Expression levels of tam receptors and ligands in the testes of rats exposed to short and middle-term 2100 MHz radiofrequency radiation.

With advances in technology, the emission of radiofrequency radiation (RFR) into the environment, particularly from mobile devices, has become a growing concern. Tyro 3, Axl, and Mer (TAM) receptors and their ligands are essential for spermatogenesis and testosterone production. RFR has been shown to induce testicular cell apoptosis by causing inflammation and disrupting homeostasis. This study aimed to investigate the role of TAM receptors and ligands in the maintenance of homeostasis and elimination of apoptotic cells in the testes (weeks), short-term sham exposure (sham/1 week), and middle-term sham exposure (sham/10 weeks). Testicular morphology was assessed using hematoxylin-eosin staining, while immunohistochemical staining was performed to assess expression levels of TAM receptors and ligands in the testes of all groups. The results showed that testicular morphology was normal in the control, sham/1 week, and sham/10 weeks groups. However, abnormal processes of spermatogenesis and seminiferous tubule morphology were observed in RFR exposure groups. Cleaved Caspase 3 immunoreactivity showed statistically significant difference in 1 and 10 weeks exposure groups compared to control group. Moreover, there was no significant difference in the immunoreactivity of Tyro 3, Axl, Mer, Gas 6, and Pros 1 between groups. Moreover, Tyro 3 expression in Sertoli cells was statistically significantly increased in RFR exposure groups compared to the control. Taken together, the results suggest that RFR exposure negatively affects TAM signalling, preventing the clearance of apoptotic cells, and this process may lead to infection and inflammation. As a result, rat testicular morphology and function may be impaired.

Analysis of increased motorcycle accidents during the COVID-19 pandemic: a single-center study from Türkiye.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has led to a unique set of circumstances, straining health-care systems and affecting the way of life in societies around the world. Measures such as social isolation, travel restrictions, and workplace closures have led to an increase in motorcycle use. Consequently, motorcycle accidents have become a significant problem during this period. This study presents detailed research conducted to examine motorcycle accidents during the COVID-19 pandemic and to understand the causes and consequences of the increase in these accidents. METHODS: This research evaluated records from a single health examination and used various models to analyze motorcycle acci-dents within a specified time period. Additionally, retrospective analyses were conducted to examine associations between motorcycle use and crashes in our country before and after the pandemic. The records of 386 patients who were injured in motorcycle accidents and followed up, received treatment, and were recorded at Biruni University Hospital between November 2015 and April 2023 were retrospectively examined. Noted details included the victims' age, gender, injury mechanism, injury site, injury severity, helmet use, presence and location of fractures, time distribution of the accident, and the severity of other important tissue injuries. The relationship between the injury site, fractures, and accident details, and the "Injury Severity Score" (ISS) was also investigated. RESULTS: Among the 386 injured victims in motorcycle accidents, 333 were male and 53 were female. Of these, 168 (43.5%) were motorcycle drivers, 137 (35.5%) were motorcycle couriers, and 81 (21%) were pedestrians. A total of 186 (48%) injuries occurred before the pandemic (November 2015-March 2020), while 200 (52%) were sustained during the pandemic. The study indicates a noticeable increase in motorcycle injuries, particularly among motor couriers, especially during the pandemic quarantine periods. Post hoc analysis revealed that motor couriers had significantly lower ISS compared to other professions (p=0.009 and p=0.045, respectively). Motorcyclists who wore helmets were found to have significantly lower ISS than those who did not wear helmets (p<0.05). Furthermore, it was found that the ISS was positively correlated with the number of bone fractures, total soft tissue injury, and significant clinical characteristics (r=0.758, r=0.756, and p<0.001, respectively). CONCLUSION: This clinical study's findings demonstrate that the measures implemented during the pandemic to limit society's mobility have led to an increase in motorcycle accidents. Notably, there has been a significant rise in the number of accidents, particularly involving individual motorcycle use and motorcycle courier services.

Effects of continuous and pulsed radiofrequency applied for 120 and 240 seconds to rats' sciatic nerve.

OBJECTIVES: Radiofrequency (RF) has been used for many years for pain treatment. The effects of RF on nerves and the underlying mechanism of these effects are not clearly understood. The aim of this study is to show the effects of Pulsed (P-RF) and Continuous (C-RF) RF in light and electron microscopy, and to determine the differences between them. METHODS: In this study, a total of 60 Rattus norvegicus rats were used in 6 groups. No procedure was performed on the control group. In the Sham group, the electrodes were placed but no current was applied. P-RF for 120 seconds, P-RF for 240 seconds, C-RF for 120 seconds, and C-RF for 240 seconds at 42 °C were applied respectively to the other groups. Sections obtained from sciatic nerves were examined with light and electron microscopy. RESULTS: Examinations of the Sham, P120, and C120 groups were normal. In P240, some morphological changes were observed, but when all samples were examined, these abnormalities were evaluated as negligible. In C240, severe deformation of both myelinated and non-myelinated nerve fibers was observed under an electron and light microscope. Dramatic structural deformities in Schwann cells were observed. CONCLUSION: P120, P240, and C120 treatments did not produce any deformities in the sciatic nerve. The application of C-RF for 240 seconds produced pathological alterations in the nerve structure.

Linagliptin in combination with insulin suppresses apoptotic unfolded protein response in ovaries exposed to type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum (ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar-lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ER stress in type 1 diabetic mouse ovaries. Eighty-four Balb/C 6-week-old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro-survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism-dependent survival in ovaries with type 1 diabetes.

Evaluation of linagliptin and insulin combined therapy on unfolded protein response in type 1 diabetic mouse heart.

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.

Electric scooters as a silent source of danger in increasing use among young people: a single-center in-depth accident analysis.

BACKGROUND: The reasons for the increase in accidents involving shared stand-up e-scooters in recent years may be the wide-spread use of e-scooters among young people, especially in metropolitan areas with heavy traffic, non-compliance with traffic rules, and insufficient legal regulations. In this study, we analyzed in detail the typical features of rider-sharing e-scooter-related injuries brought to the emergency department of our hospital in the light of current literature. METHODS: The clinical and accident characteristics of 60 patients with surgical requirements who were brought to the emergency department of our hospital due to e-scooter-related accidents between 2020 and 2020 were analyzed using statistical methods ret-rospectively. RESULTS: The majority of the victims were university students and the number of victims of the male gender was slightly higher and the mean age was 25.3±13.0 years. Most e-scooter accidents occur on weekdays. Most of the e-scooter-related accidents happen on weekdays and are non-collision type accidents. The majority of e-scooter-related accident victims were in the minor trauma group (injury severity score <9), predominantly had extremity and soft-tissue injuries and needed radiological examination (44 patients, 73.3%), and only eight victims (13.3%) required surgical operation and also all of the e-scooter victims were discharged fully healed. CONCLUSION: Among the more common collision-free e-scooter-related accidents that have a lower trauma severity score or cause minor soft-tissue injury, mono-trauma occurs more commonly than multisystem trauma; likewise, radius and nasal-weighted monofractures occur more commonly than multiple fractures, according to this study. Besides, effective measures and legal regulations should be put in place to prevent e-scooter-related accidents.

Unfolded protein response triggers differential apoptotic mechanisms in ovaries and early embryos exposed to maternal type 1 diabetes.

Diabetes mellitus (DM) has profound effects on the female mammalian reproductive system, and early embryonic development, reducing female reproductive outcomes and inducing developmental programming in utero. However, the underlying cellular and molecular mechanisms remain poorly defined. Accumulating evidence implicates endoplasmic reticulum (ER)-stress with maternal DM associated pathophysiology. Yet the direct pathologies and causal events leading to ovarian dysfunction and altered early embryonic development have not been determined. Here, using an in vivo mouse model of Type 1 DM and in vitro hyperglycaemia-exposure, we demonstrate the activation of ER-stress within adult ovarian tissue and pre-implantation embryos. In diabetic ovaries, we show that the unfolded protein response (UPR) triggers an apoptotic cascade by the co-activation of Caspase 12 and Cleaved Caspase 3 transducers. Whereas DM-exposed early embryos display differential ER-associated responses; by activating Chop in within embryonic precursors and Caspase 12 within placental precursors. Our results offer new insights for understanding the pathological effects of DM on mammalian ovarian function and early embryo development, providing new evidence of its mechanistic link with ER-stress in mice.

Effect of clinician's experience and expertise on the inter- and intra-observer reliability of hip migration index in children with cerebral palsy: A STROBE-compliant retrospective study.

ABSTRACT: Few studies have investigated the reliability of Reimers' hip migration percentage (RMP) in children with cerebral palsy (CP). Most studies on the topic reflected rating results of physician with a similar level of experience from the same expertise. This study aimed to determine the effect of clinician's experience and expertise on the intra-and inter-observer reliability of RMP.In this retrospective observational study, hip radiographs of children with CP were identified. 5 observers with different degrees of working experience from 3 different clinical fields, including orthopedics, radiology, and physical medicine and rehabilitation, performed all RMP measurements. All measurements were repeated 6 weeks later by the same observers. Inter- and intra-observer reliability for RMP measurements were assessed using Intraclass Correlation Coeficient (ICC), calculated from 2 sets of repeated measurements on a subset of 50 hips, with a 6 week apart for each observer.Fifty hip radiographs of 25 children with CP (10 females and 15 males; mean age: 6 years; age range: 2-8 years) were examined in the current study. No significant differences existed in intra-and inter-observer measurements. Excellent intra-observer reliability was observed between the 2 separate measurements for each observer, with a mean ICC of 0.976 (range: 0.956-0.989; P < .001). Among 5 observers, inter-observer reliability was excellent for the 2 separate RMP measurements, with the mean ICC minimally increasing between the 2 measurement periods (mean ICC: 0.928, range: 0.838-0.979 and mean ICC: 0.936, range: 0.861-0.983, respectively) (P < .001).Clinician's experience and expertise may not affect inter-and intra-observer reliability of RMP measurements.

BMP signalling is required for extra-embryonic ectoderm development during pre-to-post-implantation transition of the mouse embryo.

At implantation, the mouse embryo undergoes a critical transformation which requires the precise spatiotemporal control of signalling pathways necessary for morphogenesis and developmental progression. The role played by such signalling pathways during this transition are largely unexplored, due to the inaccessibility of the embryo during the implantation when it becomes engulfed by uterine tissues. Genetic studies demonstrate that mutant embryos for BMPs die around gastrulation. Here we have aimed to dissect the role of BMPs during pre-to post-implantation transition by using a protocol permitting the development of the embryo beyond implantation stages in vitro and using stem cells to mimic post-implantation tissue organisation. By assessing both the canonical and non-canonical mechanisms of BMP, we show that the loss of canonical BMP activity compromises the extra-embryonic ectoderm development. Our analyses demonstrate that BMP signalling maintains stem cell populations within both embryonic/extra-embryonic tissues during pre-to post-implantation development. These results may provide insight into the role played by BMP signalling in controlling early embryogenesis.

The effects of acute and chronic exposure to 900 MHz radiofrequency radiation on auditory brainstem response in adult rats.

The aim of this study was to determine the effects of short and long-term RFR exposure on ABR by evaluating lipid peroxidation and antioxidant status in adult rats. Sixty male albino Wistar rats were randomly divided into four groups. S1:1 week sham, S10:10 weeks sham, E1:1 week RFR, E10:10 weeks RFR. Experimental group rats were exposed to RFR 2 h/day, 5 days/week during the test period. Sham rats were kept in the same conditions without RFR. After the experiment, ABRs were recorded from the mastoids of rats using tone burst acoustic stimuli. Biochemical investigations in rat brain and ultrastructural analysis in temporal cortex were performed. ABR wave I latency prolonged in E1-group and shortened in E10-group compared to their shams. TBARS level increased in E1-group, decreased in E10-group, on the contrary, SOD and CAT activities and GSH level decreased in E1-group, increased in E10-group compared to their sham groups. Edema was present in the neuron and astrocyte cytoplasms and astrocyte end-feet in both E1 and E10 groups. Our results suggest that 900 MHz RFR may have negative effects on the auditory system in acute exposure and no adverse effects in chronic exposure without weekends.

Effect of ER stress on sphingolipid levels and apoptotic pathways in retinal pigment epithelial cells.

BACKGROUND: We aimed to determine sphingolipid levels and examine apoptotic pathways in human retinal pigment epithelial cells (ARPE-19) undergoing endoplasmic reticulum (ER) stress. METHODS: Cells were treated with tunicamycin (TM) to induce ER stress and tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was administered to decrease cytotoxicity. Cell viability was measured by MTT assay. Levels of C16-C24 sphingomyelins (SM) and C16-C24 ceramides (CERs) were determined by LC-MS/MS. Glucose-regulated protein 78-kd (GRP78) and nuclear factor kappa-b subunit 1 (NFκB1) gene expressions were evaluated by quantitative PCR analysis, while GRP 78, NF-κB p65, cleaved caspase-3 and caspase-12 protein levels were assesed by immunofluorescence. Ceramide-1-phosphate (C1P) levels were determined by immunoassay, while caspase -3 and -12 activity in cell lysates were measured via a fluorometric method. RESULTS: Induction of ER stress in TM treated groups were confirmed by significantly increased mRNA and protein levels of GRP78. TM significantly decreased cell viability compared to controls. Treatment with TUDCA along with TM significantly increased cell viability compared to the TM group. A significant increase was observed in C22-C24 CERs, C1P, caspase-3, caspase-12, NFκB1 mRNA and NF-κB p65 protein levels in cells treated with TM compared to controls. Administration of TUDCA lead to a partial decrease in GRP78 expression, NFκB1 mRNA, NF-κB p65 protein, C22-C24 CERs and C1P levels along with a decrease in caspase-3 and -12 activity. CONCLUSIONS: The results of this study reveal the presence of increased long chain CERs, C1P and apoptotic markers in retinal cells undergoing ER stress.

Neuroprotective Effects of Ozone Therapy After Sciatic Nerve Cut Injury.

A number of antioxidants have been used to treat peripheral nerve injury. However, there are few definitive experimental studies of ozone therapy for peripheral nerve cut injury. We aimed to examine the effects of mild level ozone therapy on sciatic nerve regeneration. One hundred adult male Wistar albino rats were randomly divided into four groups: group 1 (n=20) no cut injury or therapy; group 2 (n=20) sham; group 3 (n=30) nerve cut injury, no therapy; group 4 (n=30) nerve cut injury and ozone therapy. Sciatic functional index (SFI) and withdrawal reflex (WDR) were measured for all groups before nerve cut, at postoperative day 1, and at weeks 2, 4, 6 and 8. More myelinated (M) nerve fibers were observed after nerve cut injury in the ozone-therapy group. Significant differences were seen in plasma SOD (superoxide dismutase), CAT (catalase) and GPx (glutathione peroxidase) activities (p<0.05), and significant functional improvement was observed at postoperative weeks 2 and 4 (p<0.05) after ozone treatment. This is the first study conducted for the purpose of examining the effects of ozone therapy on sciatic nerve cut injury.

Spontaneous Idiopathic Cerebrospinal Fluid Rhinorrhea.

Cerebrospinal fluid rhinorrhea is described as cerebrospinal fluid flow through the nose due to the abnormal connection of the subarachnoid space and sinonasal cavity. Spontaneous idiopathic rhinorrhea is a rarely seen disease. Besides the patient's clinical presentation detailed radiological evaluation and other invasive procedures must be carried out to confirm the diagnosis. Its treatment is compelling due to high recurrence rates. In the treatment algorithm when conservative treatment modalities had been proven inadequate, surgical repair must follow in order. In this paper the authors present the details of 2 cases of spontaneous rhinorrhoea patients.

Dehydroepiandrosterone supplementation attenuates ovarian ageing in a galactose-induced primary ovarian insufficiency rat model.

PURPOSE: Almost every female classic galactosemia patient develops primary ovarian insufficiency (POI). The unique pathophysiology of classic galactosemia, with a severely reduced follicle pool at an early age, requires a new therapeutic approach. This study evaluated the effect of dehydroepiandrosterone (DHEA) on ovarian tissue in a galactose-induced POI rat model. METHODS: Pregnant rats were fed with either a normal or a 35% galactose-containing diet from day 3 of conception continuing through weaning of the litters. Galactose-exposed female offspring were further divided into 5 groups on PND21. The first group received no application. Treatment groups were fed orally by gavage once daily with sesame oil (group 2), or DHEA at doses of 0.1 mg/kg (group 3), 1 mg/kg (group 4) or 10 mg/kg (group 5) until PND70. Fertility rates of mothers with galactosemia, body weights (BWs), and ovarian weights of the litters from PND21 to PND70 were recorded. Ovarian follicle count, immunohistochemistry for proliferation and apoptosis marker expressions and TUNEL for cell death assessment were performed in offspring ovaries. RESULTS: Decreased fertility, ovarian/body weights were observed under galactosemic conditions, together with decreased follicle number and increased atresia. Improved postnatal development, primordial follicle recruitment and follicular growth were observed after DHEA treatment. After DHEA treatment, the expression of Ki67 protein was found to be increased; elevated expression of cleaved-caspase-3 under galactosemia was found to be reduced. CONCLUSIONS: Our data suggests that DHEA treatment may be a potentially useful clinical therapy to improve ovarian ageing in women with POI-induced by galactosemia.

Comparative Analysis of the Healing Effects of the Transplanted Cell Sheets to the Experimentally Injured Maxillary Sinuses.

BACKGROUND: In our study, the authors aimed to obtain a live and functional sinus epithelium with mesenchymal stem cells and nasal mucosa epithelial cells from rabbits which are cultured in temperature-responsive culture plates to get a single-layer. METHODOLOGY/PRINCIPAL: Twenty-two female New Zealand rabbits were included in the study. Two of them were used to obtain mesenchymal stem cells. A total of 40 maxillary sinuses were randomly divided into 5 groups: 1) control group which is used to investigate normal rabbit maxillary mucosa, 2) secondary healing group, 3) mesenchymal stem cell graft group, 4) differentiated mesenchymal stem cell group, and 5) nasal mucosal graft group. The animals were sacrificed at the 28th day after the surgery.Scanning electron microscopy, transmission electron microscopy, and immunohistochemical investigations were performed. RESULTS: With these investigations, it was shown that; all graft groups were histologically better than secondary healing group and when the authors compared the graft groups, differentiated mesenchymal stem cell group were the best. CONCLUSION: Our study results showed that endoscopic sinus surgery and treatment with cell sheets, which were generated in temperature-responsive culture dishes, had more functional respiratory epithelium.

Decellularization of Trachea With Combined Techniques for Tissue-Engineered Trachea Transplantation.

OBJECTIVES: The purpose of this study is to shorten the decellularization time of trachea by using combination of physical, chemical, and enzymatic techniques. METHODS: Approximately 3.5-cm-long tracheal segments from 42 New Zealand rabbits (3.5±0.5 kg) were separated into seven groups according to decellularization protocols. After decellularization, cellular regions, matrix and strength and endurance of the scaffold were followed up. RESULTS: DNA content in all groups was measured under 50 ng/mg and there was no significant difference for the glycosaminoglycan content between group 3 (lyophilization+deoxycholic acid+de-oxyribonuclease method) and control group (P=0.46). None of the decellularized groups was different than the normal trachea in tensile stress values (P>0.05). Glucose consumption and lactic acid levels measured from supernatants of all decellularized groups were close to group with cells only (76 mg/dL and 53 mg/L). CONCLUSION: Using combination methods may reduce exposure to chemicals, prevent the excessive influence of the matrix, and shorten the decellularization time.

Effects of Graft Selection in Arthroscopic Anterior Cruciate Ligament Reconstruction: Midterm Functional Results.

OBJECTIVES: This study is a comparison of the midterm clinical results of patients who underwent anterior cruciate ligament (ACL) reconstruction using an allograft and those who had an autograft procedure. METHODS: The results of 70 patients who underwent ACL reconstruction with an anterior tibial tendon (ATT) allograft (n=18) or a hamstring (HT) autograft (n=52) were evaluated retrospectively. At the last follow-up, International Knee Documentation Committee (IKDC) and Tegner-Lysholm scores were used to assess functional status, as well as results of the Lachman test, the anterior drawer test, and the pivot-shift test. RESULTS: There was no significant difference between the 2 groups in terms of age, gender, length of time before operation, graft thickness, or femoral tunnel length (p>0.05). The results were satisfactory in both groups in the postoperative period in terms of the length of time until a return to sports, IKDC score, Tegner-Lysholm score, range of motion, quadriceps circumference, and laxity, with no significant difference between the groups (p>0.05). CONCLUSION: The results of this study suggested that midterm clinical outcomes of ACL reconstruction with an ATT allograft or an HT autograft are similar when the correct technique is used according to the appropriate indications by an experienced surgeon and a successful rehabilitation program implemented after the operation.

Nephronectin is Decreased in Metastatic Breast Carcinoma and Related to Metastatic Organs.

Breast cancer causes death mostly due to distant metastasis. During metastasis, cancer cells create new conditions in which normal tissue structure can be disturbed. Nephronectin, which is the primary ligand for α8ß1 integrin, plays an important role in kidney development. There are conflicting findings regarding its role in cancer progression and metastasis, especially in breast carcinoma. The aim of this study was to determine changes in nephronectin expression in primary tumor tissues and metastatic visceral organs, using metastatic and non-metastatic cell lines in a mouse model of breast cancer. In our study, 4T1-Liver Metastatic and 4T1-Heart Metastatic cells, originally derived from 4T1-murine breast carcinoma, and non-metastatic 67NR carcinoma cells were used. Cancer cells were injected orthotopically into the mammary gland of 8-10 week-old Balb-c mice. Primary tumors, lung, liver tissues were collected on 12th and 25th days after the tumor injection. Immunohistochemistry was used to determine expression of nephronectin in tissues. We also investigated the expression levels of the protein by using western blot technique. We found that lung and liver tissue of control animals (not-injected with tumor cells) expressed nephronectin which was lost in animals bearing metastatic tumor for 25 days. In accordance, nephronectin staining of lung and liver was preserved in animals injected with non-metastatic 67NR tumors. These results demonstrate that loss of nephronectin may play an important role in formation metastatic milieu for cancer cells. This is the first study demonstrating that tumor-induced loss of nephronectin expression in visceral organs in which metastatic growth takes place.

Neutral sphingomyelinase inhibition alleviates apoptosis, but not ER stress, in liver ischemia-reperfusion injury.

Previous studies have revealed the activation of neutral sphingomyelinase (N-SMase)/ceramide pathway in hepatic tissue following warm liver ischemia reperfusion (IR) injury. Excessive ceramide accumulation is known to potentiate apoptotic stimuli and a link between apoptosis and endoplasmic reticulum (ER) stress has been established in hepatic IR injury. Thus, this study determined the role of selective N-SMase inhibition on ER stress and apoptotic markers in a rat model of liver IR injury. Selective N-SMase inhibitor was administered via intraperitoneal injections. Liver IR injury was created by clamping blood vessels supplying the median and left lateral hepatic lobes for 60 min, followed by 60 min reperfusion. Levels of sphingmyelin and ceramide in liver tissue were determined by an optimized multiple reactions monitoring (MRM) method using ultrafast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Spingomyelin levels were significantly increased in all IR groups compared with controls. Treatment with a specific N-SMase inhibitor significantly decreased all measured ceramides in IR injury. A significant increase was observed in ER stress markers C/EBP-homologous protein (CHOP) and 78 kDa glucose-regulated protein (GRP78) in IR injury, which was not significantly altered by N-SMase inhibition. Inhibition of N-SMase caused a significant reduction in phospho-NF-kB levels, hepatic TUNEL staining, cytosolic cytochrome c, and caspase-3, -8, and -9 activities which were significantly increased in IR injury. Data herein confirm the role of ceramide in increased apoptotic cell death and highlight the protective effect of N-SMase inhibition in down-regulation of apoptotic stimuli responses occurring in hepatic IR injury.