Effects of Perilla frutescens Var. Acuta in Busulfan-Induced Spermatogenesis Dysfunction Mouse Model.

PURPOSE: The leaves of Perilla frutescens var. acuta (PFA) are generally reported to have antioxidant, anti-allergic, anti-inflammatory, and antitumor effects and commonly used as a traditional medicine in East Asia. This study aimed to investigate the protective effect and antioxidant activity of PFA on busulfan-induced testicular dysfunction, histological damage, oxidative stress (OS), sperm quality, and hormone levels using a mouse model. MATERIALS AND METHODS: C57BL/6 male mice were divided into four groups: control, busulfan-only treated, and varying concentrations of PFA (100 and 200 mg/kg) with busulfan. In the busulfan group, 40 mg/kg of busulfan was intraperitoneally injected to induce azoospermia. Mice were orally administered PFA for 35 consecutive days after busulfan administration. Samples were collected and assessed for testis/body weight, testicular histopathology, sperm quality, serum hormone levels, and OS to evaluate the effects of PFA treatment on spermatogenesis dysfunction induced by busulfan. RESULTS: The busulfan-induced testicular dysfunction model showed reduced testis weight, adverse histological changes, significantly decreased sex hormones and sperm quality, and attenuated OS. These results indicate that PFA treatment significantly increased testis weight, testis/body weight, epididymal sperm count, motility, and testosterone level compared with busulfan alone. PFA treatment also attenuated the busulfan-induced histological changes. Furthermore, compared with mice treated with busulfan alone, PFA supplementation upregulated the testicular mRNA expression of the antioxidant enzymes superoxide dismutase 1 (Sod1) and glutathione peroxidase 1 (Gpx1), with a decrease in malondialdehyde (MDA) production and an increase in SOD and GPx activities. CONCLUSIONS: This study shows that PFA exerts a protective effect against testicular damage by attenuating OS induced by busulfan. Our results suggest that PFA is a potentially relevant drug used to decrease the side effects induced by busulfan on testicular function and sperm during cancer chemotherapy.

Therapeutic potential of AAV-FL-Klotho in obesity: Impact on weight loss and lipid metabolism in mice.

Klotho, an anti-aging protein, has gained attention for its protective effects against various diseases, including metabolic disorders, through recombinant Klotho administration. However, the potential of Klotho as a target for gene therapy requires further exploration, as it remains relatively understudied in the context of metabolic disorders. In this study, we demonstrate that AAV-full length(FL)-Klotho administration induces weight loss in mice and provides protection against high-fat diet (HFD)-induced obesity and hepatic steatosis, concurrently reducing the weights of white adipose tissue and liver. AAV-FL-Klotho administration also enhanced thermogenic gene expression in brown adipose tissue (BAT) and improved the morphology of interscapular BAT. The weight loss effect of AAV-FL-Klotho was found to be, at least in part, mediated by UCP1-dependent thermogenesis in brown adipocytes, potentially influenced by hepatokines secreted from AAV-FL-Klotho-transduced hepatocytes. These findings suggest that AAV-FL-Klotho is an attractive candidate for gene therapy to combat obesity. Nevertheless, unbiased experiments have also revealed disturbances in lipid metabolism due to AAV-FL-Klotho, as evidenced by the emergence of lipomas and increased expression of hepatic lipogenic proteins.

NG ,NG -Dimethylarginine Dimethylaminohydrolase 1 Expression Is Dispensable for Cold- or Diet-Induced Thermogenesis.

The strategy to activate thermogenic adipocytes has therapeutic potential to overcome obesity as they dissipate surplus energy as heat through various mechanisms. NG,NG-dimethylarginine dimethylaminohydrolases (DDAHs) are enzymes involved in the nitric oxide-protein kinase G signaling axis which increases thermogenic gene expression. However, the role of DDAHs in thermogenic adipocytes has not been elucidated. The adipocyte-specific Ddah1 knockout mice are generated by crossing Ddah1fl/fl mice with adiponectin Cre recombinase mice. Adipocyte-specific DDAH1 overexpressing mice are generated using adeno-associated virus-double-floxed inverse open reading frame (AAV-DIO) system. These mice are analyzed under basal, cold exposure, or high-fat diet (HFD) conditions. Primary inguinal white adipose tissue cells from adipocyte-specific Ddah1 knockout mice expressed comparable amounts of Ucp1 mRNA. Adipocyte-specific DDAH1 overexpressing mice do not exhibit enhanced activation of thermogenic adipocytes. In addition, when these mice are exposed to cold environment or fed an HFD, their body temperature/weight and thermogenesis-related gene and protein expressions are unchanged. These findings indicate that DDAH1 does not play a role in either cold- or diet-induced thermogenesis. Therefore, adipocyte targeting DDAH1 gene therapy for the treatment of obesity is unlikely to be effective.

Case Reports of Binge Eating Patterns in the Recovery Phase of Anorexia Nervosa Patients With and Without Food Addiction.

Food addiction refers to a condition in which individuals exhibit addictive-like behaviors toward food, like those observed in substance abuse. Although still debated, evidence supporting the validity and usefulness of the concept of food addiction is growing. Food addiction is particularly associated with obesity and eating disorders involving binge eating. This study discusses the cases of two adolescent patients who presented with anorexia nervosa. During the recovery phase of anorexia nervosa, binge eating was observed, and the patterns of binge eating significantly differed between patients, with and without food addiction. Therefore, healthcare professionals treating eating disorders should be aware of food addiction and modify their treatment strategies accordingly.

AAV-mediated skeletal muscle specific irisin expression does not contribute to weight loss in mice.

Obesity, a chronic disease, significantly increases the risk of various diseases, including diabetes, cardiovascular diseases, and cancers. Exercise is crucial for weight management not only through energy expenditure by muscle activity but also through stimulating the secretion of myokines, which affect various tissues. Irisin, derived from the proteolytic processing of fibronectin type III domain-containing protein 5 (Fndc5), is a well-studied myokine with beneficial effects on metabolism. This study explored the feasibility of adeno-associated virus (AAV)-mediated Fndc5 gene therapy to treat obesity in a mouse model using the AAV-DIO system to express Fndc5 specifically in skeletal muscle, and investigated its anti-obesity effect. Although Fndc5 was specifically expressed in the muscle, no significant impact on body weight under normal chow or high-fat diets was observed, and no change in thermogenic gene expression in inguinal white adipose tissue was detected. Notably, Fndc5 transduction did affect bone metabolism, consistent with previous reports. These findings suggest that AAV-mediated Fndc5 gene therapy may not be an efficient strategy for obesity, contrary to our expectations. Further research is needed to elucidate the complex mechanisms involved in irisin's role in obesity and related disorders.

Timing of hormone therapy and its association with cardiovascular risk and metabolic parameters in 4-vinylcyclohexene diepoxide-induced primary ovarian insufficiency mouse model.

OBJECTIVE: To evaluate the effects of various initiation time points and durations of hormone therapy (HT) on cardiovascular and metabolic parameters of premenarche, primary ovarian insufficiency (POI) mouse model, induced by 4-vinylcyclohexene diepoxide. METHODS: A total of 50 mice at 4 weeks of age were developed into POI mouse model, further randomly categorized into 5 groups: control group without any intervention; no HT group with only high-fat diet (NT); group 1 with delayed estradiol treatment (T1); group 2 with on-time, continuous estradiol treatment (T2); and group 3 with on-time estradiol treatment but early stop (T3). Cardiovascular risk and metabolic parameters were measured. RESULTS: Presenting with similar body weights, blood glucose levels of T1, T2, and T3 were all significantly lower than NT (p < .001). Serum total cholesterol and insulin were also significantly lower in all HT groups than in NT, especially in T2 (p < .001). For serum low-density lipoprotein-cholesterol, only T2 resulted in the statically lower level than those of NT, T1, and T3 (p < .001). Aortic thickness was significantly increased with aggravated fibrotic change of the intima in NT, and such consequence was significantly ameliorated in HT groups, mostly lowered in T2 (p < .05). Last, serum pro-inflammatory cytokines were significantly low in the HT groups than in NT, especially in T2 with the lowest level (p < .05). . CONCLUSIONS: On-time, continuous E2 treatment immediately after a biologic estrogen deprivation event significantly reduced metabolic and cardiovascular risks in young, pre-menarche female mouse models of POI, confirming decreased serum levels of pro-inflammatory cytokines.

A case series: patients with complicated popliteal artery entrapment syndrome successfully treated with a hybrid surgical and interventional treatment.

Background: Popliteal artery entrapment syndrome (PAES) is an underreported and underdiagnosed condition that affects the lower extremities. Previous case reports mainly presented young and uncomplicated PAES. Here, we report the cases of complicated PAES in middle-aged patients. Furthermore, we discuss the importance of a multidisciplinary team approach from diagnosis to treatment to obtain favourable clinical outcomes against this rare disease. Case summary: Two middle-aged patients presented with recent claudication and were diagnosed with popliteal artery obstruction due to a complicated PAES. At the multidisciplinary meeting, the decided treatment plan was to prioritize the gastrocnemius tendon accessory transfer and surgical thromboendarterectomy. In case the popliteal artery patency was unsatisfactory, an additional on-site percutaneous intervention was planned. Follow-up lower extremity computed tomographic angiography showed a patent popliteal artery without any claudication in both two cases. Discussion: Popliteal artery entrapment syndrome is a rare vascular disorder. Clinical suspicion and advanced imaging modalities can lead to an accurate diagnosis. A multidisciplinary team approach helps in obtaining favourable clinical results using minimally invasive hybrid surgical and interventional treatments.

Cold-induced adaptive thermogenesis is impaired by exposure of Asian sand dust in mice.

Desertification and desert sandstorms caused by the worsening global warming pose increasing risks to human health. In particular, Asian sand dust (ASD) exposure has been related to an increase in mortality and hospital admissions for respiratory diseases. In this study, we investigated the effects of ASD on metabolic tissues in comparison to diesel particulate matter (DPM) that is known to cause adverse health effects. We found that larger lipid droplets were accumulated in the brown adipose tissues (BAT) of ASD-administered but not DPM-administered mice. Thermogenic gene expression was decreased in these mice as well. When ASD-administered mice were exposed to the cold, they failed to maintain their body temperature, suggesting that the ASD administration had led to impairments in cold-induced adaptive thermogenesis. However, impaired thermogenesis was not observed in DPM-administered mice. Furthermore, mice fed a high-fat diet that were chronically administered ASD demonstrated unexplained weight loss, indicating that chronic administration of ASD could be lethal in obese mice. We further identified that ASD-induced lung inflammation was not exacerbated in uncoupling protein 1 knockout mice, whose thermogenic capacity is impaired. Collectively, ASD exposure can impair cold-induced adaptive thermogenic responses in mice and increase the risk of mortality in obese mice.

Computer simulation approach to the identification of visfatin-derived angiogenic peptides.

Angiogenesis plays an essential role in various normal physiological processes, such as embryogenesis, tissue repair, and skin regeneration. Visfatin is a 52 kDa adipokine secreted by various tissues including adipocytes. It stimulates the expression of vascular endothelial growth factor (VEGF) and promotes angiogenesis. However, there are several issues in developing full-length visfatin as a therapeutic drug due to its high molecular weight. Therefore, the purpose of this study was to develop peptides, based on the active site of visfatin, with similar or superior angiogenic activity using computer simulation techniques.Initially, the active site domain (residues 181∼390) of visfatin was first truncated into small peptides using the overlapping technique. Subsequently, the 114 truncated small peptides were then subjected to molecular docking analysis using two docking programs (HADDOCK and GalaxyPepDock) to generate small peptides with the highest affinity for visfatin. Furthermore, molecular dynamics simulations (MD) were conducted to investigate the stability of the protein-ligand complexes by computing root mean square deviation (RSMD) and root mean square fluctuation(RMSF) plots for the visfatin-peptide complexes. Finally, peptides with the highest affinity were examined for angiogenic activities, such as cell migration, invasion, and tubule formation in human umbilical vein endothelial cells (HUVECs). Through the docking analysis of the 114 truncated peptides, we screened nine peptides with a high affinity for visfatin. Of these, we discovered two peptides (peptide-1: LEYKLHDFGY and peptide-2: EYKLHDFGYRGV) with the highest affinity for visfatin. In an in vitrostudy, these two peptides showed superior angiogenic activity compared to visfatin itself and stimulated mRNA expressions of visfatin and VEGF-A. These results show that the peptides generated by the protein-peptide docking simulation have a more efficient angiogenic activity than the original visfatin.

The Role of Carbamoyl Phosphate Synthetase 1 as a Prognostic Biomarker in Patients With Acetaminophen-induced Acute Liver Failure.

BACKGROUND & AIMS: Carbamoyl phosphate synthetase 1 (CPS1) is a highly abundant mitochondrial urea cycle enzyme that is expressed primarily in hepatocytes. CPS1 is constitutively and physiologically secreted into bile but is released into the bloodstream upon acute liver injury (ALI). Given its abundance and known short half-life, we tested the hypothesis that it may serve as a prognostic serum biomarker in the setting of acute liver failure (ALF). METHODS: CPS1 levels were determined using enzyme-linked immunosorbent assay and immunoblotting of sera collected by the ALF Study Group (ALFSG) from patients with ALI and ALF (103 patients with acetaminophen and 167 non-acetaminophen ALF etiologies). A total of 764 serum samples were examined. The inclusion of CPS1 was compared with the original ALFSG Prognostic Index by area under the receiver operating characteristic curve analysis. RESULTS: CPS1 values for acetaminophen-related patients were significantly higher than for non-acetaminophen patients (P < .0001). Acetaminophen-related patients who received a liver transplant or died within 21 days of hospitalization exhibited higher CPS1 levels than patients who spontaneously survived (P = .01). Logistic regression and area under the receiver operating characteristic analysis of CPS1 enzyme-linked immunosorbent assay values improved the accuracy of the ALFSG Prognostic Index, which performed better than the Model for End-Stage Liver Disease, in predicting 21-day transplant-free survival for acetaminophen- but not non-acetaminophen-related ALF. An increase of CPS1 but not alanine transaminase or aspartate transaminase, when comparing day 3 with day 1 levels was found in a higher percentage of acetaminophen transplanted/dead patients (P < .05). CONCLUSION: Serum CPS1 determination provides a new potential prognostic biomarker to assess patients with acetaminophen-induced ALF.

Obesity mechanism after hypothalamic damage: Cohort analysis of neuroimaging, psychological, cognitive, and clinical phenotyping data.

Objective: The hypothalamus regulates energy homeostasis, and its damage results in severe obesity. We aimed to investigate the multifaceted characteristics of hypothalamic obesity. Methods: We performed multidimensional analyses of brain structure/function and psychological and behavioral phenotypes in 29 patients with hypothalamic damage (HD) (craniopharyngioma) and 31 controls (non-functional pituitary adenoma). Patients underwent structural and functional magnetic resonance imaging and completed self-reports and cognitive tasks. Results: Patients with HD showed significantly higher postoperative weight gain than controls. The HD group also showed significant hypothalamic damage and lower neural activation in the left caudate nucleus in response to food images. The HD group had significantly higher food inattention, lower satiety, and higher restrained eating behavior. Within the HD group, higher restrained eating behavior was significantly associated with lower activation in the bilateral fusiform gyrus. Conclusion: These results suggest that hypothalamic damage contributes to weight gain by altering the brain response, attention, satiety, and eating behaviors. The present study proposes novel neuro-psycho-behavioral mechanisms targeted for patients with hypothalamic obesity.

Effect of N-acetyl-L-cysteine on Testicular Tissue in Busulfan-Induced Dysfunction in the Male Reproductive System.

PURPOSE: This study aimed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) as an antioxidant on busulfan-induced testicular dysfunction in mice and elucidate its possible mechanism of action. MATERIALS AND METHODS: Thirty-two C57BL/6 male mice were randomly divided into four groups (n=8/group) as follows: (1) control group (oral administration of saline [0.1 mL daily] for 35 days); (2) NAC group (oral administration of NAC [10 mg/kg daily] for 35 days); (3) busulfan group (double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg); and (4) busulfan+NAC group (after double intraperitoneal injections of 20 mg/kg; total dose of 40 mg/kg, NAC administration [10 mg/kg daily] for 35 days). The testes were removed, weighed, and subjected to sperm parameter analysis and morphology assessment. Reproductive hormone, serum/testicular reactive oxygen species (ROS) level, oxidative stress and antioxidant markers were evaluated. The testicular expression of Nrf2 and HO-1 was examined using RT-qPCR. RESULTS: Busulfan treatment significantly decreased testicular weight, sperm count, and serum testosterone levels. Atrophy and degeneration of germinal epithelium were observed in the busulfan group. NAC administration after busulfan treatment partially attenuated the deterioration of testis weight, sperm quality, serum hormones, histomorphometric changes, and oxidative and antioxidative status. NAC treatment resulted in a considerable improvement in Nrf2 and HO-1 mRNA expression levels. CONCLUSIONS: This study provides compelling evidence that NAC as a potent antioxidant has significant protective effects against busulfan-induced male reproductive impairment possibly through modification of the Nrf2/HO-1 signaling pathway.

Induction of liver transplant immune tolerance in an outbred rat strain model using tacrolimus.

BACKGROUND: Orthotopic liver transplantation is the only option for patients with end-stage liver disease and hepatocellular carcinoma. Post-transplant immunosuppressive therapy is important to prevent graft failure. We investigated the effectiveness of tacrolimus (FK506) and their mechanisms for liver transplant immune tolerance in an outbred rat LT model. RESULTS: To investigate the therapeutic effect of the FK506 on outbred rat LT model, FK506 and postoperative therapy were administered subcutaneously once or twice daily to transplanted rats. Histopathological and immunohistochemical analyses were conducted for all groups. The regulation of inflammatory cytokine signaling in the spleen was analyzed by flow cytometry. FK506 attenuated allograft rejection and increased survival in rat orthotopic liver transplantation models. The FK506-treated group had reduced serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Furthermore, FK506 decreased the expression of inflammatory cytokines and the activation of pathogenic Th1 and Th17 cells in the liver. CONCLUSIONS: Taken together, we revealed that FK506 ameliorated strong allograft rejection in outbred liver transplantation model by anti-inflammatory effect and inhibitory peroperty of pathogenic T cells.

Liver X receptor controls follicular helper T cell differentiation via repression of TCF-1.

Liver X receptor (LXR) is a critical regulator of cholesterol homeostasis that inhibits T cell receptor (TCR)-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation remain unclear. Here, we demonstrate that LXR is a crucial negative regulator of follicular helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXRß-deficient CD4+ T cell population in response to immunization and lymphocytic choriomeningitis mammarenavirus (LCMV) infection. Mechanistically, LXRß-deficient Tfh cells express augmented levels of T cell factor 1 (TCF-1) but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with those of LXRß-sufficient Tfh cells. Loss of LXRß confers inactivation of GSK3ß induced by either AKT/Extracellular signal-regulated kinase (ERK) activation or Wnt/ß-catenin pathway, leading to elevated TCF-1 expression in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a cell-intrinsic regulatory function of LXR in Tfh cell differentiation via the GSK3ß-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases.

Sex differences in hearing impairment due to diet-induced obesity in CBA/Ca mice.

BACKGROUND: Obesity is an independent risk factor for hearing loss. Although attention has focused on major obesity comorbidities such as cardiovascular disease, stroke, and type 2 diabetes, the impact of obesity on sensorineural organs, including the auditory system, is unclear. Using a high-fat diet (HFD)-induced obese mouse model, we investigated the impact of diet-induced obesity on sexual dimorphism in metabolic alterations and hearing sensitivity. METHODS: Male and female CBA/Ca mice were randomly assigned to three diet groups and fed, from weaning (at 28 days) to 14 weeks of age, a sucrose-matched control diet (10 kcal% fat content diet), or one of two HFDs (45 or 60 kcal% fat content diets). Auditory sensitivity was evaluated based on the auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and ABR wave 1 amplitude at 14 weeks of age, followed by biochemical analyses. RESULTS: We found significant sexual dimorphism in HFD-induced metabolic alterations and obesity-related hearing loss. Male mice exhibited greater weight gain, hyperglycemia, increased ABR thresholds at low frequencies, elevated DPOAE, and lower ABR wave 1 amplitude compared to female mice. The hair cell (HC) ribbon synapse (CtBP2) puncta showed significant sex differences. The serum concentration of adiponectin, an otoprotective adipokine, was significantly higher in female than in male mice; cochlear adiponectin levels were elevated by HFD in female but not male mice. Adiponectin receptor 1 (AdipoR1) was widely expressed in the inner ear, and cochlear AdipoR1 protein levels were increased by HFD, in female but not male mice. Stress granules (G3BP1) were significantly induced by the HFD in both sexes; conversely, inflammatory (IL-1ß) responses were observed only in the male liver and cochlea, consistent with phenotype HFD-induced obesity. CONCLUSIONS: Female mice are more resistant to the negative effects of an HFD on body weight, metabolism, and hearing. Females showed increased peripheral and intra-cochlear adiponectin and AdipoR1 levels, and HC ribbon synapses. These changes may mediate resistance to HFD-induced hearing loss seen in female mice.

Pectin Based Hydrogels for Drug Delivery Applications: A Mini Review.

Over the past few decades, hydrogel systems using natural polymers have been expansively employed in drug delivery applications. Among the various reported biopolymer-based hydrogel drug delivery systems, pectin (Pec) is an exceptional natural polymer due to its unique functionalities and excellent properties such as biocompatibility, biodegradability, low-cost, and simple gelling capability, which has received considerable interest in the drug delivery fields. Since there is an increasing need for biomaterials with unique properties for drug delivery applications, in this review, hydrogels fabricated from natural pectin polymers were thoroughly investigated. Additionally, the present mini review aims to bring collectively more concise ways such as sources, extraction, properties, and various forms of Pec based hydrogel drug delivery systems and their toxicity concerns are summarized. Finally, the potential objectives and challenges based on pectin-based hydrogel drug delivery systems are also discussed.

Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients. Human PBMCs acquired from SSc patients and healthy controls were transferred into NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG) mice with concurrent bleomycin injection. Blood, skin, and lung tissues were acquired and analyzed after PBMC engraftment. In addition, we investigated whether the humanized murine model could be used to assess the efficacy of potential therapeutics for SSc. Human PBMCs from SSc patients and healthy controls were engrafted into the blood, skin, and lung tissues of NSG mice. Histological analysis of affected tissues from mice treated with SSc PBMCs (SSc hu-mice) demonstrated substantial inflammation, fibrosis and vasculopathy with human immune cell infiltration and increased expression of IL-17, TGF-ß, CCL2, CCL3, and CXCL9. The proportions of circulating and tissue-infiltrating T helper 17 (Th17) cells were elevated in SSc hu-mice. These cells showed increased expression of CXCR3 and phosphorylated STAT3. SSc hu-mice treated with rebamipide and other potential Th17-cell-modulating drugs presented significantly reduced tissue fibrosis. Mice injected with patient-derived PBMCs show promise as an animal model of SSc.

How often should percutaneous gastrostomy feeding tubes be replaced? A single-institute retrospective study.

OBJECTIVE: Percutaneous gastrostomy (PG) is a common procedure that enables long-term enteral nutrition. However, data on the durability of individual tube types are insufficient. We conducted this study to compare the longevities and features of different PG tube types. DESIGN: We performed a 5-year retrospective analysis of patients who underwent endoscopic and radiologic PG-related feeding tube procedures. The primary and secondary outcomes were tube exchange intervals and revenue costs, respectively. Demographic factors, underlying diseases, operator expertise, materials used, and complication profiles were assessed. RESULTS: A total of 599 PG-related procedures for inserting pull-type PG (PGP), balloon-type PG (PGB), PG jejunal MIC* (PGJM; gastrojejunostomy type), and PG jejunal Levin (PGJL) tubes were assessed. On univariate Kaplan-Meier analysis, PGP tubes showed longer median exchange intervals than PGB tubes (405 days (95% CI: 315 to 537) vs 210 days (95% CI: 188 to 238); p<0.001). Larger PGB tubes diameters were associated with longer durations than smaller counterparts (24 Fr: 262 days (95% CI: 201 to NA), 20 Fr: 216 days (95% CI: 189 to 239), and 18 Fr: 148 days (95% CI: 100 to 245)). The PGJL tubes lasted longer than PGJM counterparts (median durations: 168 days (95% CI: 72 to 372) vs 13 days (95% CI: 23 to 65); p<0.001). Multivariate Cox proportional regression analysis revealed that PGJL tubes had significantly lower failure rates than PGJM tubes (OR 2.97 (95% CI: 1.17 to 7.53); p=0.022). PGB tube insertion by general practitioners was the least costly, while PGP tube insertion by endoscopists was 2.9-fold more expensive; endoscopic PGJM tubes were the most expensive at two times the cost of PGJL tubes. CONCLUSION: PGP tubes require replacement less often than PGB tubes, but the latter are more cost-effective. Moreover, PGJL tubes last longer than PGJM counterparts and, owing to lower failure rates, may be more suitable for high-risk patients.

Melatonin Regulates Iron Homeostasis by Inducing Hepcidin Expression in Hepatocytes.

The pineal hormone, melatonin, plays important roles in circadian rhythms and energy metabolism. The hepatic peptide hormone, hepcidin, regulates iron homeostasis by triggering the degradation of ferroportin (FPN), the protein that transfers cellular iron to the blood. However, the role of melatonin in the transcriptional regulation of hepcidin is largely unknown. Here, we showed that melatonin upregulates hepcidin gene expression by enhancing the melatonin receptor 1 (MT1)-mediated c-Jun N-terminal kinase (JNK) activation in hepatocytes. Interestingly, hepcidin gene expression was increased during the dark cycle in the liver of mice, whereas serum iron levels decreased following hepcidin expression. In addition, melatonin significantly induced hepcidin gene expression and secretion, as well as the subsequent FPN degradation in hepatocytes, which resulted in cellular iron accumulation. Melatonin-induced hepcidin expression was significantly decreased by the melatonin receptor antagonist, luzindole, and by the knockdown of MT1. Moreover, melatonin activated JNK signaling and upregulated hepcidin expression, both of which were significantly decreased by SP600125, a specific JNK inhibitor. Chromatin immunoprecipitation analysis showed that luzindole significantly blocked melatonin-induced c-Jun binding to the hepcidin promoter. Finally, melatonin induced hepcidin expression and secretion by activating the JNK-c-Jun pathway in mice, which were reversed by the luzindole treatment. These findings reveal a previously unrecognized role of melatonin in the circadian regulation of hepcidin expression and iron homeostasis.