crops. Full article

(This article belongs to the Special Issue Regulation of Hormones Response in Plant Development and Stress Response: Dilemma or Synergy)

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21 pages, 5052 KiB

Open AccessArticle

Inhibition of PGE2 in Subchondral Bone Attenuates Osteoarthritis

by Qi Sun, Yuanzhen Zhang, Yilan Ding, Wenqing Xie, Hengzhen Li, Shaohua Li, Yusheng Li and Ming Cai

Cells 2022, 11(17), 2760; https://doi.org/10.3390/cells11172760 - 05 Sep 2022

Cited by 10 | Viewed by 2408

Abstract

Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study [...] Read more.

Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone’s abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment. Full article

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16 pages, 2319 KiB

Open AccessArticle

Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound

by Rodrigo Tomas-Grau, Florencia González-Lizárraga, Diego Ploper, César L. Avila, Sergio B. Socías, Pierre Besnault, Aurore Tourville, Rosa M. Mella, Patricia Villacé, Clarisa Salado, Clémence Rose, Blandine Seon-Méniel, Jean-Michel Brunel, Laurent Ferrié, Rita Raisman-Vozari, Patrick P. Michel, Bruno Figadère and Rosana Chehín

Cells 2022, 11(17), 2759; https://doi.org/10.3390/cells11172759 - 04 Sep 2022

Cited by 3 | Viewed by 2934

Abstract

The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved [...] Read more.

The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved neuroprotective effects. The molecule was obtained by removal the dimethylamino substituent at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-Syn_PFF) in biophysical assays and in a SH-SY5Y-α-Syn-tRFP cell model. In addition, DDMC rendered α-Syn_PFF less inflammogenic. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in Parkinson’s disease and other synucleinopathies. Full article

(This article belongs to the Collection Feature Papers in 'Cells of the Nervous System' Section)

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14 pages, 1238 KiB

Open AccessReview

Lung Organoids as Model to Study SARS-CoV-2 Infection

by Li Peng, Li Gao, Xinya Wu, Yuxin Fan, Meixiao Liu, Jingjing Chen, Jieqin Song, Jing Kong, Yan Dong, Bingxue Li, Aihua Liu and Fukai Bao

Cells 2022, 11(17), 2758; https://doi.org/10.3390/cells11172758 - 04 Sep 2022

Cited by 8 | Viewed by 2538

Abstract

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has severely affected socio-economic conditions and people’s life. The lung is the major target organ infected and (seriously) damaged by SARS-CoV-2, so a comprehensive understanding [...] Read more.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has severely affected socio-economic conditions and people’s life. The lung is the major target organ infected and (seriously) damaged by SARS-CoV-2, so a comprehensive understanding of the virus and the mechanism of infection are the first choices to overcome COVID-19. Recent studies have demonstrated the enormous value of human organoids as platforms for virological research, making them an ideal tool for researching host–pathogen interactions. In this study, the various existing lung organoids and their identification biomarkers and applications are summarized. At the same time, the seven coronaviruses currently capable of infecting humans are outlined. Finally, a detailed summary of existing studies on SARS-CoV-2 using lung organoids is provided and includes pathogenesis, drug development, and precision treatment. This review highlights the value of lung organoids in studying SARS-CoV-2 infection, bringing hope that research will alleviate COVID-19-associated lung infections. Full article

(This article belongs to the Special Issue Advances in iPSC-Based Disease Modeling: From Two Dimensional Monolayers to Organoids)

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11 pages, 805 KiB

Open AccessReview

Altered Immune Response to the Epstein–Barr Virus as a Prerequisite for Multiple Sclerosis

by Fabienne Läderach and Christian Münz

Cells 2022, 11(17), 2757; https://doi.org/10.3390/cells11172757 - 04 Sep 2022

Cited by 9 | Viewed by 3616

Abstract

Strong epidemiologic evidence links Epstein–Barr virus (EBV) infection and its altered immune control to multiple sclerosis (MS) development. Clinical MS onset occurs years after primary EBV infection and the mechanisms linking them remain largely unclear. This review summarizes the epidemiological evidence for this [...] Read more.

Strong epidemiologic evidence links Epstein–Barr virus (EBV) infection and its altered immune control to multiple sclerosis (MS) development. Clinical MS onset occurs years after primary EBV infection and the mechanisms linking them remain largely unclear. This review summarizes the epidemiological evidence for this association and how the EBV specific immune control is altered in MS patients. The two main possibilities of mechanisms for this association are further discussed. Firstly, immune responses that are induced during a symptomatic primary EBV infection, namely infectious mononucleosis, might be amplified during the following years to finally cause central nervous system (CNS) inflammation and demyelination. Secondly, genetic predisposition and environmental factors might not allow for an efficient immune control of the EBV-infected B cells that might drive autoimmune T cell stimulation or CNS inflammation. These two main hypotheses for explaining the association of the EBV with MS would implicate opposite therapeutic interventions, namely either dampening CNS inflammatory EBV-reactive immune responses or strengthening them to eliminate the autoimmunity stimulating EBV-infected B cell compartment. Nevertheless, recent findings suggest that EBV is an important puzzle piece in the pathogenesis of MS, and understanding its contribution could open new treatment possibilities for this autoimmune disease. Full article

(This article belongs to the Special Issue Immunology of Multiple Sclerosis)

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11 pages, 2923 KiB

Open AccessArticle

Patient-Derived Pancreatic Cancer Cells Induce C2C12 Myotube Atrophy by Releasing Hsp70 and Hsp90

by Hong-Yu Wu, Jose G. Trevino, Bing-Liang Fang, Andrea N. Riner, Vignesh Vudatha, Guo-Hua Zhang and Yi-Ping Li

Cells 2022, 11(17), 2756; https://doi.org/10.3390/cells11172756 - 03 Sep 2022

Cited by 7 | Viewed by 2282

Abstract

Pancreatic cancer (PC) patients are highly prone to cachexia, a lethal wasting syndrome featuring muscle wasting with an undefined etiology. Recent data indicate that certain murine cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 through extracellular vesicles (EVs) to activate p38β [...] Read more.

Pancreatic cancer (PC) patients are highly prone to cachexia, a lethal wasting syndrome featuring muscle wasting with an undefined etiology. Recent data indicate that certain murine cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 through extracellular vesicles (EVs) to activate p38β MAPK-mediated catabolic pathways primarily through Toll-like receptor 4 (TLR4). However, whether human PC induces cachexia through releasing Hsp70 and Hsp90 is undetermined. Here, we investigated whether patient-derived PC cells induce muscle cell atrophy directly through this mechanism. We compared cancer cells isolated from patient-derived xenografts (PDX) from three PC patients who had cachexia (PCC) with those of three early-stage lung cancer patients without cachexia (LCC) and two renal cancer patients who were not prone to cachexia (RCC). We observed small increases of Hsp70 and Hsp90 released by LCC and RCC in comparison to non-cancer control cells (NCC). However, PCC released markedly higher levels of Hsp70 and Hsp90 (~ 6-fold on average) than LCC and RCC. In addition, PCC released similarly increased levels of Hsp70/90-containing EVs. In contrast to RCC and LCC, PCC-conditioned media induced a potent catabolic response in C2C12 myotubes including the activation of p38 MAPK and transcription factor C/EBPβ, upregulation of E3 ligases UBR2 and MAFbx, and increase of autophagy marker LC3-II, resulting in the loss of the myosin heavy chain (MHC ~50%) and myotube diameter (~60%). Importantly, the catabolic response was attenuated by Hsp70- and Hsp90-neutralizing antibodies in a dose-dependent manner. These data suggest that human PC cells release high levels of Hsp70 and Hsp90 that induce muscle atrophy through a direct action on muscle cells. Full article

(This article belongs to the Special Issue Redox Control of Cell Signaling in Cardiac and Skeletal Muscle)

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26 pages, 10993 KiB

Open AccessArticle

Leptin Promotes Angiogenesis via Pericyte STAT3 Pathway upon Intracerebral Hemorrhage

by Qi Cui, Yingmei Zhang, Ning Tian, Jiaxin Yang, Dongshan Ya, Wenjing Xiang, Zixian Zhou, Yanlin Jiang, Jungang Deng, Bin Yang, Xiaohui Lin, Qinghua Li and Rujia Liao

Cells 2022, 11(17), 2755; https://doi.org/10.3390/cells11172755 - 03 Sep 2022

Cited by 8 | Viewed by 2172

Abstract

Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, [...] Read more.

Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, leptin triggers post-ICH angiogenesis through pericyte, an important component of forming new blood vessels, which remains unclear. Here, we reported that exogenous leptin infusion dose-dependent promoted vascular endothelial cells survival and proliferation at chronic stage of ICH mice. Additionally, leptin robustly ameliorated pericytes loss, enhanced pericytes proliferation and migration in ICH mice in vivo, and in ICH human brain microvascular pericytes (HBVPC) in vitro. Notably, we showed that pericytes-derived pro-angiogenic factors were responsible for enhancing the survival, proliferation and tube formation followed leptin treatment in human brain microvascular endothelial cells (HCMEC/D3)/HBVPC co-culture models. Importantly, considerable improvements in neurobehavioral function and hostile microenvironment were observed in leptin treatment ICH mice, indicating that better vascular functionality post ICH improves outcome. Mechanistically, this study unveiled that leptin boost post-ICH angiogenesis potentially through modulation of leptin receptor (leptinR)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pericyte. Thus, leptin may be a lucrative option for the treatment of ICH. Full article

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23 pages, 4508 KiB

Open AccessArticle

Actin-Related Protein 4 and Linker Histone Sustain Yeast Replicative Ageing

by Mateusz Mołoń, Karolina Stępień, Patrycja Kielar, Bela Vasileva, Bonka Lozanska, Dessislava Staneva, Penyo Ivanov, Monika Kula-Maximenko, Eliza Molestak, Marek Tchórzewski, George Miloshev and Milena Georgieva

Cells 2022, 11(17), 2754; https://doi.org/10.3390/cells11172754 - 03 Sep 2022

Cited by 1 | Viewed by 1969

Abstract

Ageing is accompanied by dramatic changes in chromatin structure organization and genome function. Two essential components of chromatin, the linker histone Hho1p and actin-related protein 4 (Arp4p), have been shown to physically interact in Saccharomyces cerevisiae cells, thus maintaining chromatin dynamics and function, [...] Read more.

Ageing is accompanied by dramatic changes in chromatin structure organization and genome function. Two essential components of chromatin, the linker histone Hho1p and actin-related protein 4 (Arp4p), have been shown to physically interact in Saccharomyces cerevisiae cells, thus maintaining chromatin dynamics and function, as well as genome stability and cellular morphology. Disrupting this interaction has been proven to influence the stability of the yeast genome and the way cells respond to stress during chronological ageing. It has also been proven that the abrogated interaction between these two chromatin proteins elicited premature ageing phenotypes. Alterations in chromatin compaction have also been associated with replicative ageing, though the main players are not well recognized. Based on this knowledge, here, we examine how the interaction between Hho1p and Arp4p impacts the ageing of mitotically active yeast cells. For this purpose, two sets of strains were used—haploids (WT(n), arp4, hho1Δ and arp4 hho1Δ) and their heterozygous diploid counterparts (WT(2n), ARP4/arp4, HHO1/hho1Δ and ARP4 HHO1/arp4 hho1Δ)—for the performance of extensive morphological and physiological analyses during replicative ageing. These analyses included a comparative examination of the yeast cells’ chromatin structure, proliferative and reproductive potential, and resilience to stress, as well as polysome profiles and chemical composition. The results demonstrated that the haploid chromatin mutants arp4 and arp4 hho1Δ demonstrated a significant reduction in replicative and total lifespan. These findings lead to the conclusion that the importance of a healthy interaction between Arp4p and Hho1p in replicative ageing is significant. This is proof of the concomitant importance of Hho1p and Arp4p in chronological and replicative ageing. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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23 pages, 3543 KiB

Open AccessArticle

Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation

by Irina Yu. Petrushanko, Artem M. Tverskoi, Evgeny P. Barykin, Aleksandra V. Petrovskaya, Maria A. Strelkova, Olga G. Leonova, Anastasia A. Anashkina, Anna P. Tolstova, Alexei A. Adzhubei, Anna Yu. Bogdanova, Alexander A. Makarov and Vladimir A. Mitkevich

Cells 2022, 11(17), 2753; https://doi.org/10.3390/cells11172753 - 03 Sep 2022

Cited by 4 | Viewed by 1998

Abstract

Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ₄₂ oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological [...] Read more.

Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ₄₂ oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ₄₂ interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ₄₂ monomer, triggering Src kinase activation. The co-localization of Aβ₄₂ with α1- and β1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aβ₄₂ causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ₄₂ with α1β1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aβ-induced Src kinase activation. Stimulatory effect of Aβ₄₂ on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aβ₄₂ receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ₄₂ in the nervous system. Full article

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17 pages, 3799 KiB

Open AccessArticle

Inhibition of Mcl-1 Synergistically Enhances the Antileukemic Activity of Gilteritinib and MRX-2843 in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia

by Shuangshuang Wu, Holly Edwards, Deying Wang, Shuang Liu, Xinan Qiao, Jenna Carter, Yue Wang, Jeffrey W. Taub, Guan Wang and Yubin Ge

Cells 2022, 11(17), 2752; https://doi.org/10.3390/cells11172752 - 03 Sep 2022

Cited by 2 | Viewed by 2054

Abstract

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have [...] Read more.

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development. Full article

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12 pages, 1563 KiB

Open AccessArticle

Age and Sex-Related Changes in Retinal Function in the Vervet Monkey

by Catarina Micaelo-Fernandes, Joseph Bouskila, Roberta M. Palmour, Jean-François Bouchard and Maurice Ptito

Cells 2022, 11(17), 2751; https://doi.org/10.3390/cells11172751 - 03 Sep 2022

Cited by 1 | Viewed by 1629

Abstract

Among the deficits in visual processing that accompany healthy aging, the earliest originate in the retina. Moreover, sex-related differences in retinal function have been increasingly recognized. To better understand the dynamics of the retinal aging trajectory, we used the light-adapted flicker electroretinogram (ERG) [...] Read more.

Among the deficits in visual processing that accompany healthy aging, the earliest originate in the retina. Moreover, sex-related differences in retinal function have been increasingly recognized. To better understand the dynamics of the retinal aging trajectory, we used the light-adapted flicker electroretinogram (ERG) to functionally assess the state of the neuroretina in a large cohort of age- and sex-matched vervet monkeys (N = 35), aged 9 to 28 years old, with no signs of obvious ocular pathology. We primarily isolated the cone–bipolar axis by stimulating the retina with a standard intensity light flash (2.57 cd/s/m²) at eight different frequencies, ranging from 5 to 40 Hz. Sex-specific changes in the voltage and temporal characteristics of the flicker waveform were found in older individuals (21–28 years-old, N = 16), when compared to younger monkeys (9–20 years-old, N = 19), across all stimulus frequencies tested. Specifically, significantly prolonged implicit times were observed in older monkeys (p < 0.05), but a significant reduction of the amplitude of the response was only found in old male monkeys (p < 0.05). These changes might reflect ongoing degenerative processes targeting the retinal circuitry and the cone subsystem in particular. Altogether, our findings corroborate the existing literature in humans and other species, where aging detrimentally affects photopic retinal responses, and draw attention to the potential contribution of different hormonal environments. Full article

(This article belongs to the Collection Retina in Health and Disease)

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14 pages, 5136 KiB

Open AccessArticle

Mineralocorticoid Receptor Antagonists Mitigate Mitral Regurgitation-Induced Myocardial Dysfunction

by Wei-Ting Chang, Yu-Wen Lin, Chin-Yu Chen, Zhih-Cherng Chen, Jhih-Yuan Shih, Chia-Ching Wu, Chwan-Yau Luo and Ping-Yen Liu

Cells 2022, 11(17), 2750; https://doi.org/10.3390/cells11172750 - 03 Sep 2022

Viewed by 1639

Abstract

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can [...] Read more.

Mitral regurgitation (MR), the disruption of the mitral valve, contributes to heart failure (HF). Under conditions of volume overload, excess mineralocorticoids promote cardiac fibrosis. The mineralocorticoid receptor antagonist spironolactone is a potassium-sparing diuretic and a guideline-recommended therapy for HF, but whether it can ameliorate degenerative MR remains unknown. Herein, we investigate the efficacy of spironolactone in improving cardiac remodeling in MR-induced HF compared with that of a loop diuretic, furosemide. Using a novel and mini-invasive technique, we established a rat model of MR. We treated the rats with spironolactone or furosemide for twelve weeks. The levels of cardiac fibrosis, apoptosis, and stress-associated proteins were then measured. In parallel, we compared the cardiac remodeling of 165 patients with degenerative MR receiving either spironolactone or furosemide. Echocardiography was performed at baseline and at six months. In MR rats treated with spironolactone, left ventricular function—especially when strained—and the pressure volume relationship significantly improved compared to those of rats treated with furosemide. Spironolactone treatment demonstrated significant attenuation of cardiac fibrosis and apoptosis in left ventricular tissue compared to furosemide. Further, spironolactone suppressed the expression of apoptosis-, NADPH oxidase 4 (NOX4)- and inducible nitric oxide synthase (iNOS)-associated proteins. Similarly, compared with MR patients receiving furosemide those prescribed spironolactone demonstrated a trend toward reduction in MR severity and showed improvement in left ventricular function. Collectively, MR-induced cardiovascular dysfunction, including fibrosis and apoptosis, was effectively attenuated by spironolactone treatment. Our findings suggest a potential therapeutic option for degenerative MR-induced HF. Full article

(This article belongs to the Collection Cardiovascular Disease: From Molecular and Cellular Mechanisms to Therapeutic Opportunities)

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13 pages, 961 KiB

Open AccessPerspective

LACTB, a Metabolic Therapeutic Target in Clinical Cancer Application

by Xiaohua Li, Zhongkai Ren, Xiaohong Huang and Tengbo Yu

Cells 2022, 11(17), 2749; https://doi.org/10.3390/cells11172749 - 03 Sep 2022

Cited by 1 | Viewed by 1862

Abstract

Serine beta-lactamase-like protein (LACTB) is the only mammalian mitochondrial homolog evolved from penicillin-binding proteins and β-lactamases (PBP-βLs) in bacteria. LACTB, an active-site serine protease, polymerizes into stable filaments, which are localized to the intermembrane space (IMS) of mitochondrion and involved in the submitochondrial [...] Read more.

Serine beta-lactamase-like protein (LACTB) is the only mammalian mitochondrial homolog evolved from penicillin-binding proteins and β-lactamases (PBP-βLs) in bacteria. LACTB, an active-site serine protease, polymerizes into stable filaments, which are localized to the intermembrane space (IMS) of mitochondrion and involved in the submitochondrial organization, modulating mitochondrial lipid metabolism. Cancer pathogenesis and progression are relevant to the alterations in mitochondrial metabolism. Metabolic reprogramming contributes to cancer cell behavior. This article (1) evidences the clinical implications of LACTB on neoplastic cell proliferation and migration and tumor growth and metastasis as well as LACTB’s involvement in chemotherapeutic and immunotherapeutic responses; (2) sketches the structural basis for LACTB activity and function; and (3) highlights the relevant regulatory mechanisms to LACTB. The abnormal expression of LACTB has been associated with clinicopathological features of cancer tissues and outcomes of anticancer therapies. With the current pioneer researches on the tumor-suppressed function, structural basis, and regulatory mechanism of LACTB, the perspective hints at a great appeal of enzymic property, polymerization, mutation, and epigenetic and post-translational modifications in investigating LACTB’s role in cancer pathogenesis. This perspective provides novel insights for LACTB as a metabolic regulator with potential to develop targeted cancer therapies or neoadjuvant therapeutic interventions. Full article

(This article belongs to the Special Issue Signaling Pathways/Metabolic Reprogramming Crosstalk in Cancer Cells)

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18 pages, 3503 KiB

Open AccessArticle

Functional Intercellular Transmission of miHTT via Extracellular Vesicles: An In Vitro Proof-of-Mechanism Study

by Roberto D. V. S. Morais, Marina Sogorb-González, Citlali Bar, Nikki C. Timmer, M. Leontien Van der Bent, Morgane Wartel and Astrid Vallès

Cells 2022, 11(17), 2748; https://doi.org/10.3390/cells11172748 - 03 Sep 2022

Cited by 4 | Viewed by 2776

Abstract

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by GAG expansion in exon 1 of the huntingtin (HTT) gene. AAV5-miHTT is an adeno-associated virus serotype 5-based vector expressing an engineered HTT-targeting microRNA (miHTT). Preclinical studies demonstrate the brain-wide spread of [...] Read more.

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by GAG expansion in exon 1 of the huntingtin (HTT) gene. AAV5-miHTT is an adeno-associated virus serotype 5-based vector expressing an engineered HTT-targeting microRNA (miHTT). Preclinical studies demonstrate the brain-wide spread of AAV5-miHTT following a single intrastriatal injection, which is partly mediated by neuronal transport. miHTT has been previously associated with extracellular vesicles (EVs), but whether EVs mediate the intercellular transmission of miHTT remains unknown. A contactless culture system was used to evaluate the transport of miHTT, either from a donor cell line overexpressing miHTT or AAV5-miHTT transduced neurons. Transfer of miHTT to recipient (HEK-293T, HeLa, and HD patient-derived neurons) cells was observed, which significantly reduced HTT mRNA levels. miHTT was present in EV-enriched fractions isolated from culture media. Immunocytochemical and in situ hybridization experiments showed that the signal for miHTT and EV markers co-localized, confirming the transport of miHTT within EVs. In summary, we provide evidence that an engineered miRNA—miHTT—is loaded into EVs, transported across extracellular space, and taken up by neighboring cells, and importantly, that miHTT is active in recipient cells downregulating HTT expression. This represents an additional mechanism contributing to the widespread biodistribution of AAV5-miHTT. Full article

(This article belongs to the Special Issue Extracellular Vesicle-Associated Non-Coding RNAs)

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12 pages, 2653 KiB

Open AccessCommunication

Experiences with Glofitamab Administration following CAR T Therapy in Patients with Relapsed Mantle Cell Lymphoma

by Alexander D. Heini, Ulrike Bacher, Naomi Porret, Gertrud Wiedemann, Myriam Legros, Denise Stalder Zeerleder, Katja Seipel, Urban Novak, Michael Daskalakis and Thomas Pabst

Cells 2022, 11(17), 2747; https://doi.org/10.3390/cells11172747 - 02 Sep 2022

Cited by 5 | Viewed by 2829

Abstract

Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and [...] Read more.

Mantle cell lymphoma (MCL) is a rare type of B-cell Non-Hodgkin lymphoma (NHL) affecting predominantly male patients. While complete remissions following first-line treatment are frequent, most patients ultimately relapse, with a usually aggressive further disease course. The use of cytarabine-comprising induction chemotherapy and autologous stem cell transplantation, Rituximab maintenance, Bruton’s tyrosine kinase (BTK) inhibitors and CAR T therapy has substantially improved survival. Still, options for patients relapsing after CAR T therapy are limited and recommendations for the treatment of these patients are lacking. We report two cases of patients with mantle cell lymphoma who relapsed after CAR T therapy and were treated with the bispecific CD20/CD3 T cell engaging antibody glofitamab. Both patients showed marked increases of circulating CAR T cells and objective responses after glofitamab administration. Therapy was tolerated without relevant side effects in both patients. One patient completed all 12 planned cycles of glofitamab therapy and was alive and without clinical progression at the last follow-up. The second patient declined further treatment after the first cycle and succumbed to disease progression. We review the literature and investigate possible mechanisms involved in the observed responses after administration of glofitamab, such as proliferation of CAR T cells, anti-tumor effects of the bispecific antibody and the role of other possibly contributing factors. Therapy with bispecific antibodies might offer an effective and well-tolerated option for patients with mantle cell lymphoma relapsing after CAR T therapy. Full article

(This article belongs to the Special Issue New Insights into Cellular Transplantation and Immunotherapy)

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11 pages, 1419 KiB

Open AccessArticle

Reduced miR-146a-5p Is a Biomarker of Infant Respiratory Diseases Contributing to Immune Dysregulation in Small Airway Epithelial Cells

by José M. Rodrigo-Muñoz, Marta Gil-Martínez, Clara Lorente-Sorolla, Beatriz Sastre, María Luz García-García, Cristina Calvo, Inmaculada Casas and Victoria del Pozo

Cells 2022, 11(17), 2746; https://doi.org/10.3390/cells11172746 - 02 Sep 2022

Viewed by 1861

Abstract

Respiratory diseases such as bronchiolitis, and those with wheezing episodes, are highly important during infancy due to their potential chronicity. Immune response dysregulation is critical in perpetuating lung damage. Epigenetic modifications including microRNA (miRNA) post-transcriptional regulation are among the factors involved in alleviating [...] Read more.

Respiratory diseases such as bronchiolitis, and those with wheezing episodes, are highly important during infancy due to their potential chronicity. Immune response dysregulation is critical in perpetuating lung damage. Epigenetic modifications including microRNA (miRNA) post-transcriptional regulation are among the factors involved in alleviating inflammation. We evaluated the expression of miR-146a-5p, a previously described negative regulator of immunity, in infants with respiratory diseases, in order to study epigenetic regulation of the immune response. Nasopharyngeal aspirate (NPA) was obtained from infants with bronchiolitis (ongoing and post-disease) or with wheezing episodes in addition to healthy controls. Virus presence was determined by nested PCR, while miRNA and gene expression were studied in cells from NPAs using qPCR. Healthy small airway epithelial cells (SAECs) were used as an in vitro model. We observe a reduction in miR-146a-5p expression in infants with either of the two diseases compared to controls, suggesting the potential of this miRNA as a disease biomarker. Post-bronchiolitis, miR-146a-5p expression increases, though without reaching levels of healthy controls. MiR-146a-5p expression correlates inversely with the immune-related gene PTGS2, while its expression correlates directly with TSLP. When heathy donor SAECs are stimulated by poly:IC, we observe an increase in miR-146a-5p, with wounds having a synergistic effect. In conclusion, infants with respiratory diseases present reduced miR-146a-5p expression, possibly affecting immune dysregulation. Full article

(This article belongs to the Topic MicroRNA: Mechanisms of Action, Physio-Pathological Implications, and Disease Biomarkers)

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17 pages, 2815 KiB

Open AccessFeature PaperArticle

ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes

by Antonia T. L. Zech, Maksymilian Prondzynski, Sonia R. Singh, Niels Pietsch, Ellen Orthey, Erda Alizoti, Josefine Busch, Alexandra Madsen, Charlotta S. Behrens, Moritz Meyer-Jens, Giulia Mearini, Marc D. Lemoine, Elisabeth Krämer, Diogo Mosqueira, Sanamjeet Virdi, Daniela Indenbirken, Maren Depke, Manuela Gesell Salazar, Uwe Völker, Ingke Braren, William T. Pu, Thomas Eschenhagen, Elke Hammer, Saskia Schlossarek and Lucie Carrier Show full author list Hide full author list

Cells 2022, 11(17), 2745; https://doi.org/10.3390/cells11172745 - 02 Sep 2022

Cited by 8 | Viewed by 3085

Abstract

Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created [...] Read more.

Genetic variants in α-actinin-2 (ACTN2) are associated with several forms of (cardio)myopathy. We previously reported a heterozygous missense (c.740C>T) ACTN2 gene variant, associated with hypertrophic cardiomyopathy, and characterized by an electro-mechanical phenotype in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively. We evaluated their impact on cardiomyocyte structure and function, using a combination of different technologies, including immunofluorescence and live cell imaging, RNA-seq, and mass spectrometry. This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs. Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues. In conclusion, our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant, which may contribute to human ACTN2-associated cardiomyopathies. Full article

(This article belongs to the Collection Applications of Stem Cells in Cardiovascular Functional Genomics 2022)

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20 pages, 5925 KiB

Open AccessArticle

Impairment of Neuronal Mitochondrial Quality Control in Prion-Induced Neurodegeneration

by Mo-Jong Kim, Hee-Jun Kim, Byungki Jang, Hyun-Ji Kim, Mohd Najib Mostafa, Seok-Joo Park, Yong-Sun Kim and Eun-Kyoung Choi

Cells 2022, 11(17), 2744; https://doi.org/10.3390/cells11172744 - 02 Sep 2022

Cited by 9 | Viewed by 3006

Abstract

Mitochondrial dynamics continually maintain cell survival and bioenergetics through mitochondrial quality control processes (fission, fusion, and mitophagy). Aberrant mitochondrial quality control has been implicated in the pathogenic mechanism of various human diseases, including cancer, cardiac dysfunction, and neurological disorders, such as Alzheimer’s disease, [...] Read more.

Mitochondrial dynamics continually maintain cell survival and bioenergetics through mitochondrial quality control processes (fission, fusion, and mitophagy). Aberrant mitochondrial quality control has been implicated in the pathogenic mechanism of various human diseases, including cancer, cardiac dysfunction, and neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, and prion disease. However, the mitochondrial dysfunction-mediated neuropathological mechanisms in prion disease are still uncertain. Here, we used both in vitro and in vivo scrapie-infected models to investigate the involvement of mitochondrial quality control in prion pathogenesis. We found that scrapie infection led to the induction of mitochondrial reactive oxygen species (mtROS) and the loss of mitochondrial membrane potential (ΔΨm), resulting in enhanced phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and its subsequent translocation to the mitochondria, which was followed by excessive mitophagy. We also confirmed decreased expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes and reduced ATP production by scrapie infection. In addition, scrapie-infection-induced aberrant mitochondrial fission and mitophagy led to increased apoptotic signaling, as evidenced by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. These results suggest that scrapie infection induced mitochondrial dysfunction via impaired mitochondrial quality control processes followed by neuronal cell death, which may have an important role in the neuropathogenesis of prion diseases. Full article

(This article belongs to the Special Issue Advances in Mitochondrial Dynamics and Neurodegeneration)

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22 pages, 4183 KiB

Open AccessArticle

Immune Determinants of Viral Clearance in Hospitalised COVID-19 Patients: Reduced Circulating Naïve CD4+ T Cell Counts Correspond with Delayed Viral Clearance

by Mihaela Zlei, Igor A. Sidorov, Simone A. Joosten, Mirjam H. M. Heemskerk, Sebenzile K. Myeni, Cilia R. Pothast, Caroline S. de Brouwer, A. Linda Boomaars-van der Zanden, Krista E. van Meijgaarden, Shessy T. Morales, Els Wessels, Jacqueline J. Janse, Jelle J. Goeman, Christa M. Cobbaert, Aloys C. M. Kroes, Suzanne C. Cannegieter, Meta Roestenberg, Leonardus G. Visser, Marjolein Kikkert, Mariet C. W. Feltkamp, Sesmu M. Arbous, Frank J. T. Staal, Tom H. M. Ottenhoff, Jacques J. M. van Dongen, Anna H. E. Roukens, Jutte J. C. de Vries, in collaboration with BEAT-COVID and in collaboration with LUMC COVID Show full author list Hide full author list

Cells 2022, 11(17), 2743; https://doi.org/10.3390/cells11172743 - 02 Sep 2022

Cited by 10 | Viewed by 2539

Abstract

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to [...] Read more.

Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19. Full article

(This article belongs to the Collection Cellular Immunology and COVID-19)

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13 pages, 2686 KiB

Open AccessArticle

Around-the-Clock Noise Induces AD-like Neuropathology by Disrupting Autophagy Flux Homeostasis

by Pengfang Zheng, Xiaojun She, Chunping Wang, Yingwen Zhu, Bo Fu, Kefeng Ma, Honglian Yang, Xiujie Gao, Xiaofang Li, Fangshan Wu and Bo Cui

Cells 2022, 11(17), 2742; https://doi.org/10.3390/cells11172742 - 02 Sep 2022

Cited by 3 | Viewed by 1563

Abstract

Environmental noise is a common hazard in military operations. Military service members during long operations are often exposed to around-the-clock noise and suffer massive emotional and cognitive dysfunction related to an Alzheimer’s disease (AD)-like neuropathology. It is essential to clarify the mechanisms underlying [...] Read more.

Environmental noise is a common hazard in military operations. Military service members during long operations are often exposed to around-the-clock noise and suffer massive emotional and cognitive dysfunction related to an Alzheimer’s disease (AD)-like neuropathology. It is essential to clarify the mechanisms underlying the effects of around-the-clock noise exposure on the central nervous system. Here, Wistar rats were continuously exposed to white noise (95 dB during the on-duty phase [8:00–16:00] and 75 dB during the off-duty phase (16:00–8:00 the next day)) for 40 days. The levels of phosphorylated tau, amyloid-β (Aβ), and neuroinflammation in the cortex and hippocampus were assessed and autophagosome (AP) aggregation was observed by transmission electron microscopy. Dyshomeostasis of autophagic flux resulting from around-the-clock noise exposure was assessed at different stages to investigate the potential pathological mechanisms. Around-the-clock noise significantly increased Aβ peptide, tau phosphorylation at Ser396 and Ser404, and neuroinflammation. Moreover, the AMPK-mTOR signaling pathway was depressed in the cortex and the hippocampus of rats exposed to around-the-clock noise. Consequently, autophagosome–lysosome fusion was deterred and resulted in AP accumulation. Our results indicate that around-the-clock noise exposure has detrimental influences on autophagic flux homeostasis and may be associated with AD-like neuropathology in the cortex and the hippocampus. Full article

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Open AccessReview

Comparative Analysis of Arsenic Transport and Tolerance Mechanisms: Evolution from Prokaryote to Higher Plants

by Jie Zhang, Jiayou Liu, Fubin Zheng, Min Yu, Sergey Shabala and Won-Yong Song

Cells 2022, 11(17), 2741; https://doi.org/10.3390/cells11172741 - 02 Sep 2022

Cited by 5 | Viewed by 2002

Abstract

Arsenic (As) is a toxic metalloid for all living organisms and can cause serious harm to humans. Arsenic is also toxic to plants. To alleviate As toxicity, all living organisms (from prokaryotes to higher plants) have evolved comprehensive mechanisms to reduce cytosolic As [...] Read more.

Arsenic (As) is a toxic metalloid for all living organisms and can cause serious harm to humans. Arsenic is also toxic to plants. To alleviate As toxicity, all living organisms (from prokaryotes to higher plants) have evolved comprehensive mechanisms to reduce cytosolic As concentration through the set of As transporters localized at the plasma and tonoplast membranes, which operate either in arsenite As(III) extrusion out of cells (via ArsB, ACR3, and aquaporins) or by sequestering arsenic into vacuoles (by ABC transporters). In addition, a special arsenate resistance mechanism found in some bacterial systems has evolved in an As hyperaccumulating fern Pteris vittata, which involves transforming arsenate As(V) to an As(V) phosphoglycerate derivative by a glyceraldehyde 3-phosphate dehydrogenase and transporting this complex by an efflux transporter. In the present review, we summarize the evolution of these arsenic resistance mechanisms from prokaryotes to eukaryotes and discuss future approaches that could be utilized to better understand and improve As resistance mechanisms in plants. Full article

(This article belongs to the Special Issue Links between Heavy Metal Stress and Plant Signaling)

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Cells, Volume 11, Issue 17 (September-1 2022) – 152 articles

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