An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models.

AIMS/HYPOTHESIS: Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood. METHODS: We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). RESULTS: Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. CONCLUSIONS/INTERPRETATION: The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

Angiographic management of percutaneous renal procedure-related bleeding: A single-center experience.

OBJECTIVES: To present the radiological and clinical results of transcatheter arterial embolization in patients with active bleeding after percutaneous renal procedures. METHODS: A total of 79 consecutive patients who underwent angiography for percutaneous renal procedure-related bleeding were included in the present retrospective analysis. Patient characteristics, angiographic management and clinical outcomes were analyzed. RESULTS: On angiography, bleeding foci were observed in 81.0% of the patients (64/79), all of whom underwent transcatheter arterial embolization. Among the 15 patients (19.0%) with negative angiographic findings, empirical transcatheter arterial embolization was carried out in six patients (40.0%). The technical success rate in 64 patients with positive angiographic findings was 100%, and the clinical success rate in 70 patients who underwent transcatheter arterial embolization was 85.7% (60/70). A total of 14.3% (10/70) of patients with clinical failure underwent repeat transcatheter arterial embolization and all achieved clinical recovery. There were no major complications. There was no statistical difference in estimated glomerular filtration rate values before the percutaneous renal procedure and those measured 7 days after transcatheter arterial embolization (43.4 ± 24.4 to 44.6 ± 25.1 mL/min/1.73 m2 ; P = 0.189). Clinical failure was not associated with age, sex, type of renal procedures, bleeding tendency, presence of active bleeding on angiography, latency time and embolic agents used (P > 0.05). CONCLUSIONS: Transcatheter arterial embolization is a safe and effective method of treating percutaneous renal procedure-related bleeding without renal function deterioration.

Crif1 deficiency reduces adipose OXPHOS capacity and triggers inflammation and insulin resistance in mice.

Impaired mitochondrial oxidative phosphorylation (OXPHOS) has been proposed as an etiological mechanism underlying insulin resistance. However, the initiating organ of OXPHOS dysfunction during the development of systemic insulin resistance has yet to be identified. To determine whether adipose OXPHOS deficiency plays an etiological role in systemic insulin resistance, the metabolic phenotype of mice with OXPHOS-deficient adipose tissue was examined. Crif1 is a protein required for the intramitochondrial production of mtDNA-encoded OXPHOS subunits; therefore, Crif1 haploinsufficient deficiency in mice results in a mild, but specific, failure of OXPHOS capacity in vivo. Although adipose-specific Crif1-haploinsufficient mice showed normal growth and development, they became insulin-resistant. Crif1-silenced adipocytes showed higher expression of chemokines, the expression of which is dependent upon stress kinases and antioxidant. Accordingly, examination of adipose tissue from Crif1-haploinsufficient mice revealed increased secretion of MCP1 and TNFα, as well as marked infiltration by macrophages. These findings indicate that the OXPHOS status of adipose tissue determines its metabolic and inflammatory responses, and may cause systemic inflammation and insulin resistance.

Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure.

AIM/HYPOTHESIS: Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown. METHODS: We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane. RESULTS: Crif1(beta-/-) mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1(beta-/-) mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1(beta-/-) mice. CONCLUSIONS/INTERPRETATION: Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1(beta-/-) mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.

Transcatheter arterial embolisation for the management of obstetric haemorrhage associated with placental abnormality in 40 cases.

OBJECTIVE: To evaluate pelvic artery embolisation (PAE) in the emergency management of intractable postpartum haemorrhage (PPH) associated with placenta accreta (PA). METHODS: Forty such patients (PAE for PPH/PA) were retrospectively reviewed. Medical records were reviewed regarding the delivery and PAE procedure. Follow-up gynaecological outcomes after PAE were obtained by telephone interviews. RESULTS: Technical success was achieved in all women (100 %). The initial clinical success rate was 82.5 % (33/40). Three patients with PA underwent hysterectomy after PAE failed to stop the bleeding within 24 h after the embolisation. The other three patients underwent re-embolisation (two patients underwent re-embolisation on the next day and one patient had undergone re-embolisation 6 h after the first embolisation), and bleeding had stopped eventually. The clinical success rate was 92.5 %. There were four cases of immediate complications, such as, pelvic pain, nausea and urticaria. There were three late minor complications, temporary menopause, but no late major complications. After the procedure, 35 patients resumed normal menstruation, including two uncomplicated pregnancies. One patient expired owing to disseminated intravascular coagulopathy and intracerebral haemorrhage, despite successful embolisation. CONCLUSION: PAE can be performed safely and effectively for patients with PPH and PA and can preserve the uterus in many patients.

Usefulness of pelvic artery embolization in cesarean section compared with vaginal delivery in 176 patients.

PURPOSE: To evaluate the efficacy and safety of transcatheter arterial embolization of the pelvic arteries for the treatment of postpartum hemorrhage (PPH) associated with cesarean section compared with vaginal delivery. MATERIALS AND METHODS: A retrospective analysis of 176 patients undergoing transcatheter arterial embolization of the pelvic arteries for PPH from January 2006 through August 2011 was conducted at two institutions. The mean patient age was 33.9 years (range, 24-46 years). Data including delivery details, hematology and coagulation results, embolization details, and clinical outcomes were collected. Technical success was defined as cessation of bleeding on angiography or angiographically successful embolization of the bleeding artery. Clinical success was defined as the obviation of repeated embolization or surgical intervention. RESULTS: The technical success rate was 98.8% (n = 174), and the clinical success rate was 89.7% (n = 158). Among 176 patients, 71 had cesarean sections, and 105 underwent normal vaginal deliveries. Of the 105 patients who underwent normal vaginal deliveries, 11 (10.5%) required repeat embolization or surgical intervention. Of the 71 patients who had cesarean sections, 7 (9.8%) required repeat embolization or surgical intervention. The clinical success rate and complication rate were not related to the mode of delivery. All women resumed menses after transcatheter arterial embolization, and most (n = 125) described their menses as unchanged. Subsequent spontaneous pregnancies occurred in 13 women. CONCLUSIONS: The cesarean mode of delivery is not a predictor of poorer outcomes of transcatheter arterial embolization; however, further study is needed to clarify this relationship.

Galectin-3 Plays an Important Role in BMP7-Induced Cementoblastic Differentiation of Human Periodontal Ligament Cells by Interacting with Extracellular Components.

Human periodontal ligament stem cells (hPDLSCs) contain multipotent postnatal stem cells that differentiate into PDL progenitors, osteoblasts, and cementoblasts. Previously, we obtained cementoblast-like cells from hPDLSCs using bone morphogenetic protein 7 (BMP7) treatment. Differentiation into appropriate progenitor cells requires interactions and changes between stem or progenitor cells and their so-called environment niches, and cell surface markers play an important role. However, cementoblast-specific cell surface markers have not yet been fully studied. Through decoy immunization with intact cementoblasts, we developed a series of monoclonal antibodies against cementoblast-specific membrane/extracellular matrix (ECM) molecules. One of these antibodies, the anti-CM3 antibody, recognized an approximate 30 kDa protein in a mouse cementoblast cell line, and the CM3 antigenic molecule accumulated in the cementum region of human tooth roots. Using mass spectrometric analysis, we found that the antigenic molecules recognized by the anti-CM3 antibody were galectin-3. As cementoblastic differentiation progressed, the expression of galectin-3 increased, and it localized at the cell surface. Inhibition of galectin-3 via siRNA and a specific inhibitor showed the complete blockage of cementoblastic differentiation and mineralization. In contrast, ectopic expression of galectin-3 induced cementoblastic differentiation. Galectin-3 interacted with laminin α2 and BMP7, and these interactions were diminished by galectin-3 inhibitors. These results suggested that galectin-3 participates in binding to the ECM component and trapping BMP7 to induce, in a sustained fashion, the upregulation of cementoblastic differentiation. Finally, galectin-3 could be a potential cementoblast-specific cell surface marker, with functional importance in cell-to-ECM interactions.

Usefulness of transcatheter arterial embolization for eighty-three patients with secondary postpartum hemorrhage: Focusing on difference in angiographic findings.

BACKGROUND: Transcatheter arterial embolization (TAE) has been widely used as an effective and a safe treatment method and was often used as an alternative to the surgical management, but there are limited studies on the efficacy and the safety for patients undergoing their secondary postpartum hemorrhage (PPH). AIM: To evaluate the usefulness of TAE for secondary PPH focusing on the angiographic findings. METHODS: We conducted a research from January 2008 to July 2022 on all 83 patients (mean: 32 years, range: 24-43 years) presented with secondary PPH and they were treated with TAE in two university hospitals. The medical records and angiography were retrospective reviewed in order to evaluate the patients' characteristics, delivery details, clinical status and peri-embolization management, angiography and embolization details, technical/clinical success and complications. The group with active bleeding sign and the group without it were also compared and analyzed. RESULTS: On angiography, 46 (55.4%) patients showed active bleeding signs such as contrast extravasation (n = 37) or pseudoaneurysm (n = 8) or both (n = 1), and 37 (44.6%) patients showed non-active bleeding signs such as only spastic uterine artery (n = 2) or hyperemia (n = 35). In the active bleeding sign group there were more multiparous patients, low platelet count, prothrombin time prolongation, and high transfusion requirements. The technical success rates were 97.8% (45/46) in active bleeding sign group and 91.9% (34/37) in non-active bleeding sign group, and the overall clinical success rates were 95.7% (44/46) and 97.3% (36/37). An uterine rupture with peritonitis and abscess formation occurred to one patient after the embolization, therefore hysterostomy and retained placenta removal were performed which was a major complication. CONCLUSION: TAE is an effective and a safe treatment method for controlling secondary PPH regardless of angiographic findings.

Transcatheter embolization for hemorrhage from aberrant testicular artery after partial nephrectomy: A case report.

BACKGROUND: Arterial bleeding typically involves the renal artery following partial nephrectomy; in this study, we present a case of bleeding originating from the testicular artery that has not been reported in previous studies. CASE SUMMARY: A 52-year-old man suffered hemorrhage from a perinephric branch of the aberrant left testicular artery after an open nephron-sparing surgery for renal cell carcinoma. Clinical signs of bleeding were manifested by the patient, such as fresh blood drainage from the catheter, decreased hemoglobin levels, and significant vital sign changes. Since computed tomography did not show evidence of active bleeding, transcatheter angiography was conducted to identify the bleeding site. Fluoroscopic spot images confirmed bleeding derived from a perinephric branch of the testicular artery originating from the segmental artery of the left renal artery. Using n-butyl-2-cyanoacrylate, successful transcatheter arterial embolization of the affected branch was performed. Immediately after the embolization procedure, the bleeding ceased, and the patient experienced complete recovery devoid of complications. CONCLUSION: In patients with postoperative arterial hemorrhage after partial nephrectomy, the testicular artery can be a rare but notable source of bleeding. Accurate bleeding site localization via angiographic evaluation, followed by transcatheter arterial embolization, can be instrumental for safe, prompt, and effective hemostasis.

Hyponatremia may reflect severe inflammation in children with febrile urinary tract infection.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality in clinical practice, but little is known about the association between febrile urinary tract infection (UTI) and hyponatremia or its significance to clinical outcomes. METHODS: Data from 140 children with febrile UTI between 2000 and 2010 were retrospectively analyzed. Laboratory examinations [white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum sodium concentration], renal ultrasonography, (99m)Technetium-dimercaptosuccinic acid (DMSA) scintigraphy, and voiding cystourethrogram were performed. Culture growing >50,000 colonies of one single bacterial species on a urine sample obtained by catheter or >100,000 colonies on two clean-catch samples was required to establish diagnosis of UTI. RESULTS: In children with renal cortical defects diagnosed after DMSA scintigraphy (group 1), duration of fever was significantly longer (P = 0.038) and WBC (P = 0.047) and CRP (P < 0.0001) levels significantly higher than in those without renal cortical defects (group 2). However, serum sodium levels were significantly lower in group 1 than group 2 (135.9 ± 2.4 vs 137.4 ± 2.7 mEq/L, P = 0.007). Hyponatremia (serum sodium ≤ 135 mEq/L) was also more frequent in group 1 than in group 2 (74.1 % vs 45.3 %, P = 0.012). Serum sodium concentration was negatively correlated with WBC count (r = -0.156, P = 0.011) and CRP levels (r = -0.160, P= 0.028). CONCLUSIONS: Our study indicates that hyponatremia may be a substantial inflammatory marker and is significantly and independently associated with the degree of inflammation in children with febrile UTI.

Transcriptome Profile of Membrane and Extracellular Matrix Components in Ligament-Fibroblastic Progenitors and Cementoblasts Differentiated from Human Periodontal Ligament Cells.

Ligament-fibroblastic cells and cementoblasts, two types of progenitor cells that differentiate from periodontal ligament stem cells (hPDLSCs), are responsible for the formation of the adhesive tissues in the tooth root. Since one of the factors that determines the fate of stem cell differentiation is the change in the microenvironment of the stem/progenitor cells, this study attempted to compare and analyze the molecular differences in the membrane and ECM of the two progenitor cells. Single cells derived from hPDLSCs were treated with TGF-ß1 and BMP7 to obtain ligament-fibroblastic and cementoblastic cells, respectively. The transcriptome profiles of three independent replicates of each progenitor were evaluated using next-generation sequencing. The representative differentially expressed genes (DEGs) were verified by qRT-PCR, Western blot analysis, and immunohistochemistry. Among a total of 2245 DEGs identified, 142 and 114 DEGs related to ECM and cell membrane molecules were upregulated in ligament-fibroblastic and cementoblast-like cells, respectively. The major types of integrin and cadherin were found to be different between the two progenitor cells. In addition, the representative core proteins for each glycosaminoglycan-specific proteoglycan class were different between the two progenitors. This study provides a detailed understanding of cell-cell and cell-ECM interactions through the specific components of the membrane and ECM for ligament-fibroblastic and cementoblastic differentiation of hPDLSCs.

Golgin Subfamily A Member 5 Is Essential for Production of Extracellular Matrix Proteins during TGF-ß1-Induced Periodontal Ligament-Fibroblastic Differentiation.

Human periodontal ligament stem cells (hPDLSCs) can be differentiated into periodontal ligament- (PDL-) fibroblastic progenitors by treatment with low concentrations of transforming growth factor beta 1 (TGF-ß1). Although much is known about the profibrotic effects of TGF-ß1, the molecular mechanisms mediating the activation of fibroblasts in periodontal ligament-fibroblastic differentiation are not well known. Our study was to investigate the mechanism of the fibroblastic process in the periodontal ligament differentiation of hPDLSCs through the discovery of novel markers. One of the monoclonal antibodies previously established through decoy immunization was the anti-LG11 antibody, which recognized Golgi subfamily A member 5 (GOLGA5) as a PDL-fibroblastic progenitor-specific antigen. GOLGA5/LG11 was significantly upregulated in TGF-ß1-induced PDL-fibroblastic progenitors and accumulated in the PDL region of the tooth root. GOLGA5 plays a role in vesicle tethering and docking between the endoplasmic reticulum and the Golgi apparatus. siRNA-mediated depletion of endogenous GOLGA5 upregulated in TGF-ß1-induced PDL-fibroblastic progenitors resulted in downregulation of representative PDL-fibroblastic markers and upregulation of osteoblast markers. When the TGF-ß1 signaling pathway was blocked or GOLGA5 was depleted by siRNA, the levels of extracellular matrix (ECM) proteins, such as type I collagen and fibronectin, decreased in PDL-fibroblastic progenitors. In addition, Golgi structures in the perinuclear region underwent fragmentation under these conditions. These results suggest that GOLGA5/LG11 is a PDL-fibroblastic marker with functional importance in ECM protein production and secretion, which are important processes in PDL-fibroblastic differentiation.

Identifying Small Bowel Gastrointestinal Stromal Tumor as the Culprit Lesion in Obscure Gastrointestinal Bleeding: Emphasis on Angiographic Findings.

Gastrointestinal stromal tumors (GISTs) are not uncommon and often cause gastrointestinal bleeding. GISTs occurring in the small intestine are occasionally difficult to identify by endoscopy and CT. In this case, the patient underwent CT three times before surgery, and the lesion was found to be located in a different area of the abdominal cavity on each CT scan. Moreover, the lesion was missed in the first two CT images because it was difficult to distinguish it from the nearby collapsed small intestine. The lesion was eventually detected through angiography; however, the correct diagnosis and treatment were delayed for 3 years because it was mistaken for a vascular malformation, which is the most common cause of obscure GI bleeding in elderly patients. This report emphasizes the need for interventional radiologists to be updated and vigilant of the angiographic features of GISTs to make an accurate diagnosis and establish a management strategy.

Transarterial Embolization for Sporadic Renal Angiomyolipoma: Patient Selection and Technical Considerations for Optimal Therapeutic Outcomes.

Although renal angiomyolipoma (AML) is a benign tumor, treatment may be necessary occasionally because it can cause potentially life-threatening retroperitoneal hemorrhage. Transarterial embolization (TAE) is a safe and effective treatment option to prevent the hemorrhagic rupture of AMLs and relieve the symptoms caused by enlarged lesions or active bleeding. However, there is no clear consensus regarding the indications for prophylactic TAE in patients with sporadic renal AMLs. In urgent TAE for bleeding AMLs, there is a likelihood of incomplete embolization when the focus is on stabilizing the clinical symptoms. This pictorial essay discusses the patient selection and technical considerations to achieve optimal therapeutic effects as well as the follow-up findings after TAE.

Cell Surface Accumulation of Intracellular Leucine Proline-Enriched Proteoglycan 1 Enhances Odontogenic Potential of Human Dental Pulp Stem Cells.

Primary dental pulp cells can be differentiated into odontoblast-like cells, which are responsible for dentin formation and mineralization. Successful differentiation of primary dental pulp cells can be verified using a few markers. However, odontoblast-specific cell surface markers have not been fully studied yet. LEucine PRoline-Enriched Proteoglycan 1 (LEPRE1) is a basement membrane-associated proteoglycan. LEPRE1 protein levels are increased during odontoblastic differentiation of human dental pulp cells (hDPCs). Intracellular and cell surface accumulation of this protein completely disappeared during dentin maturation and mineralization. Cell surface binding of an anti-LEPRE1 monoclonal antibody that could recognize an extracellular region was gradually increased in the odontoblastic stage. Overexpression and knockdown experiments showed that accumulation of intracellular LEPRE1 could lead to inefficient odontoblastic differentiation and that the movement of LEPRE1 from intracellular region to the cell surface was required for odontoblastic differentiation. Indeed, when LEPRE1 already located on the cell surface was blocked by the anti-LEPRE1 monoclonal antibody, odontoblastic differentiation of hDPCs was inhibited. In this study, we looked at other aspects of LEPRE1 function as a cell surface molecule rather than its known intracellular hydroxylase activity. Our results indicate that this protein has potential as a specific cell surface marker in odontoblastic differentiation.

Growth differentiation factor-15 prevents glucotoxicity and connexin-36 downregulation in pancreatic beta-cells.

Pancreatic beta cell dysfunction is a hallmark of type 2 diabetes. Growth differentiation factor 15 (GDF15), which is an energy homeostasis regulator, has been shown to improve several metabolic parameters in the context of diabetes. However, its effects on pancreatic beta-cell remain to be identified. We, therefore, performed experiments using cell models and histological sectioning of wild-type and knock-out GDF15 mice to determine the effect of GDF15 on insulin secretion and cell viability. A bioinformatics analysis was performed to identify GDF15-correlated genes. GDF15 prevents glucotoxicity-mediated altered glucose-stimulated insulin secretion (GSIS) and connexin-36 downregulation. Inhibition of endogenous GDF15 reduced GSIS in cultured mouse beta-cells under standard conditions while it had no impact on GSIS in cells exposed to glucolipotoxicity, which is a diabetogenic condition. Furthermore, this inhibition exacerbated glucolipotoxicity-reduced cell survival. This suggests that endogenous GDF15 in beta-cell is required for cell survival but not GSIS in the context of glucolipotoxicity.

Mitoribosome insufficiency in ß cells is associated with type 2 diabetes-like islet failure.

Genetic variations in mitoribosomal subunits and mitochondrial transcription factors are related to type 2 diabetes. However, the role of islet mitoribosomes in the development of type 2 diabetes has not been determined. We investigated the effects of the mitoribosomal gene on ß-cell function and glucose homeostasis. Mitoribosomal gene expression was analyzed in datasets from the NCBI GEO website (GSE25724, GSE76894, and GSE76895) and the European Nucleotide Archive (ERP017126), which contain the transcriptomes of type 2 diabetic and nondiabetic organ donors. We found deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1. The phenotypes of haploinsufficiency in a single mitoribosomal gene were examined using ß-cell-specific Crif1 (Mrpl59) heterozygous-deficient mice. Crif1beta+/- mice had normal glucose tolerance, but their islets showed a loss of first-phase glucose-stimulated insulin secretion. They also showed increased ß-cell mass associated with higher expression of Reg family genes. However, Crif1beta+/- mice showed earlier islet failure in response to high-fat feeding, which was exacerbated by aging. Haploinsufficiency of a single mitoribosomal gene predisposes rodents to glucose intolerance, which resembles the early stages of type 2 diabetes in humans.

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The inferior mesenteric artery is a rare source of postpartum hemorrhage. We report two cases of primary postpartum hemorrhage that originated from the inferior mesenteric artery after vaginal delivery. Both patients showed signs of hypovolemic shock, and disseminated intravascular coagulation was suspected. The bleeding continued even after embolization of the uterine artery, a typical source of postpartum hemorrhage. Inferior mesenteric arteriography confirmed contrast extravasation from the superior rectal artery, and selective embolization was performed using N-butyl cyanoacrylate. This report highlights that the inferior mesenteric artery can be a source of bleeding in patients with intractable and persistent postpartum hemorrhage due to birth canal injury.

Cellular and Intercellular Homeostasis in Adipose Tissue with Mitochondria-Specific Stress.

Paracrine interactions are imperative for the maintenance of adipose tissue intercellular homeostasis, and intracellular organelle dysfunction results in local and systemic alterations in metabolic homeostasis. It is currently accepted that mitochondrial proteotoxic stress activates the mitochondrial unfolded protein response (UPRmt) in vitro and in vivo. The induction of mitochondrial chaperones and proteases during the UPRmt is a key cell-autonomous mechanism of mitochondrial quality control. The UPRmt also affects systemic metabolism through the secretion of cell non-autonomous peptides and cytokines (hereafter, metabokines). Mitochondrial function in adipose tissue plays a pivotal role in whole-body metabolism and human diseases. Despite continuing interest in the role of the UPRmt and quality control pathways of mitochondria in energy metabolism, studies on the roles of the UPRmt and metabokines in white adipose tissue are relatively sparse. Here, we describe the role of the UPRmt in adipose tissue, including adipocytes and resident macrophages, and the interactive roles of cell non-autonomous metabokines, particularly growth differentiation factor 15, in local adipose cellular homeostasis and systemic energy metabolism.

Th2 Cytokines Increase the Expression of Fibroblast Growth Factor 21 in the Liver.

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13-STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.