Search Results (50)

Background/Objectives: In liver transplant surgery, ischemia–reperfusion (I-R) maneuvers are frequently employed to control bleeding; however, such interventions can result in injury not only to the liver but also to remote organs. The lungs, in particular, are highly susceptible due to their extensive vascularization and inflammatory response. While pulmonary injury secondary to hepatic I-R is recognized, and despite the fact that various antioxidant compounds have been investigated for their potential to mitigate I-R-induced damage to hepatic tissue, few studies have focused on evaluating therapeutic agents aimed at mitigating lung damage in this setting. This study aimed to evaluate the protective effect of apigenin on pulmonary tissue following liver I-R injury using an experimental rat model. Methods: Sixty-three male albino Wistar rats (approximately 15 weeks old, weighing 220–350 g) were randomly allocated into three groups: a sham group (open–close surgery; n = 7), a control (C) group subjected to liver I-R injury only (n = 28), and an apigenin (Ap) group receiving intraperitoneal apigenin administration immediately after liver ischemia and prior to reperfusion (n = 28). Both the C and Ap groups were subdivided into four equal subgroups corresponding to euthanasia at 60-, 120-, 180-, and 240 min post-reperfusion. Lung tissues were harvested for immunohistochemical analysis targeting the expression of matrix metalloproteinase-3 (MMP-3) and monocyte chemoattractant protein-1 (MCP-1). Results: The apigenin-treated groups exhibited significantly reduced expression levels of MMP-3 and MCP-1 across all time points when compared to the control groups. In contrast, no expression of MMP-3 or MCP-1 was observed in the sham group. Conclusions: The findings support the protective role of the antioxidant apigenin in reducing pulmonary injury following liver I-R. The diminished expression of MMP-3 and MCP-1 in the apigenin-treated rats provides compelling evidence for its protective effects on remote organs. Full article

Peroxisome proliferator-activated receptors (PPARs), including PPAR-α, PPAR-β/δ, and PPAR-γ, are involved in various cellular responses, including metabolism and cell proliferation. Increasing evidence suggests that PPARs are closely associated with tumorigenesis and metastasis. However, the exact role of PPARs in energy metabolism and cancer stem cell (CSC) proliferation remains unclear. This study investigated the role of PPARs in energy metabolism and tumorigenesis in ovarian CSCs. The expression of PPARs and fatty acid consumption as an energy source increased in spheroids derived from A2780 ovarian cancer cells (A2780-SP) compared with their parental cells. GW6471, a PPARα inhibitor, induced apoptosis in A2780-SP. PPARα silencing mediated by small hairpin RNA reduced A2780-SP cell proliferation. Treatment with GW6471 significantly inhibited the respiratory oxygen consumption of A2780-SP cells, with reduced dependency on fatty acids, glucose, and glutamine. In a xenograft tumor transplantation mouse model, intraperitoneal injection of GW6471 inhibited in vivo tumor growth of A2780-SP cells. These results suggest that PPARα plays a vital role in regulating the proliferation and energy metabolism of CSCs by altering mitochondrial activity and that it offers a promising therapeutic target to eradicate CSCs. Full article

This preclinical study was conducted to investigate the efficacy of interstitial PDT (i-PDT) for malignant gliomas arising deep within the brain, which are difficult to remove. C6 glioma cells were implanted into the basal ganglia of rats, and 3 weeks later, the second-generation photosensitizer talaporfin sodium (TPS) was administered intraperitoneally. Ninety minutes after administration, a prototype fine plastic optical fiber was punctured into the tumor tissue, and semiconductor laser light was irradiated into the tumor from a 2-mm cylindrical light-emitting source under various conditions. The brain was removed 24 h after the i-PDT and analyzed pathologically. The optical fiber was able to puncture the tumor center in all cases, enabling i-PDT to be performed. Histological analysis showed that tumor necrosis was induced in areas close to the light source, correlating with the irradiation energy dose, whereas apoptosis was induced at some distance from the light source. Irradiation using high energy levels resulted in tissue swelling from strong tumor necrosis, and irradiation at 75 J/cm² was most suitable for inducing apoptosis. An experimental system of i-PDT using TPS was established using malignant glioma cells transplanted into the rat brain. Tumor cell death, which correlated with the light propagation, was induced in tumor tissue. Full article

Background and Objectives: Mycobacterium bovis Bacillus Calmette–Guérin (BCG) vaccine administration has been suggested to prevent glucose metabolism abnormalities and fatty liver in genetically obese ob/ob mice; however, it is not clear whether the beneficial effects of BCG are also observed in the progression of glucose intolerance induced by a high-fat diet (HFD). Therefore, the effects of BCG vaccination on changes in glucose tolerance and insulin response were investigated in HFD-fed C57BL/6 mice. Materials and Methods: We used the BCG Tokyo 172 strain to determine effects on abnormalities in glucose metabolism. For vaccination, five-week-old male mice were injected intraperitoneally with BCG and maintained on a HFD for three weeks. The mice were regularly subjected to intraperitoneal glucose tolerance and insulin tolerance tests (IGTTs and ITTs). These tests were also performed in mice transplanted with bone marrow cells from BCG-vaccinated donor mice. Results: Significant effects of BCG vaccination on blood glucose levels in the IGTTs and ITTs were observed from week 12 of the experiment. BCG vaccination significantly improved changes in fasting glucose and insulin levels, insulin resistance indexes, and glucagon-to-insulin ratios in conjunction with the HFD at the end of the experiment. Significant inhibitory effects in the IGTTs and ITTs on glucose intolerance were also observed with transplantation with bone marrow cells derived from BCG-vaccinated donor mice. Conclusions: BCG vaccination significantly delayed glucose intolerance progression, suggesting a beneficial effect of BCG on the pathogenesis of type 2 diabetes. It has also been suggested that the effects of BCG vaccination may be at least partially due to an immune memory (trained immunity) for hematopoietic stem and progenitor cells of the bone marrow. Full article

Background: Peritoneal sclerosis (PS) and its most severe form, encapsulating PS (EPS), are rare entities that can occur in various procedures (liver transplantation, intraperitoneal chemotherapy) or secondary to medications (beta-blockers); however, PS or EPS typically occur in patients undergoing peritoneal dialysis as a form of renal function substitution. Medical or surgical treatments can be applied, but morbidity and mortality have high rates. This condition typically presents clinically as an intestinal obstruction caused by the inclusion of the intestinal loops in the peritoneal fibrous membrane. Methods: Herein, we present data from a single tertiary surgery center that has dedicated teams for patients receiving dialysis. Over 12 years, we analyzed a group of 63 patients admitted for catheter replacement/removal or for acute surgical pathology. In five cases (7.9%), we diagnosed EPS. Two patients with EPS presented with atypical abdominal pathologies requiring emergency surgery: one case of hemoperitoneum caused by a ruptured ovarian cyst and one case of uterine fibroids and metrorrhagia. Results: The definitive diagnoses were established intraoperatively and by analyzing the morpho-pathological changes in the peritoneum. The possible intraoperative challenges included laborious dissection, difficulties in restoring the correct anatomical landmarks, an increased duration of the surgical intervention and a high rate of incidents and accidents. Conclusions: The aim of the present study was to emphasize the possibility of other surgical pathologies overlapping with EPS, increasing the complexity of the surgical intervention. Full article

The route of administration of implanted cells may affect the outcome of cell therapy by directing cell migration to the damaged site. However, the question of the relationship between the route of administration, the efficacy of colonisation of a given organ, and the efficacy of cell therapy has not been resolved. The aim of the study was to localise transplanted intravenously and intraperitoneally human amniotic epithelial cells (hAECs) in the tissues of mice, both healthy and injured, in an animal experimental model of acute liver failure (ALF). Mice intoxicated with D-Galactosamine (D-GalN) at a dose of 150 mg/100 g body weight received D-GalN alone or with a single dose of hAECs administered by different routes. Subsequently, at 6, 24, and 72 h after D-GaIN administration and at 3, 21, and 69 h after hAEC administration, lungs, spleen, liver, and blood were collected from recipient mice. The degree of liver damage and regeneration was assessed based on biochemical blood parameters, histopathological evaluation (H&E staining), and immunodetection of proliferating (Ki67⁺) and apoptotic (Casp⁺) cells. The biodistribution of the administered cells was based on immunohistochemistry and the identification of human DNA. It has been shown that after intravenous administration, in both healthy and intoxicated mice, most of the transplanted hAECs were found in the lungs, while after intraperitoneal administration, they were found in the liver. We concluded that a large number of hAECs implanted in the lungs following intravenous administration can exert a therapeutic effect on the damaged liver, while the regenerative effect of intraperitoneally injected hAECs on the liver was very limited due to the relatively lower efficiency of cell engraftment. Full article

Background: Diabetic retinopathy (DR) is a vision-threatening complication that affects virtually all diabetic patients. Various treatments have been attempted, but they have many side effects and limitations. Alternatively, stem cell therapy is being actively researched, but it faces challenges due to a low cell survival rate. In this study, stem cells were pretreated with sirolimus, which is known to promote cell differentiation and enhance the survival rate. Additionally, the subconjunctival route was employed to reduce complications following intravitreal injections. Methods: Diabetes mellitus was induced by intraperitoneal injection of 55 mg/kg of streptozotocin (STZ), and DR was confirmed at 10 weeks after DM induction through electroretinogram (ERG). The rats were divided into four groups: intact control group (INT), diabetic retinopathy group (DR), DR group with subconjunctival MSC injection (DR-MSC), and DR group with subconjunctival sirolimus-pretreated MSC injection (DR-MSC-S). The effects of transplantation were evaluated using ERG and histological examinations. Results: The ERG results showed that the DR-MSC-S group did not significantly differ from the INT in b-wave amplitude and exhibited significantly higher values than the DR-MSC and DR groups (p < 0.01). The flicker amplitude results showed that the DR-MSC and DR-MSC-S groups had significantly higher values than the DR group (p < 0.01). Histological examination revealed that the retinal layers were thinner in the DR-induced groups compared to the INT group, with the DR-MSC-S group showing the thickest retinal layers among them. Conclusions: Subconjunctival injection of sirolimus-pretreated MSCs can enhance retinal function and mitigate histological changes in the STZ-induced DR rat model. Full article

Sinusoidal obstruction syndrome (SOS) is a serious liver disorder that occurs after liver transplantation, hematopoietic stem cell transplantation, and the administration of anticancer drugs. Since SOS is a life-threatening condition that can progress to liver failure, early detection and prompt treatment are required for the survival of patients with this condition. In this study, female CD1 mice were divided into treatment and control groups after the induction of an SOS model using monocrotaline (MCT, 270 mg/kg body weight intraperitoneally). The mice were analyzed at 0, 12, 24, and 48 h after MCT administration, and blood and liver samples were collected for assays and histopathology tests. SOS was observed in the livers 12 h after MCT injection. In addition, immunohistochemical findings demonstrated CD42b-positive platelet aggregations, positive signals for von Willebrand factor (VWF), and a disintegrin-like metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) in the MCT-exposed liver sinusoid. Although ADAMTS13’s plasma concentrations peaked at 12 h, its enzyme activity continuously decreased by 75% at 48 h and, inversely and proportionally, concentrations in the VWF-A2 domain, in which the cleavage site of ADAMTS13 is located, increased after MCT injection. These findings suggest that the plasma concentration and activity of ADAMTS13 could be useful biomarkers for early detection and therapeutic intervention in patients with SOS. Full article

Sarcomas are a rare tumor of mesenchymal origin. The liposarcoma is the most common sarcoma of the retroperitoneum. Liposarcomas are typically low grade, and present at an advanced stage and a large size. We report a case of a large retroperitoneal liposarcoma, approximately 50 kg, encasing both kidneys, which was managed via a two-stage resection and staged renal auto-transplantation into the intra-peritoneal pelvis. The patient maintained normal renal function throughout, and remains disease free two years post-resection. Renal auto-transplantation with pelvic placement may facilitate improved margin-free resection. Renal relocation may allow the use of curative-intent ablative therapies such as radiofrequency ablation and radiation in cases of retroperitoneal recurrence. Full article

Type 1 diabetes mellitus (T1DM) was established to be ameliorated by islet transplantation, but the shortage of the transplanted human islet tissue and the use of immunosuppressive drugs to inhibit the rejection of allogeneic grafts make this type of therapy is limited. Nowadays, therapy with stem cells is one of the most promising future treatments. This kind of therapy could have a profound impact on both replacement, as well as regenerative therapies, to improve or even cure various disorders, including diabetes mellitus. Flavonoids have also been shown to possess anti-diabetic effects. Thus, this study aims to evaluate the effectiveness of the bone marrow-derived mesenchymal stem cells (BM-MSCs) and hesperetin in the treatment of a T1DM rat model. T1DM was induced in male Wistar rats that had been starved for 16 h via intraperitoneal injection of STZ at a dose of 40 mg/kg body weight (b.wt.). After 10 days of STZ injection, the diabetic rats were allocated into four groups. The first diabetic animal group was considered a diabetic control, while the other three diabetic animal groups were treated for six weeks, respectively, with hesperetin (given orally at a dose of 20 mg/kg b.wt.), BM-MSCs (injected intravenously at a dose of 1 × 10⁶ cells/rat/week), and their combination (hesperetin and BM-MSCs). The use of hesperetin and BM-MSCs in the treatment of STZ-induced diabetic animals significantly improved the glycemic state, serum fructosamine, insulin and C-peptide levels, liver glycogen content, glycogen phosphorylase, glucose-6-phosphatase activities, hepatic oxidative stress, and mRNA expressions of NF-κB, IL-1β, IL-10, P53, and Bcl-2 in pancreatic tissue. The study suggested the therapy with both hesperetin and BM-MSCs produced marked antihyperglycemic effects, which may be mediated via their potencies to ameliorate pancreatic islet architecture and insulin secretory response, as well as to decrease hepatic glucose output in diabetic animals. The improvement effects of hesperetin and BM-MSCs on the pancreatic islets of diabetic rats may be mediated via their antioxidant, anti-inflammatory, and antiapoptotic actions. Full article

Growing evidence indicates that hepatocyte growth factor (HGF) possesses potent antifibrotic activity. Furthermore, macrophages migrate to inflamed sites and have been linked to the progression of fibrosis. In this study, we utilized macrophages as vehicles to express and deliver the HGF gene and investigated whether macrophages carrying the HGF expression vector (HGF-M) could suppress peritoneal fibrosis development in mice. We obtained macrophages from the peritoneal cavity of mice stimulated with 3% thioglycollate and used cationized gelatin microspheres (CGMs) to produce HGF expression vector-gelatin complexes. Macrophages phagocytosed these CGMs, and gene transfer into macrophages was confirmed in vitro. Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) for three weeks; seven days after the first CG injection, HGF-M was administered intravenously. Transplantation of HGF-M significantly suppressed submesothelial thickening and reduced type III collagen expression. Moreover, in the HGF-M-treated group, the number of α-smooth muscle actin- and TGF-β-positive cells were significantly lower in the peritoneum, and ultrafiltration was preserved. Our results indicated that the transplantation of HGF-M prevented the progression of peritoneal fibrosis and indicated that this novel gene therapy using macrophages may have potential for treating peritoneal fibrosis. Full article

This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1β-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity. Full article

β-glucan, a plant polysaccharide, mainly exists in plant cell walls of oats, barley, and wheat. It is attracting attention due to its high potential for use as functional foods and pharmaceuticals. We have previously reported that low-molecular-weight Aureobasidium pullulans-fermented β-D-glucan (LMW-AP-FBG) could inhibit inflammatory responses by inhibiting mitogen-activated protein kinases and nuclear factor-κB signaling pathways. Bases on previous results, the objective of the present study was to investigate the therapeutic potential of LMW-AP-FBG in BALB/c mice intracutaneously transplanted with CT-26 colon cancer cells onto their backs. Daily intraperitoneal injections of LMW-AP-FBG (5 mg/kg) for two weeks significantly suppressed tumor growth in mice bearing CT-26 tumors by reducing tumor proliferation and inducing apoptosis as compared to phosphate buffer-treated control mice. In addition, LMW-AP-FBG treatment reduced the viability of CT-26 cells in a dose-dependent manner by inducing apoptosis with loss of mitochondrial transmembrane potential and increased activated caspases. Taken together, LMW-AP-FBG exhibits anticancer properties both in vivo and in vitro. Full article

Animal research in intestinal ischemia-reperfusion injury (IRI) is mainly performed in rodent models. Previously, intraperitoneal (I.P.) injections with ketamine–xylazine mixtures were used. Nowadays, volatile anesthetics (isoflurane) are more common. However, the impact of the anesthetic method on intestinal IRI has not been investigated. We aim to analyze the different anesthetic methods and their influence on the extent of intestinal IRI in a rat model. Male Sprague–Dawley rats were used to investigate the effect of I.P. anesthesia on 60 min of intestinal ischemia and 60 min of reperfusion in comparison to hyperoxygenation (100% O₂) and volatile isoflurane anesthesia. In comparison to I.P. anesthesia with room air (21% O₂), supplying 100% O₂ improved 7-day survival by cardiovascular stabilization, reducing lactic acidosis and preventing vascular leakage. However, this had no effect on the intestinal epithelial damage, permeability, and inflammatory response observed after intestinal IRI. In contrast to I.P. + 100% O₂, isoflurane anesthesia reduced intestinal IRI by preventing ongoing low-flow reperfusion hypotension, limiting intestinal epithelial damage and permeability, and by having anti-inflammatory effects. When translating the aforementioned results of this study to clinical situations, such as intestinal ischemia or transplantation, the potential protective effects of hyperoxygenation and volatile anesthetics require further research. Full article

Due to the high incidence of diabetes mellitus (DM) and poor response to the first-line treatment of DM-induced erectile dysfunction (DMED), new therapeutic strategies for DMED are needed. Adipose-derived stem cell (ADSC) transplantation is considered a promising treatment modality for DMED but is limited by poor survival and efficacy after transplantation. In this study, we aimed to increase the therapeutic effect of DMED by overexpressing the relaxin family peptide receptor 1 (RXFP1) using a clustered regularly interspaced short palindromic repeats activation (CRISPRa) system in ADSCs. Two lentiviruses carrying the CRISPRa system transfected ADSCs to overexpress RXFP1 (RXFP1-ADSCs). The intracavernous injection of ADSCs was performed in DMED rats induced by the intraperitoneal injection of streptozotocin. Four weeks after transplantation, we measured erectile function and collected specimens of the corpus cavernosum for follow-up detection. The results showed that ADSCs improved erectile function in diabetic rats, and the RXFP1-ADSCs were more significant. We detected reduced levels of oxidative stress, apoptosis and fibrosis together with relative normalization of endothelial and smooth muscle cell function in the penis after ADSC transplantation. RXFP1-ADSCs had more potent efficacy in the above alterations compared to negative control ADSCs due to the high levels of survival and paracrine capacity in RXFP1-ADSCs. The results revealed that RXFP1-ADSC transplantation could partially preserve erectile function in DMED rats associated with the regulation of oxidative stress, apoptosis, fibrosis and endothelial and smooth muscle cell dysfunction. RXFP1 may be the new target for the genetic modification of ADSCs, which benefits the management of DMED. Full article