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Iranian Journal of Immunology : IJI Jun 2024Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for β-thalassemia major in children. However, it often induces graft-versus-host-disease...
Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for β-thalassemia major in children. However, it often induces graft-versus-host-disease (GVHD), which is associated with complications. In the present study, we used cyclophosphamide (Cy) to treat a thalassemia patient post-HSCT to reduce the adverse effects of GVHD. We monitored the numbers and phenotype of granulocytes. In this case study, an 11-year-old female patient, diagnosed with β-thalassemia major (Pesaro class II), was treated with Cy before and after HSCT with mobilized CD34+ cells. Both the relative and absolute granulocyte counts, as well as CD33+CD11b+ cell counts, increased significantly after HSCT until day 56. However, they suddenly began to decrease after day 56, accompanied by severe diarrhea, skin rash, and a decrease in bilirubin levels compared to day -12. Furthermore, compared to day -12, IL-22 levels increased until day 56, and then decreased, while IDO levels continued to rise after day 56. Our data suggest the potential use of IL-22 and IDO as biomarkers for GVHD assessment. It also indicates that Cy promotes HSCT reconstitution by increasing CD33+CD11b+ cells, which may play a crucial role in reducing GVHD risks. However, further studies are needed to elucidate the mechanism behind GVHD recurrence.
Topics: Humans; Female; Hematopoietic Stem Cell Transplantation; Cyclophosphamide; Child; Graft vs Host Disease; beta-Thalassemia; Treatment Outcome; Biomarkers; Immunosuppressive Agents
PubMed: 38943529
DOI: 10.22034/iji.2024.101584.2752 -
Stem Cells and Development Jun 2024The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells...
The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells (MaSCs) and that these stem cells participate in two division modes: symmetric cell division (SCD) and asymmetric cell division (ACD). Although both of these modes are key to the process of breast development and their imbalance is closely associated with the onset of BC, the molecular mechanisms underlying these phenomena deserve in-depth exploration. In this review, we first outline the molecular mechanisms governing ACD/SCD and analyze the role of ACD/SCD in various stages of breast development. We describe that the changes in telomerase activity, the role of polar proteins, and the stimulation of ovarian hormones subsequently lead to two distinct consequences: breast development or carcinogenesis. Finally, gene mutations, abnormalities in polar proteins, modulation of signal-transduction pathways, and alterations in the microenvironment disrupt the balance of breast cancer stem cells (BCSCs) division modes and cause BC. Important regulatory factors such as mammalian Inscuteable (mInsc), Numb, Eya1, PKCα, PKCθ, p53, and IL-6 also play significant roles in regulating pathways of ACD/SCD and may constitute key targets for future research on stem cell division, breast development, and tumor therapy.
PubMed: 38943275
DOI: 10.1089/scd.2024.0035 -
European Journal of Medical Research Jun 2024Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive... (Review)
Review
Cancer, a prevalent and complex disease, presents a significant challenge to the medical community. It is characterized by irregular cell differentiation, excessive proliferation, uncontrolled growth, invasion of nearby tissues, and spread to distant organs. Its progression involves a complex interplay of several elements and processes. Extracellular vesicles (EVs) serve as critical intermediaries in intercellular communication, transporting critical molecules such as lipids, RNA, membrane, and cytoplasmic proteins between cells. They significantly contribute to the progression, development, and dissemination of primary tumors by facilitating the exchange of information and transmitting signals that regulate tumor growth and metastasis. However, EVs do not have a singular impact on cancer; instead, they play a multifaceted dual role. Under specific circumstances, they can impede tumor growth and influence cancer by delivering oncogenic factors or triggering an immune response. Furthermore, EVs from different sources demonstrate distinct advantages in inhibiting cancer. This research examines the biological characteristics of EVs and their involvement in cancer development to establish a theoretical foundation for better understanding the connection between EVs and cancer. Here, we discuss the potential of EVs from various sources in cancer therapy, as well as the current status and future prospects of engineered EVs in developing more effective cancer treatments.
Topics: Extracellular Vesicles; Humans; Neoplasms; Cell Communication; Animals
PubMed: 38943222
DOI: 10.1186/s40001-024-01937-x -
Journal of Orthopaedic Surgery and... Jun 2024Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a...
Platelet-derived exosomes alleviate tendon stem/progenitor cell senescence and ferroptosis by regulating AMPK/Nrf2/GPX4 signaling and improve tendon-bone junction regeneration in rats.
BACKGROUND
Tendon stem/progenitor cell (TSPC) senescence contributes to tendon degeneration and impaired tendon repair, resulting in age-related tendon disorders. Ferroptosis, a unique iron-dependent form of programmed cell death, might participate in the process of senescence. However, whether ferroptosis plays a role in TSPC senescence and tendon regeneration remains unclear. Recent studies reported that Platelet-derived exosomes (PL-Exos) might provide significant advantages in musculoskeletal regeneration and inflammation regulation. The effects and mechanism of PL-Exos on TSPC senescence and tendon regeneration are worthy of further study.
METHODS
Herein, we examined the role of ferroptosis in the pathogenesis of TSPC senescence. PL-Exos were isolated and determined by TEM, particle size analysis, western blot and mass spectrometry identification. We investigated the function and underlying mechanisms of PL-Exos in TSPC senescence and ferroptosis via western blot, real-time quantitative polymerase chain reaction, and immunofluorescence analysis in vitro. Tendon regeneration was evaluated by HE staining, Safranin-O staining, and biomechanical tests in a rotator cuff tear model in rats.
RESULTS
We discovered that ferroptosis was involved in senescent TSPCs. Furthermore, PL-Exos mitigated the aging phenotypes and ferroptosis of TSPCs induced by t-BHP and preserved their proliferation and tenogenic capacity. The in vivo animal results indicated that PL-Exos improved tendon-bone healing properties and mechanical strength. Mechanistically, PL-Exos activated AMPK phosphorylation and the downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway, leading to the suppression of lipid peroxidation. AMPK inhibition or GPX4 inhibition blocked the protective effect of PL-Exos against t-BHP-induced ferroptosis and senescence.
CONCLUSION
In conclusion, ferroptosis might play a crucial role in TSPC aging. AMPK/Nrf2/GPX4 activation by PL-Exos was found to inhibit ferroptosis, consequently leading to the suppression of senescence in TSPCs. Our results provided new theoretical evidence for the potential application of PL-Exos to restrain tendon degeneration and promote tendon regeneration.
Topics: Animals; Ferroptosis; Exosomes; NF-E2-Related Factor 2; Cellular Senescence; Rats; Signal Transduction; Phospholipid Hydroperoxide Glutathione Peroxidase; Regeneration; AMP-Activated Protein Kinases; Stem Cells; Tendons; Male; Blood Platelets; Rats, Sprague-Dawley; Rotator Cuff Injuries; Disease Models, Animal
PubMed: 38943181
DOI: 10.1186/s13018-024-04869-8 -
Molecular Medicine (Cambridge, Mass.) Jun 2024L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of...
BACKGROUND
L-theanine is a unique non-protein amino acid in tea that is widely used as a safe food additive. We investigated the cardioprotective effects and mechanisms of L-theanine in myocardial ischemia-reperfusion injury (MIRI).
METHODS
The cardioprotective effects and mechanisms of L-theanine and the role of Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling were investigated in MIRI mice using measures of cardiac function, oxidative stress, and apoptosis.
RESULTS
Administration of L-theanine (10 mg/kg, once daily) suppressed the MIRI-induced increase in infarct size and serum creatine kinase and lactate dehydrogenase levels, as well as MIRI-induced cardiac apoptosis, as evidenced by an increase in Bcl-2 expression and a decrease in Bax/caspase-3 expression. Administration of L-theanine also decreased the levels of parameters reflecting oxidative stress, such as dihydroethidium, malondialdehyde, and nitric oxide, and increased the levels of parameters reflecting anti-oxidation, such as total antioxidant capacity (T-AOC), glutathione (GSH), and superoxide dismutase (SOD) in ischemic heart tissue. Further analysis showed that L-theanine administration suppressed the MIRI-induced decrease of phospho-JAK2 and phospho-STAT3 in ischemic heart tissue. Inhibition of JAK2 by AG490 (5 mg/kg, once daily) abolished the cardioprotective effect of L-theanine, suggesting that the JAK2/STAT3 signaling pathway may play an essential role in mediating the anti-I/R effect of L-theanine.
CONCLUSIONS
L-theanine administration suppresses cellular apoptosis and oxidative stress in part via the JAK2/STAT3 signaling pathway, thereby attenuating MIRI-induced cardiac injury. L-theanine could be developed as a potential drug to alleviate cardiac damage in MIRI.
Topics: Animals; Janus Kinase 2; STAT3 Transcription Factor; Oxidative Stress; Myocardial Reperfusion Injury; Apoptosis; Glutamates; Signal Transduction; Male; Mice; Cardiotonic Agents
PubMed: 38943069
DOI: 10.1186/s10020-024-00865-0 -
Acta Diabetologica Jun 2024The primary cause of the pandemic scale of type 2 diabetes (T2D) is the excessive and/or abnormal accumulation of adiposity resulting from a chronic positive energy...
The primary cause of the pandemic scale of type 2 diabetes (T2D) is the excessive and/or abnormal accumulation of adiposity resulting from a chronic positive energy balance. Any form of weight loss dramatically affects the natural history of T2D, favoring prevention, treatment, and even remission in the case of significant weight loss. However, weight regain, which is often accompanied by the recurrence or worsening of obesity complications such as T2D, is an inevitable biological phenomenon that is an integral part of the pathophysiology of obesity. This can occur not only after weight loss, but also during obesity treatment if it is not effective enough to counteract the physiological responses aimed at restoring adiposity to its pre-weight-loss equilibrium state. Over the past few years, many controlled and randomized studies have suggested a superior efficacy of bariatric surgery compared to conventional therapy in terms of weight loss, glycemic control, and rates of T2D remission. Recently, the therapeutic armamentarium in the field of diabetology has been enriched with new antihyperglycemic drugs with considerable efficacy in reducing body weight, which could play a pathogenetic role in the remission of T2D, not through the classical incretin effect, but by improving adipose tissue functions. All these concepts are discussed in this position statement, which aims to deepen the pathogenetic links between obesity and T2D, shift the paradigm from a "simple" interaction between insulin resistance and insulin deficiency, and evaluate the efficacy of different therapeutic interventions to improve T2D management and induce diabetes remission whenever still possible.
PubMed: 38942960
DOI: 10.1007/s00592-024-02317-x -
Human Reproduction Update Jun 2024Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating...
BACKGROUND
Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy.
OBJECTIVE AND RATIONALE
This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy.
SEARCH METHODS
A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine).
OUTCOMES
The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors.
WIDER IMPLICATIONS
Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field.
REGISTRATION NUMBER
Not applicable.
PubMed: 38942605
DOI: 10.1093/humupd/dmae020 -
Journal of the American Academy of... Jul 2024Anxiety is one of the most common mental health problems in childhood, and causes severe and persistent impairment in children's lives. Parents can play a key role in...
Anxiety is one of the most common mental health problems in childhood, and causes severe and persistent impairment in children's lives. Parents can play a key role in the development of children's anxiety symptoms; yet, the evidence of parent-focused interventions is relatively thin. This may be because little is known about what the optimal content of these interventions should be. Interventions typically either use parents as lay therapists, or target multiple different family risk factors at the same time. Traditional randomized trials of these "package deal" interventions provide little insight into what specific parental risk factors should be targeted to most effectively reduce children's anxiety. We will examine the effects of targeting distinct parental risk factors to provide more information on the role of these factors in children's anxiety, and to guide the development of intervention programs.
Topics: Humans; Child; Risk Factors; Parents; Female; Male; Anxiety; Anxiety Disorders; Parent-Child Relations
PubMed: 38942499
DOI: 10.1016/j.jaac.2024.01.013 -
Biomedicine & Pharmacotherapy =... Jun 2024Over the last decade, discovery of novel therapeutic method has been attention by the researchers and has changed the therapeutic perspective of hematological... (Review)
Review
Over the last decade, discovery of novel therapeutic method has been attention by the researchers and has changed the therapeutic perspective of hematological malignancies. Although NK cell play a pivotal role in the elimination of abnormal and cancerous cells, there are evidence that NK cell are disarm in hematological malignancy. Chimeric antigen receptor NK (CAR-NK) cell therapy, which includes the engineering of NK cells to detect tumor-specific antigens and, as a result, clear of cancerous cells, has created various clinical advantage for several human malignancies treatment. In the current review, we summarized NK cell dysfunction and CAR-NK cell based immunotherapy to treat AML patient.
PubMed: 38941897
DOI: 10.1016/j.biopha.2024.117024 -
Stem Cell Research Jun 2024Cardiovascular disease remains a global health concern. Stem cell therapy utilizing human cardiac progenitor cells (hCPCs) shows promise in treating cardiac vascular...
Cardiovascular disease remains a global health concern. Stem cell therapy utilizing human cardiac progenitor cells (hCPCs) shows promise in treating cardiac vascular disease. However, limited availability and senescence of hCPCs hinder their widespread use. To address these challenges, researchers are exploring innovative approaches. In this study, a bioengineered cell culture plate was developed to mimic the natural cardiac tissue microenvironment. It was coated with a combination of extracellular matrix (ECM) peptide motifs and mussel adhesive protein (MAP). The selected ECM peptide motifs, derived from fibronectin and vitronectin, play crucial roles in hCPCs. Results revealed that the Fibro-P and Vitro-P coated plates significantly improved hCPC adhesion, proliferation, migration, and differentiation compared to uncoated plates. Additionally, long-term culture on the coated plates delayed cellular senescence and maintained hCPC stemness. These enhancements were attributed to the activation of integrin downstream signaling pathways. The findings suggest that the engineered ECM peptide motif-MAP-coated plates hold potential for enhancing the therapeutic efficacy of stem cell-based therapies in cardiac tissue engineering and regenerative medicine.
PubMed: 38941882
DOI: 10.1016/j.scr.2024.103476