PD-L1 protein expression by Combined Positive Score (CPS) in patients with muscle invasive or advanced urothelial carcinoma: a single institution experience.

INTRODUCTION: Immune checkpoint inhibitors have revolutionized the treatment of patients with advanced urothelial carcinoma (UC) in the frontline and relapsed settings. Lebanon has one of the highest incidence of UC worldwide, yet no data exists regarding the expression of PD-L1 by Combined Positive Score (CPS) in advanced disease. METHODS: We reviewed all patients treated at our institution for high grade UC, stage pT2 and above, between January 2017 and March 2021. We assessed the expression of PD-L1 by immunohistochemistry using 22C3 clone, and analyzed the association between PD-L1 expression and clinicopathological characteristics. PD-L1 positivity was defined as CPS score ≥ 10. RESULTS: A total of 101 patients with advanced UC were included, with a median age of 71 years (range, 38 to 96 years); 78% were ever-smokers. Ninety-three of 101 patients (92%) had conventional UC and 43 patients (43%) had positive PD-L1 expression, with 12 patients having CPS of 100. The analysis by molecular subtype showed that patients with maximal CPS of 100 were enriched in "basal" molecular subtype. However, no association was found between PD-L1 expression (positive versus negative) and clinicopathological characteristics. CONCLUSION: The positivity of PD-L1 expression as assessed by CPS using the 22C3 clone in our population was almost comparable to the results reported in the occidental literature. Therefore, PD-L1 expression, as a potential predictor of response to immunotherapy, concerns the same percentage of the Lebanese UC patients.

Epidemiology of bone tumors in Lebanon: a retrospective study from 2000 to 2022 at a tertiary center.

Aim: Bone tumors are rare and have an uneven geographic distribution. Methods: 730 patients diagnosed with bone tumors were included in this retrospective analysis. Results: With a 64% rate of malignancy, the most common tumors were metastasis (40%) mostly in the axial skeleton, Osteosarcoma (9%) mostly in the femur, Osteochondroma (8%) mostly in the femur, giant cell tumors (7%) mostly in the knee, and Ewing's sarcoma (6%) mostly in the axial skeleton. Conclusion: Even though a some of the tumors have a predilection for certain localizations in the human body, they may differ in the middle-eastern population. One must also pay attention to the higher rates of malignancies as compared with other cohorts.

With significant morbidity and mortality, bone tumors incidence is low and varies geographically. In our Lebanese population, Seven-hundred-thirty patients with bone tumors were identified with a 64% rate of malignancy with osteosarcoma being the most common primary bone cancer and metastasis being the overall most prevalent bone malignancy. This higher rate of malignancy compared with other populations should be taken into consideration when evaluating Lebanese or Middle eastern patients.

TRPC3 Regulates Islet Beta-Cell Insulin Secretion.

Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose-stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3-dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3-/- mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3-controlled insulin secretion is KATP -independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small-molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.

Clinical and pathological features associated with high-risk, multiple, and recurrent basal cell carcinomas: a retrospective cohort analysis from the Levantine coast of the Mediterranean Sea.

Basal cell carcinoma (BCC) data coming from the Levantine coast of the Mediterranean Sea are limited. The study aimed to primarily analyze the demographic, clinical, pathological, and prognostic characteristics of BCC in this region of the world and secondarily identify features associated with high-risk, recurrent, or multiple BCCs. Patients with at least one diagnosis of BCC registered in the pathology department between January 2015 and December 2019 were included in this analytical retrospective single-center cohort study. Patients with basal cell nevus syndrome were excluded. Patients' characteristics and pathological features were collected through file check for a first analysis. Risk factors and evolution were sought through a phone call interview for the second analysis. The first analysis included 506 BCCs corresponding to 365 patients with a mean age of 65 ± 15 years, twenty-two (6%) were less than 40 years old, 180 (49.3%) were women, and 85 (23.3%) had two or more BCCs. The second analysis included 279 BCCs corresponding to 205 patients. Periorificial and infiltrative BCCs were more frequent in men. Periorificial tumors were more frequently nodular or infiltrative and were associated with recurrence. Tumors with perineural involvement were histologically never nodular nor superficial. Recurrence was more frequent in BCCs having periorificial location, a size larger than 2 cm, or an infiltrative subtype. Multiple BCCs were more frequent in patients with light skin type or familial history of skin cancer. High-risk BCCs were more common in patients with low sun exposure.

Pirfenidone mitigates TGF-ß1-mediated fibrosis in an idiopathic inflammatory myositis-associated interstitial lung disease model.

Idiopathic inflammatory myositis (IIM) is a group of rare diseases of unknown etiology, with a pathognomonic muscular deficiency. Antisynthetase syndrome is a subtype of IIM with an associated interstitial lung disease (ILD), characterized by pulmonary inflammation and fibrosis mediated by TGF-ß. Pirfenidone is a new molecule with anti-inflammatory and anti-fibrotic properties, used for the treatment of idiopathic ILD, but has never been assessed in IIM. The aim of our study is to evaluate the effect of pirfenidone on IIM-associated ILD. Thirty-two BALB/c male mice were divided into three groups: Sham, IIM-untreated (IIM), and IIM pirfenidone-treated (IIM + PIR). IIM was induced by intramuscular injections of guinea pig muscle myosin extract and intraperitoneal injections of Pertussis toxin. Pirfenidone was given orally at a dose of 30 mg kg-1 day-1 for two months. Muscle force, blood and bronchoalveolar lavage fluid samples, as well as muscle and lung tissues, were analyzed. Progressive deterioration of muscle force and infiltration of the muscular tissue by inflammatory cells were observed with IIM. Auto-immune antibodies specific to the antisynthetase syndrome were also increased in IIM mice. Pirfenidone attenuated IIM-associated ILD with anti-inflammatory properties evidenced by decreased peribronchial inflammation and TGF-ß1 in bronchoalveolar lavage fluid. Likewise, pirfenidone attenuated pulmonary fibrosis by fine-tuning TGF-ß1-mediated epithelial-to-mesenchymal and fibrotic signaling pathways; pro-fibrotic SMAD3, ZEB2 and STAT1 expression and activation were decreased, whereas anti-fibrotic SMAD2 activation was increased. This study unravels for the first time that pirfenidone has the potential to fine-tune TGF-ß1 fibrotic signaling in IIM-associated ILD.

Osteitis fibrosa cystica mimicking bone tumor, a case report.

BACKGROUND: We report a case of osteitis fibrosa cystica, a rare benign resorptive bone lesion caused by hyperparathyroidism, that presented on imaging as an aggressive bone tumor. CASE PRESENTATION: The patient is a 51-year-old male complaining of severe sustained pain of the right hip region. Imaging studies were suspicious for a malignant tumor of the right iliac bone. Biopsy under CT guidance was performed and showed remodeled bone trabeculae with numerous osteoclasts, excluding bone tumor and raising the possibility of osteitis fibrosa cystica. Complementary tests disclosed elevated blood level of parathyroid hormone and a partially cystic enlarged left inferior parathyroid gland consistent with adenoma. After parathyroidectomy, the clinical symptoms were relieved and the radiological findings were significantly improved, which confirmed the diagnosis. CONCLUSIONS: Metabolic diseases-associated bone lesions should always be considered in the differential diagnosis of bone tumors, to avoid unnecessary surgeries and treatments.

A 58-Year-Old Woman with Acute Gastric Perforation Due to Metastatic Ductal Carcinoma 18 Years Following Bilateral Mastectomy for Invasive Ductal Carcinoma of the Breast.

BACKGROUND Invasive lobular carcinoma and ductal carcinoma of the breast can metastasize to all sites in the body, including the gastrointestinal tract. Late presentation of metastases of lobular carcinoma of the breast to the gastrointestinal tract have previously been reported, but late metastasis of ductal carcinoma of the breast to the gastric mucosa is rare. This report is of a 58-year-old Lebanese woman who presented with acute gastric perforation due to metastatic ductal carcinoma,18 years following bilateral mastectomy for invasive ductal carcinoma of the breast. CASE REPORT We present the case of a 58-year-old woman who underwent a right modified mastectomy for an invasive ductal carcinoma in 2002 combined with a contralateral prophylactic mastectomy for cosmetic purposes. She presented a secondary gastric lesion 18 years later. The clinical presentation resembled perforated ulcer. The choice of gastrectomy was denied due to retrogastric and pancreatic invasion by the tumor. A laparoscopic gastric closure failed to heal the perforation. A supraumbilical laparotomy incision was performed for the placement of a Pezzer tube in the gastric perforation and the installation of a feeding jejunostomy. CONCLUSIONS This report is of a rare presentation of metastatic ductal carcinoma of the breast to the gastric mucosa associated with gastric perforation that presented 18 years after bilateral mastectomy. This case highlights the importance of obtaining a full past medical history to identify previous primary malignancy, and also is a reminder that ductal carcinoma of the breast can present with metastatic involvement in the gastrointestinal tract several months, or even years, following mastectomy.

New insights in gut-liver axis in wild-type murine imiquimod-induced lupus.

BACKGROUND: Intestinal and hepatic manifestations of lupus seem to be underestimated in comparison to other major organ lesions. Although recent data point to gut-liver axis involvement in lupus, gut permeability dysfunction and liver inflammation need to be more investigated. OBJECTIVE: This study aims to assess fecal calprotectin, intestinal tight junction proteins and liver inflammation pathway in wild-type murine imiquimod- induced lupus. METHODS: C57BL/6 mice were topically treated on their right ears with 1.25 mg of 5% imiquimod cream, three times per week for six weeks. Fecal calprotectin was collected at day 0, 22 and 45. Renal, liver and intestinal pathology, as well as inflammatory markers, intestinal tight junction proteins, and E. coli protein in liver were assessed at sacrifice. RESULTS: At six weeks, lupus nephritis was confirmed on histopathology and NGAL and KIM-1 expression. Calprotectin rise started at day 22 and persists at day 45. Protein expression of Claudine, ZO-1 and occludin was significantly decreased. E. coli protein was significantly increased in liver with necro-inflammation and increased TLR4, TLR7, and pNFκB/NFκB liver expression. CONCLUSION: This study is the first to demonstrate early fecal calprotectin increase and liver activation of TLR4- NFκB pathway in wild-type murine imiquimod-induced lupus.

Hydrocortisone mitigates ICU-AW by fine-tuning of muscle atrophic and hypertrophic signaling pathways in a sepsis model with limb immobilization.

AIMS: Intensive care unit-acquired weakness (ICU-AW) is a complex spectrum of disability that delays recovery of critically ill-immobilized patients with sepsis. Much discrepancy remain on the use of corticosteroids and their impact on muscle regeneration in critical illness management. Therefore, the aim of this study is to investigate whether hydrocortisone (HCT) modulates muscle mass turnover in ICU-AW induced by sepsis with limb immobilization (SI). MAIN METHODS: Sepsis by cecal ligation puncture (CLP) with forelimb-immobilization were performed in rats. The study consisted of four groups: Sham (left forelimb-immobilization), Sham HCT (left forelimb-immobilization + HCT), SI (CLP + left forelimb-immobilization) and SI HCT (CLP + left forelimb-immobilization + HCT). Motor force, blood and muscle sampling were assessed. KEY FINDINGS: HCT prevented body weight loss associated with SI and attenuated systemic and muscular inflammation. Besides, myosin was restituted in SI HCT group in conjunction to muscle mass and strength restoration. Pro-hypertrophic calcineurin (PP2B-Aß) and nuclear factor of activated T-cells C3 (NFATc3) but not protein kinase B (Akt) were re-activated by HCT. Finally, pro-atrophic extracellular signal-regulated kinases (ERK1/2) and p38 mitogen-activated protein kinases (p38) but not nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) were inhibited in SI HCT group. SIGNIFICANCE: This study unravels new molecular events thought to control muscle protein synthesis in ICU-AW induced by sepsis and limb immobilization. HCT has a potential to fine-tune muscle-signaling pathways and to reduce the negative outcomes of ICU-AW.

Peritoneal Carcinomatosis of Colorectal Origin in Cyclosporine Immunosuppressed Rats.

OBJECTIVE: We evaluate the seeding step of peritoneal carcinomatosis cancer as a surrogate for the role of the omentum in colorectal tumors. METHODS: The study included 5 groups of adult male Sprague Dawley rats: immunocompetent rats (group 1), immunosuppressed rats without omentectomy (group 2), immunosuppressed rats with omentectomy (group 3), immunosuppressed rats with omentectomy receiving NSAID (group 4), and immunosuppressed rats without omentectomy receiving NSAID (group 5). Except for group 1, the rats were immunosuppressed using cyclosporine orally at a dose of 25 mg/kg/day that was started 48 hours before tumor cell infiltration in the peritoneum. All the rats received an intraperitoneal suspension of 10 million Caco-2 cancer cells. Rats in groups 1, 2, and 3 were followed up without further interventions and rats in groups 4 and 5 received naproxen 180mg/kg until rat sacrifice. Cyclosporine and naproxen were continued in the corresponding groups until the killing after 21 days of tumor cell infiltration. RESULTS: Fourteen rats survived the experiment during the observation period and remained in good clinical condition except for one rat (from group 4) that deceased at week 2. At day 21 before sacrifice, mean weight variations showed a +4% in group 0, -9% in group 1, -18% in group 2, -31% in group 3 and -36% in group 4. Light microscopy did not identify any tumor cells in the abdominal cavity or thorax solid organs but showed a granulomatous reaction that involved the majority of the organs. CONCLUSION: The conclusions of this study are limited by the small number of rats as it is a pilot study to design an animal model with peritoneal carcinomatosis. Further steps in this study will include more aggressive cancer cell lines such as HT29 and more aggressive immunosuppression in a larger number of rats.

Moderate chronic ethanol consumption exerts beneficial effects on nonalcoholic fatty liver in mice fed a high-fat diet: possible role of higher formation of triglycerides enriched in monounsaturated fatty acids.

PURPOSE: Several clinical studies suggested that light-to-moderate alcohol intake could alleviate nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism is still poorly understood. METHODS: Mice fed a high-fat diet (HFD) were submitted or not to moderate ethanol intake for 3 months (ca. 10 g/kg/day) via drinking water. Biochemical, analytical and transcriptomic analyses were performed in serum and liver. RESULTS: Serum ethanol concentrations in ethanol-treated HFD mice comprised between 0.5 and 0.7 g/l throughout the experiment. NAFLD improvement was observed in ethanol-treated HFD mice as assessed by reduced serum transaminase activity. This was associated with less microvesicular and more macrovacuolar steatosis, the absence of apoptotic hepatocytes and a trend towards less fibrosis. Liver lipid analysis showed increased amounts of fatty acids incorporated in triglycerides and phospholipids, reduced proportion of palmitic acid in total lipids and higher desaturation index, thus suggesting enhanced stearoyl-coenzyme A desaturase activity. mRNA expression of several glycolytic and lipogenic enzymes was upregulated. Genome-wide expression profiling and gene set enrichment analysis revealed an overall downregulation of the expression of genes involved in collagen fibril organization and leukocyte chemotaxis and an overall upregulation of the expression of genes involved in oxidative phosphorylation and mitochondrial respiratory chain complex assembly. In addition, mRNA expression of several proteasome subunits was upregulated in ethanol-treated HFD mice. CONCLUSIONS: Moderate chronic ethanol consumption may alleviate NAFLD by several mechanisms including the generation of non-toxic lipid species, reduced expression of profibrotic and proinflammatory genes, restoration of mitochondrial function and possible stimulation of proteasome activity.

A Case Report Presenting an Undifferentiated Pancreatic Carcinoma with Osteoclastic-Like Giant Cells with an Unusual Indolent Course.

BACKGROUND Undifferentiated pancreatic carcinoma with osteoclast-like giant cells represents less than 1% of pancreatic cancers. Histogenesis and prognosis are still debated. Three subtypes are defined by the World Health Organization: osteoclastic, pleomorphic, and mixed. The differential diagnosis of a pancreatic tumor with giant cells varies from a benign osteoclastoma to an undifferentiated pancreatic carcinoma with osteoclastic-like cells. The specimen should be carefully examined to rule out conventional pancreatic adenocarcinoma even in the presence of the giant cells. CASE REPORT A 77-year-old male was diagnosed with a pancreatic tail tumor with osteoclastic like cells revealed by a biopsy done by echo-endoscopy; the patient was lost to follow up for 24 months before he was admitted to our institute for severe abdominal pain. A computed tomography showed the same lesion without progression. He was operated on using laparoscopic distal pancreatectomy with splenectomy. Pathology analysis revealed the presence of osteoclast-like giant cells without pleomorphic cells. Mutated KRAS on molecular study confirmed the diagnosis of undifferentiated pancreatic carcinoma with osteoclast-like giant cells. The patient was in good performance status and disease-free 19 months after surgery without any sign of progression. CONCLUSIONS Undifferentiated pancreatic carcinoma with osteoclast-like cells has a challenging pathology diagnosis. Molecular and immunostaining are essential to diagnosis. The absence of pleomorphic cells in the present case has classified it into the osteoclastic subtype. Further cases and studies are needed to confirm the heterogeneity of the malignant course between subtypes.

Corrigendum: Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mesenchymal Stem Cells Through a TNF/NF-κB-Dependent Mechanism.

[This corrects the article DOI: 10.3389/fimmu.2019.01482.].

Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mesenchymal Stem Cells Through a TNF/NF-κB-Dependent Mechanism.

Introduction: Adipose-derived mesenchymal stem cells (ADSC) have been shown to have remarkable immune-modulating effects. However, their efficacy in clinical trials has yet to be fully demonstrated. This could be due to a lack of a proper inflammatory environment in vivo that primes ADSC. Here, we define how the articular microenvironment of rheumatoid arthritis (RA) patients modulates the therapeutic efficiency of ADSC. Methods: Synovial fluids (SF) were collected from 8 RA patients, 2 Spondyloarthritis patients and one control synovial fluid from a patient undergoing traumatic-related surgery. SF inflammatory status was determined by routine analysis and quantification of pro-inflammatory cytokines. ADSC were first treated with SF and ADSC proliferation and gene expression of immunomodulatory factors was evaluated. In order to determine the mechanisms underlying the effect of SF on ADSC, tumor necrosis factor (TNF), interleukin-6 (IL-6), and NF-κB neutralization assays were performed. To evaluate the effect of SF on ADSC functions, ADSC were pre-treated with SF and then co-cultured with either macrophages or T cells. The modulation of their phenotype was assessed by flow cytometry. Results: Pro-inflammatory RASF maintained the proliferative capacity of ADSC and upregulated the gene expression of cyclooxygenase-2 (COX2), indoleamine-1,2-dioxygenase (IDO), interleukin-6 (IL-6), tumor-necrosis factor stimulated gene 6 (TSG6), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and programmed death-ligand 1 (PD-L1), all factors involved in ADSC immunomodulatory potential. The RASF-induced gene expression was mainly mediated by TNF alone or in combination with IL-6 and signaled through the NF-κB pathway. Conditioning ADSC with pro-inflammatory RASF enhanced their ability to induce CD4+Foxp3+CD25high regulatory T cells (Tregs) and inhibit pro-inflammatory markers CD40 and CD80 in activated macrophages. Conclusions: Inflammatory synovial fluids from RA patients had the capacity to modulate ADSC response, to induce Tregs and modulate the phenotype of macrophages. The clinical use of ADSC in affected joints should take into account the influence of the local articular environment on their potential. Having a sufficient pro-inflammatory microenvironment will determine whether optimal immunoregulatory response should be expected. Direct ADSC intra-articular delivery to patients could be a potential strategy to properly prime their immunomodulatory potential and enhance their clinical benefits.

Circadian Rhythm Disruption Aggravates DSS-Induced Colitis in Mice with Fecal Calprotectin as a Marker of Colitis Severity.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic immunologically mediated pathology that remains a major health burden. Circadian rhythm disruption leads to a deregulation in the immune system which is a major risk factor for IBD. AIMS: Since fecal calprotectin (FC) has been a useful tool for monitoring IBD, we aimed to evaluate the effect of circadian rhythm alteration on gut inflammation status and whether FC is associated with the severity of colitis. METHODS: C57BL/6J mice were exposed to circadian shifts for 3 months, and then colitis was induced by 2% dextran sulfate sodium (DSS). Colitis was evaluated according to clinical symptoms and histological scoring. Plasma and intestinal inflammatory and permeability markers as well as fecal and intestinal calprotectin were assessed. RESULTS: Circadian shifts aggravated DSS-induced colitis with increased diarrhea, flatulence, and fecal blood associated with decreased colon length. In addition, intestinal cryptic architecture was lost with the presence of increased inflammation, mucosal muscle thickening, and cryptic abscesses. Plasma tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and C-reactive protein upregulations were paralleled by the deterioration of intestinal permeability. Calprotectin expression and distribution increased in the intestines and feces of shifted animals, and levels highly correlated with the increases in intestinal inflammation and permeability. CONCLUSIONS: Circadian rhythm disruption aggravates DSS-induced colitis, whereas fecal and intestinal calprotectin associates with the severity of disease. Calprotectin might be a useful marker and tool for assessing patients at risk of IBD due to lifestyles with disruptive sleep patterns.

Fructose threshold for inducing organ damage in a rat model of nonalcoholic fatty liver disease.

A fructose-enriched diet has been shown to be associated with an increase in fatty infiltration of liver, kidney, and pancreas. Our objective was to determine the concentration threshold at which a fructose-enriched diet induces damage in these organs. We hypothesized that a 20% fructose-enriched diet will induce steatosis or histopathological changes in the kidneys or pancreas. In this study, 40 Wistar male rats were randomly divided into 4 groups of 10, and each group was assigned a diet of equal quantity (15 g/rat) but of varying fructose amount. The first group (control group) was fed a standardized diet. The second and third groups were fed 10% and 20% fructose-enriched diets, respectively, whereas the fourth group was fed a high-fructose diet (30% fructose). At week 16, the 30% fructose group had the highest percentage of fat-enriched cells (10%) and a significant decrease in adiponectin as compared with week 1 (P < .05). Twenty percent of this group developed interstitial fibrosis, but none presented changes in the pancreatic islet structure or fibrosis. The 10% fructose group showed the absence of perisinusoidal and interstitial fibrosis, whereas these were present in the 20% fructose group, but neither group showed significant steatosis (5%) or pancreatic damage. The results suggest that a 20% fructose-enriched diet could be considered as the threshold for inducing kidney and liver damage in the rat. Nutritional interventions to reduce fructose to less than 20% of the total energy intake should be considered to prevent metabolic risks and organ damage.

VEGF-C attenuates renal damage in salt-sensitive hypertension.

Salt-sensitive hypertension is a major risk factor for renal impairment leading to chronic kidney disease. High-salt diet leads to hypertonic skin interstitial volume retention enhancing the activation of the tonicity-responsive enhancer-binding protein (TonEBP) within macrophages leading to vascular endothelial growth factor C (VEGF-C) secretion and NOS3 modulation. This promotes skin lymphangiogenesis and blood pressure regulation. Whether VEGF-C administration enhances renal and skin lymphangiogenesis and attenuates renal damage in salt-sensitive hypertension remains to be elucidated. Hypertension was induced in BALB/c mice by a high-salt diet. VEGF-C was administered subcutaneously to high-salt-treated mice as well as control animals. Analyses of kidney injury, inflammation, fibrosis, and biochemical markers were performed in vivo. VEGF-C reduced plasma inflammatory markers in salt-treated mice. In addition, VEGF-C exhibited a renal anti-inflammatory effect with the induction of macrophage M2 phenotype, followed by reductions in interstitial fibrosis. Antioxidant enzymes within the kidney as well as urinary RNA/DNA damage markers were all revelatory of abolished oxidative stress under VEGF-C. Furthermore, VEGF-C decreased the urinary albumin/creatinine ratio and blood pressure as well as glomerular and tubular damages. These improvements were associated with enhanced TonEBP, NOS3, and lymphangiogenesis within the kidney and skin. Our data show that VEGF-C administration plays a major role in preserving renal histology and reducing blood pressure. VEGF-C might constitute an interesting potential therapeutic target for improving renal remodeling in salt-sensitive hypertension.

Transient Receptor Potential Canonical 3 and Nuclear Factor of Activated T Cells C3 Signaling Pathway Critically Regulates Myocardial Fibrosis.

AIMS: Cardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activated T cells c3 (NFATc3) signaling in rodent and human ventricular CFs, and whether their modulation would limit MF. RESULTS: A positive feedback loop between TRPC3 and NFATc3 drove a rat ventricular CF fibrotic phenotype. In these cells, polyphenols (extract of grape pomace polyphenol [P.E.]) decreased basal and angiotensin II-mediated Ca2+ entries through a direct modulation of TRPC3 channels and subsequently NFATc3 signaling, abrogating myofibroblast differentiation, fibrosis and inflammation, as well as an oxidative stress-associated phenotype. N(ω)-nitro-l-arginine methyl ester (l-NAME) hypertensive rats developed coronary perivascular, sub-epicardial, and interstitial fibrosis with induction of embryonic epicardial progenitor transcription factors in activated CFs. P.E. treatment reduced ventricular CF activation by modulating the TRPC3-NFATc3 pathway, and it ameliorated echocardiographic parameters, cardiac stress markers, and MF in l-NAME hypertensive rats independently of blood pressure regulation. Further, genetic deletion (TRPC3-/-) and pharmacological channel blockade with N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-benzenesulfonamide (Pyr10) blunted ventricular CF activation and MF in l-NAME hypertensive mice. Finally, TRPC3 was present in human ventricular CFs and upregulated in MF, whereas pharmacological modulation of TRPC3-NFATc3 decreased proliferation and collagen secretion. Innovation and Conclusion: We demonstrate that TRPC3-NFATc3 signaling is modulated by P.E. and critically regulates ventricular CF phenotype and MF. These findings strongly argue for P.E., through TRPC3 targeting, as potential and interesting therapeutics for MF management.

Mifepristone reduces hypothalamo-pituitary-adrenal axis activation and restores weight loss in rats subjected to dietary restriction and methylphenidate administration.

This study evaluates the efficacy of mifepristone on weight restoration in rats subjected to dietary restriction and methylphenidate administration. 25 female rats aged between 9 and 12 months were divided into 2 groups: 5 controls (exposed only to dietary restriction) and 20 rats that were administered 5 mg/kg/d of methylphenidate before meal exposure, for 36 days. Among rats who responded to methylphenidate (weight loss of 15-25%) weeks after its administration, a group of 6 rats continued to receive only methylphenidate ("Met" group), and another group received 10 mg/kg/d of mifepristone in addition to methylphenidate for 18 days ("Met+Mif" group; n = 6). The mean weight of the "Met+Mif" group remained significantly lower when compared to the control group (87.63 ±â€¯2.83% vs 96.29 ±â€¯3.26%; p < 0.001 respectively) but was significantly higher than that of the "Met" group (87.63 ±â€¯2.83% vs. 80.61 ±â€¯3.52%; p < 0.001 respectively). Plasma concentrations of adiponectin and gene expression of its receptors in rats brain were significantly higher in the "Met" group as compared to the "Met+Mif" and control groups (p < 0.01). Accordingly, mifepristone reduces HPA axis activation and restores weight through adipose tissue recovering. It might be considered a promising treatment for anorexia nervosa patients in future studies.