Development of a new treatment for preterm birth complications using amniotic fluid stem cell therapy

This paper describes the current status of studies and clinical trials on the use of mesenchymal stem cells (MSCs) and amniotic fluid stem cells (AFSCs) for complications of preterm birth (PTB), an urgent issue in the perinatal field. PTB is a serious challenge in clinical medicine that is increasing globally, and effective control of its complications is necessary for newborns’ subsequent long life. Classical treatments are inadequate, and many patients have PTB complications. A growing body of evidence provided by translational medicine and others indicates that MSCs, and among them, the readily available AFSCs, may be useful in treating PTB complications. AFSCs are the only MSCs available prenatally and are known to be highly antiinflammatory and tissue-protective and do not form tumors when transplanted. Furthermore, because they are derived from the amniotic fluid, a medical waste product, no ethical issues are involved. AFSCs are an ideal cell resource for MSC therapy in neonates. This paper targets the brain, lungs, and intestines, which are the vital organs most likely to be damaged by PTB complications. The evidence to date and future prospects with MSCs and AFSCs for these organs are described

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease

AimsLimited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH.MethodsThis retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death.ResultsThe 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45–13.73; P = .009).ConclusionsThe IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered

Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice

Mesenchymal stem cells (MSCs) affect immune cells and exert anti-inflammatory effects. Human amniotic fluid stem cells (hAFSCs), a type of MSCs, have a high therapeutic effect in animal models of inflammation-related diseases. hAFSCs can be easily isolated and cultured from amniotic fluid, which is considered a medical waste. Hence, amniotic fluid can be a source of cells for MSC therapy of inflammatory diseases. However, the effect of hAFSCs on acquired immunity in vivo, especially on regulatory T cells, has not yet been fully elucidated. Therefore, in this study, we aimed to understand the effects of hAFSCs on acquired immunity, particularly on regulatory T cells. We showed that hAFSCs ameliorated the thioglycollate-induced inflammation by forming aggregates with host immune cells, such as macrophages, T cells, and B cells in the peritoneal cavity. Further, the regulatory T cells increased in the peritoneal cavity. These results indicated that, in addition to helping the innate immunity, hAFSCs could also aid the acquired immune system in vivo against inflammation-related diseases by increasing regulatory T cells

Nitric oxide-dependent cell death in glioblastoma and squamous cell carcinoma via prodeath mitochondrial clustering

Besides the fission–fusion dynamics, the cellular distribution of mitochondria has recently emerged as a critical biological parameter in regulating mitochondrial function and cell survival. We previously found that mitochondrial clustering on the nuclear periphery, or monopolar perinuclear mitochondrial clustering (MPMC), accompanies the anticancer activity of air plasma-activated medium (APAM) against glioblastoma and human squamous cell carcinoma, which is closely associated with oxidant-dependent tubulin remodeling and mitochondrial fragmentation. Accordingly, this study investigated the regulatory roles of nitric oxide (NO) in the anticancer activity of APAM. Time-lapse analysis revealed a time-dependent increase in NO accompanied by MPMC. In contrast, APAM caused minimal increases in MPMC and NO levels in nontransformed cells. NO, hydroxyl radicals, and lipid peroxide levels increased near the damaged nuclear periphery, possibly within mitochondria. NO scavenging prevented tubulin remodeling, MPMC, perinuclear oxidant production, nuclear damage, and cell death. Conversely, synthetic NO donors augmented all the prodeath events and acted synergistically with APAM. Salinomycin, an emerging drug against multidrug-resistant cancers, had similar NO-dependent effects. These results suggest that APAM and salinomycin induce NO-dependent cell death, where MPMC and oxidative mitochondria play critical roles. Our findings encourage further investigations on MPMC as a potential target for NO-driven anticancer agents against drug-resistant cancers

The Efficacy of Transarterial Embolization for Postpartum Hemorrhage Complicated with Disseminated Intravascular Coagulation: A Single-Center Experience

Indications for the use of transarterial embolization (TAE) for postpartum hemorrhage (PPH) have been established. However, the efficacy of TAE for PPH complicated by disseminated intravascular coagulation (DIC) remains controversial. In this study, we investigated the efficacy of TAE for PPH complicated by DIC. A database review was conducted to identify patients who were treated with TAE for PPH at our hospital. TAE was performed in 41 patients during the study period. Effective hemostasis was achieved in all cases, but additional procedures, such as re-embolization or hysterectomy, were required in five patients (12.2%). The typical causes of PPH included uterine atony (18 cases), placenta previa (15 cases), amniotic fluid embolism (DIC-type) (11 cases), and placenta accreta spectrum (10 cases). The mean blood loss was 3836 mL. The mean obstetrical DIC and the International Society on Thrombosis and Hemostasis DIC scores were 7.9 and 2.6, respectively. The efficacy of hemostasis was comparable between patients with and without DIC. However, the complete success rate of TAE was lower in patients with DIC as the condition worsened than that in non-DIC patients. Overall, TAE is effective as a minimally invasive treatment for PPH complicated by DIC

Air Plasma-Activated Medium Evokes a Death-Associated Perinuclear Mitochondrial Clustering

Intractable cancers such as osteosarcoma (OS) and oral cancer (OC) are highly refractory, recurrent, and metastatic once developed, and their prognosis is still disappointing. Tumor-targeted therapy, which eliminates cancers effectively and safely, is the current clinical choice. Since aggressive tumors are substantially resistant to multidisciplinary therapies that target apoptosis, tumor-specific activation of another cell death modality is a promising avenue for meeting this goal. Here, we report that a cold atmospheric air plasma-activated medium (APAM) can kill OS and OC by causing a unique mitochondrial clustering. This event was named monopolar perinuclear mitochondrial clustering (MPMC) based on its characteristic unipolar mitochondrial perinuclear accumulation. The APAM caused apoptotic and nonapoptotic cell death. The APAM increased mitochondrial ROS (mROS) and cell death, and the antioxidants such as N-acetylcysteine (NAC) prevented them. MPMC occurred following mitochondrial fragmentation, which coincided with nuclear damages. MPMC was accompanied by mitochondrial lipid peroxide (mLPO) accumulation and prevented by NAC, Ferrostatin-1, and Nocodazole. In contrast, the APAM induced minimal cell death, mROS generation, mLPO accumulation, and MPMC in fibroblasts. These results suggest that MPMC occurs in a tumor-specific manner via mitochondrial oxidative stress and microtubule-driven mitochondrial motility. MPMC induction might serve as a promising target for exerting tumor-specific cytotoxicity

<i>BACH1</i> Expression Is Promoted by Tank Binding Kinase 1 (<i>TBK1</i>) in Pancreatic Cancer Cells to Increase Iron and Reduce the Expression of E-Cadherin

BTB and CNC homology 1 (BACH1) represses the expression of genes involved in the metabolism of iron, heme and reactive oxygen species and promotes metastasis of various cancers including pancreatic ductal adenocarcinoma (PDAC). However, it is not clear how BACH1 is regulated in PDAC cells. Knockdown of Tank binding kinase 1 (TBK1) led to reductions of BACH1 mRNA and protein amounts in AsPC−1 human PDAC cells. Gene expression analysis of PDAC cells with knockdown of TBK1 or BACH1 suggested the involvement of TBK1 and BACH1 in the regulation of iron homeostasis. Ferritin mRNA and proteins were both increased upon BACH1 knockdown in AsPC−1 cells. Flow cytometry analysis showed that AsPC−1 cells with BACH1 knockout or knockdown contained lower labile iron than control cells, suggesting that BACH1 increased labile iron by repressing the expression of ferritin genes. We further found that the expression of E-cadherin was upregulated upon the chelation of intracellular iron content. These results suggest that the TBK1-BACH1 pathway promotes cancer cell metastasis by increasing labile iron within cells