Metabolomics analyses reveal the crucial role of ERK in regulating metabolic pathways associated with the proliferation of human cutaneous T-cell lymphoma cells treated with Glabridin.

Cutaneous T-cell lymphomas (CTC) are a heterogeneous group of T-cell lymphoproliferative malignancies of the skin with limited treatment options, increased resistance and remission. Metabolic reprogramming is vital in orchestrating the uncontrolled growth and proliferation of cancer cells. Importantly, deregulated signalling plays a significant role in metabolic reprogramming. Considering the crucial role of metabolic reprogramming in cancer-cell growth and proliferation, target identification and the development of novel and multi-targeting agents are imperative. The present study explores the underlying mechanisms and metabolic signalling pathways associated with Glabridin mediated anti-cancer actions in CTCL. Our results show that Glabridin significantly inhibits the growth of CTCL cells through induction of programmed cell death (PCD) such as apoptosis, autophagy and necrosis. Interestingly, results further show that Glabridin induces PCD in CTCL cells by targeting MAPK signalling pathways, particularly the activation of ERK. Further, Glabridin also sensitized CTCL cells to the anti-cancer drug, bortezomib. Importantly, LC-MS-based metabolomics analyses further showed that Glabridin targeted multiple metabolites and metabolic pathways intricately involved in cancer cell growth and proliferation in an ERK-dependent fashion. Overall, our findings revealed that Glabridin induces PCD and attenuates the expression of regulatory proteins and metabolites involved in orchestrating the uncontrolled proliferation of CTCL cells through ERK activation. Therefore, Glabridin possesses important features of an ideal anti-cancer agent.

Anti-MRSA and cytotoxic activities of different solvent extracts from Artemisia herba-alba grown in Shubak, Jordan.

Background: Globally, resistance to antimicrobial drugs is a major hazard to public health. Infections that were once easily treatable with antibiotics are becoming harder to control, leading to prolonged illnesses, increased mortality rates, and higher healthcare costs. Aim: This study intended to assess the antimicrobial, specifically the anti-Methicillin resistant Staphylococcus aureus (MRSA), and anticancer properties of different extracts obtained from A. herba-alba (AHA). Methods: The antibacterial tests of AHA were performed on two Gram-negative bacterial strains (Escherichia coli and Klebsiella pneumonia), two Gram-positive bacterial strains (Methicillin-resistant Staphylococcus aureus (MRSA), and Staphylococcus aureus). Initial screening for antibacterial activities was conducted using the well diffusion technique. Subsequently, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined through the broth-dilution assay. The anticancer test was carried out in vitro on a human colorectal carcinoma cell line (HCT-116) using MTT assay. Results: Among all extracts, n-hexane extract of AHA was the most effective against S. aureus with the highest inhibition zone (24.67 mm ± 0.58) compared to standard antibiotic (erythromycin, 24.00 mm) followed by the methanolic extract against MRSA (24.00 mm ± 1.73). The methanol extract of AHA showed the highest antibacterial activity against MRSA. The results of MIC and MBC of the AHA methanol extract against MRSA were 1.17 ± 1.09 and 9.375 ± 0.0 mg/ml, respectively, demonstrating therapeutically significant antibacterial activity. Ethyl acetate extract has no antibacterial activity against E. coli and K. pneumonia. The findings indicated that the methanol extract of AHA exhibited the highest efficacy against the colorectal carcinoma cell line (HCT-116), with an IC50 value of 126.61 ± 13.35 µg/ml. Conclusion: These findings suggest that the methanol extract of AHA could be considered as a potential agent to serve as a source of antibacterial and anticancer compounds.

The ameliorative effect of bergamot oil nano-emulsion in stressed rabbit bucks: Influence on blood biochemical parameters, redox status, immunity indices, inflammation markers, semen quality, testicular changes and the expression of HSPs genes.

This work explored the activities of bergamot oil nano-emulsion (NBG) in modulating blood biochemical parameters, redox status, immunity indices, inflammation markers, semen quality, testicular changes and the expression of HSPs genes in stressed rabbit bucks. Twenty-four mature rabbit bucks (5 months) were randomly divided into three groups; control group (NBG0) received 1 ml of distilled water, while the other two groups received NBG orally at doses of 50 and 100 mg/kg (bw) twice a week. The present study's findings revealed that treated groups had lower values of total and direct bilirubin, triglyceride, lactate dehydrogenase, and creatinine compared with NBG0 group (p < 0.05). NBG100 group recorded the greatest of total protein, albumin, GPx, T3 and T4 values as well as the lowest values of uric acid, MDA, and indirect bilirubin. Both treated groups showed significantly reduced 8-OhDG, Amyloid A, TLR 4, while significantly increased nitric oxide, IgA, IgM, TAC, and SOD levels. Semen characteristics such as volume, sperm count, sperm motility, normal sperm, and vitality were significantly higher in the NBG100 group compared to the NBG50 and NBG0 groups, whereas sperm abnormalities and dead sperm were significantly reduced. HSP70, HSP72, and HSPA9 gene overexpression showed that testicular integrity was maintained after buck received oral doses of 50 or 100 mg/kg of NBG. Existing findings indicate that oral administration of NBG improves heat tolerance in rabbit bucks primarily as e result of its antioxidant and anti-inflammatory effects.

Epigenetic programing of cancer stemness by transcription factors-non-coding RNAs interactions.

Cancer 'stemness' is fundamental to cancer existence. It defines the ability of cancer cells to indefinitely perpetuate as well as differentiate. Cancer stem cell populations within a growing tumor also help evade the inhibitory effects of chemo- as well as radiation-therapies, in addition to playing an important role in cancer metastases. NF-κB and STAT-3 are representative transcription factors (TFs) that have long been associated with cancer stemness, thus presenting as attractive targets for cancer therapy. The growing interest in non-coding RNAs (ncRNAs) in the recent years has provided further insight into the mechanisms by which TFs influence cancer stem cell characteristics. There is evidence for a direct regulation of TFs by ncRNAs, such as, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) as well as circular RNAs (circRNAs), and vice versa. Additionally, the TF-ncRNAs regulations are often indirect, involving ncRNA-target genes or the sponging of other ncRNA species by individual ncRNAs. The information is rapidly evolving and this review provides a comprehensive review of TF-ncRNAs interactions with implications on cancer stemness and in response to therapies. Such knowledge will help uncover the many levels of tight regulations that control cancer stemness, providing novel opportunities and targets for therapy in the process.

Effects of alginates on the growth, haematological, immunity, antioxidant and pro-inflammatory responses of rabbits under high temperature.

Heat stress (HS) is one of the most severe hurdles impacting rabbit growth, immunity, homeostasis, and productivity. Alginate oligosaccharides (AOS) have considerable beneficial effects due to their plausible antioxidant and immune-stimulatory properties. This work was planned to explore the preventive function of AOS as a new bio-feed additive against the harmful effects caused by environmental HS on growing rabbits. Rabbits were allotted in four experimental groups (25 animals in each group) and fed on a basal diet supplemented with 0.0 (AOS0), 50 (AOS50), 100 (AOS100), and 150 (AOS150) mg AOS/kg diet reared under summer conditions. Dietary AOS supplementation improved significantly (P ≤ 0.001) feed conversion rate, while both AOS100 and AOS150 significantly (P ≤ 0.001) enhanced the final body weight and body weight gain. All AOS addition significantly increased nitric oxide and lysosome activity and significantly reduced interferon-gamma (IFNγ) compared with those in the control group. Tumor necrosis factor α (TNFα), interleukin1ß (IL-1ß), myeloperoxidase and protein carbonyl levels were significantly reduced in rabbits fed diets containing AOS (100 and 150 mg/kg) compared with those in the control group under heat stress conditions. In addition, glutathione (GSH) and catalase (CAT) were significantly (P ≤ 0.001) improved with increasing AOS dietary levels compared with the control group. Still, total antioxidant capacity (TAC), malondialdehyde (MDA), hematocrit, mean corpuscular volume (MCV), eosinophils, and lymphocytes did not change. Erythrocyte's indices improved significantly (P ≤ 0.001), while neutrophils and white blood cell counts were decreased by dietary AOS inclusion. Immunological (IgM and IgG) were markedly reduced in AOS-treated groups compared with the control group. The current investigation exemplified that AOS as a novel bio-feed additive that could be an effective strategy to extenuate prejudicial effects in heat-stressed rabbits via enhancing immunity, and antioxidant defence system, further regulating the inflammation cytokines.

Targeting deregulated oxidative stress in skin inflammatory diseases: An update on clinical importance.

Skin, the largest vital organ of the human body, provides the first line of defense against biological, non-biological and xenobiotics exposure. Over the years, due to increased anthropogenic activities including industrialization and pollution, a steep increase in cutaneous pathological conditions such as malignancies, dermatitis, and psoriasis has been detected. Indeed, due to the complex nature of cutaneous inflammatory diseases, further investigations are required to produce a better outcome in patient care. However, research obtained over the last few decades has revolutionized the understanding of cutaneous disease pathogenesis and therapeutic developments. In this line, increasing data from pre-clinical and clinical studies implicates the crucial role of oxidative stress in pathogenesis and complications of cutaneous inflammatory diseases, including atopic dermatitis and psoriasis. Taking into consideration the current challenge, this review aims to highlight the novel updates exploring reactive oxygen species (ROS) induced mechanistic signaling mechanisms in conjunction with pathways converging towards atopic dermatitis and psoriasis. Additionally, an exploration of the clinical importance of natural products for management of cutaneous diseases has been included. Overall, this review highlights the therapeutic importance of targeting oxidative stress in the pathogenesis, symptoms, and complications of inflammatory diseases of the skin.

Therapeutic Potential of Thymoquinone and Its Nanoformulations in Pulmonary Injury: A Comprehensive Review.

As a crucial organ, the lung is exposed to various harmful agents that may induce inflammation and oxidative stress, which may cause chronic or acute lung injury. Nigella sativa, also known as black seed, has been widely used to treat various diseases and is one of the most extensively researched medicinal plants. Thymoquinone (TQ) is the main component of black seed volatile oil and has been proven to have antioxidant, anti-inflammatory, and antineoplastic properties. The potential therapeutic properties of TQ against various pulmonary disorders have been studied in both in vitro and in vivo studies. Furthermore, the application of nanotechnology may increase drug solubility, cellular absorption, drug release (sustained or control), and drug delivery to lung tissue target sites. As a result, fabricating TQ as nanoparticles (NPs) is a potential therapeutic approach against a variety of lung diseases. In this current review, we summarize recent findings on the efficacy of TQ and its nanotypes in lung disorders caused by immunocompromised conditions such as cancer, diabetes, gastric ulcers, and other neurodegenerative diseases. It is concluded that TQ nanoparticles with anti-inflammatory, antioxidant, antiasthma, and antitumor activity may be safely applied to treat lung disorders. However, more research is required before TQ nanoparticles can be used as pharmaceutical preparations in human studies.

Ameliorative Effect of Thymoquinone-Loaded PLGA Nanoparticles on Chronic Lung Injury Induced by Repetitive Intratracheal Instillation of Lipopolysaccharide in Rats.

Thymoquinone (TQ), the active constituent of Nigella sativa, possesses several benefits in traditional and modern medicines. This study examined the effect of a single dose of Nano-TQ on chronic lung injury induced by repetitive intratracheal installation of lipopolysaccharide (LPS). Rats received LPS twice weekly for 8 weeks via intratracheal installation and a single dose of TQ-PLGA NPs on the day after the last dose of LPS. Six rats from each group were sacrificed after 8 and 10 weeks, and samples were collected for analysis. Repetitive intratracheal installation of LPS caused histopathological alterations, including partial or complete obstruction of the alveoli, interstitial edema, mild fibroblastic proliferation, fibrous strands besides lymphocytes and plasma infiltrations, suffered fetalization, bronchiectasis, hypertrophied arterioles, and others. Investigation of the ultrastructure revealed prominent necrotic pneumocytes with destructed chromatin and remnant of necrotic debris in the narrowing alveolar lumen in LPS-induced rats. TQ-PLGA NPs effectively ameliorated LPS-induced histopathological and ultrastructural alterations in the lung of rats. In addition, TQ-PLGA NPs significantly alleviated serum levels of IL-10 and TGF-ß1 in LPS-induced rats. In conclusion, TQ-PLGA NPs prevented inflammation and tissue injury in the lungs of rats challenged with repetitive intratracheal installation of LPS. Therefore, TQ-PLGA NPs represent a promising candidate for the prevention of lung injury induced by LPS, pending further studies to determine its safety and exact protective mechanism.

Antihyperlipidemic and Antioxidant Effects of Averrhoa Carambola Extract in High-Fat Diet-Fed Rats.

The present study explored the antihyperlipidemic potential of a standardized methanolic extract of Averrhoa carambola (A. carambola) leaf (MEACL) in high-fat diet (HFD)-fed rats. The standardized MEACL was orally administered at different doses (250, 500, and 1000 mg/kg) to HFD-induced hyperlipidemic rats for five weeks. Serum lipid profile, body weight changes, body mass index (BMI), daily food intake, relative organ weight, and histology of the liver were evaluated. In addition, the effect of MEACL on HMG-CoA reductase and pancreatic lipase activities as well as hepatic and fecal lipids was demonstrated. MEACL supplementation reduced serum lipids in HFD-fed rats in a dose-dependent manner. Histopathological scores revealed that 1000 mg/kg MEACL restored the damage to liver tissue in hyperlipidemic rats. MEACL decreased the body mass index (BMI), atherogenic index, and hepatic cholesterol and triglycerides and increased fecal cholesterol and bile acids in HFD-fed rats. Also, MEACL ameliorated lipid peroxidation and improved antioxidant defenses in the liver of HFD-fed rats. Furthermore, HMG-CoA reductase and lipase were suppressed by MEACL. In conclusion, this study shows the potential effect of MEACL to ameliorate hyperlipidemia and oxidative stress in HFD-fed rats. It prevented hepatic lipid accumulation and exerted an inhibitory effect on HMG-CoA reductase and lipase.

Galangin Activates Nrf2 Signaling and Attenuates Oxidative Damage, Inflammation, and Apoptosis in a Rat Model of Cyclophosphamide-Induced Hepatotoxicity.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent; however, its clinical application is limited because of its multi-organ toxicity. Galangin (Gal) is a bioactive flavonoid with promising biological activities. This study investigated the hepatoprotective effect of Gal in CP-induced rats. Rats received Gal (15, 30 and 60 mg/kg/day) for 15 days followed by a single dose of CP at day 16. Cyclophosphamide triggered liver injury characterized by elevated serum transaminases, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and histopathological manifestations. Increased hepatic reactive oxygen species, malondialdehyde, nitric oxide, and oxidative DNA damage along with declined glutathione and antioxidant enzymes were demonstrated in CP-administered rats. CP provoked hepatic nuclear factor-kappaB (NF-κB) phosphorylation and increased mRNA abundance of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) both expression and serum levels. Gal prevented CP-induced liver injury, boosted antioxidants and suppressed oxidative stress, DNA damage, NF-κB phosphorylation and pro-inflammatory mediators. Gal diminished Bax and caspase-3, and increased B-cell lymphoma-2 (Bcl-2) in liver of CP-administered rats. In addition, Gal increased peroxisome proliferator-activated receptor gamma (PPARγ) expression and activated hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) signaling showed by the increase in Nrf2, NAD(P)H: quinone acceptor oxidoreductase-1 (NQO-1) and heme oxygenase 1 (HO-1) in CP-administered rats. These findings suggest that Gal prevents CP hepatotoxicity through activation of Nrf2/HO-1 signaling and attenuation of oxidative damage, inflammation and cell death. Therefore, Gal might represent a promising adjuvant therapy to prevent hepatotoxicity in patients on CP treatment.

Living-Donor Liver Transplantation in Hepatitis C Virus Era: A Report of 500 Consecutive Cases in a Single Center.

BACKGROUND: Living donor liver transplantation (LDLT) is considered a safe alternative to deceased donor liver transplantation (DDLT). In Egypt, DDLT program is still awaited, making LDLT the only hope for patients with end-stage liver disease, mainly due to chronic hepatitis C virus (HCV) infection. The current study is conducted to evaluate our experience of LDLT and discuss the lessons learned from 500 consecutive cases in HCV area. METHODS: We reviewed the data of patients who underwent LDLT at Gastrointestinal Surgery Center, Mansoura University during the period between May 2004 and March 2017. RESULTS: During the study period, 500 cases underwent LDLT at our unit. The median age was 51 years, and most of our cases were males (446, 89.2%) and had HCV infection (453, 90.6%). The median MELD score was 15. Median ICU stay was 5 days, and hospital stay was 22 days. Postoperative morbidities occurred in 220 cases (44%). Early mortality occurred in 69 patients (13.8%), and late mortality occurred in 45 patients (9%). The 1-, 3-, 5-, and 7-year overall survival rates of all cases were 80.9%, 78.2%, 75.7%, and 75%, respectively. Preoperative creatinine, worm ischemia, blood transfusion, ICU stay, postoperative morbidities, and small for size syndrome were independent predictors for overall survival. CONCLUSIONS: In countries lacking DDLT, LDLT is the only effective alternative. LDLT requires a teamwork to achieve successful outcomes. LDLT should only be performed in centers with the adequate experience to avoid and decrease the hazards related to this procedure.

Predictive Factors of Liver Dysfunction After Right Hemihepatectomy for Adult Living Donor Liver Transplantation.

BACKGROUND: Living liver donors represent a special group of patients. They are healthy individuals who are exposed to a major surgery, in which the dominant liver proportion is extracted as a graft. Of all potential donor-related morbidities, posthepatectomy liver dysfunction (PHLD) is the most significant as it may be directly related to donor mortality. We aimed to review our data of adult living donor liver transplantation (LDLT) utilizing the right hemiliver grafts to determine the incidence and potential predictors for the development of PHLD, defined according to the International Study Group of Liver Surgery. METHODS: We reviewed the data of all adult living donors who underwent right hemihepatectomy during the period between May 2004 and 2016. RESULTS: During the study period, 434 cases underwent right hemihepatectomy for adult LDLT. We divided our cases into 2 groups according to the occurrence of PHLD. A significant lower residual liver volume and percentage were noted in PHLD group. Longer intensive care unit stay and hospital stay, and more postoperative morbidities, were observed in PHLD group. PHLD occurred in 50 cases (11.5%), and most of them were grade A (47 cases [10.8%]). Two cases (0.5%) had grade B requiring diuretic therapy, and 1 case (0.2%) had grade C requiring ultrasound guided tube drainage and surgical exploration finally. CONCLUSIONS: We should not underestimate the risks of liver donation surgery, especially when utilizing the right hemiliver graft. Donor safety should be ensured by accurate preoperative volumetric assessment of the remnant liver and remnant liver volume limitations must be strictly followed.

Antihyperlipidemic, Antioxidant and Cytotoxic Activities of Methanolic and Aqueous Extracts of Different Parts of Star Fruit.

BACKGROUND: Star fruit (Averrhoa carambola) is a well-known plant in Malaysia which bears a great significance in traditional medicine. OBJECTIVES: This study aimed to evaluate the antihyperlipidemic effect, antioxidant potential and cytotoxicity of aqueous and methanolic extracts of ripe and unripe fruits, leaves and stem of A. carambola. METHODS: Antihyperlipidemic activity was assessed in poloxamer-407 (P-407) induced acute hyperlipidemic rat's model. The antioxidant activity was assessed in vitro using 2, 2'-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging, 1-diphenyl-2-dipicrylhydrazyl radical scavenging (DPPH) and ferric reducing antioxidant power (FRAP) assays. In addition, cytotoxicity of A. carambola extracts was assessed using MTS assay on four leukemic cell lines (human colon cancer, human promyeloid leukemia, erythroid leukemia, acute myeloid leukemia) and one normal cell (human umbilical vein endothelial cells). RESULTS: Methanolic extract of leaves had the most potent antihyperlipidemic activity in P-407 model, whereby it significantly reduced serum levels of total cholesterol (P<0.01), triglycerides (P<0.01), low-density lipoprotein (P<0.05), verylow- density lipoprotein (P<0.01) and atherogenic index (P<0.01). On the other hand, methanolic extracts of A. carambola stem and leaves showed the strongest antioxidant activity. Total phenolic and flavonoid contents of the extracts exhibited significant correlations with antioxidant but not with antihyperlipidemic activities. All plant parts showed no cytotoxic effect on the selected cancer or normal cell lines. CONCLUSION: Antihyperlipidemic activity of different parts of A. carambola is greatly affected by extraction solvents used. Methanolic extract of A. carambola leaves exhibited higher antihyperlipidemic and antioxidant potentials compared to other parts of the plant.

Surgical management of peri-ampullary tumors: a retrospective study.

BACKGROUND/AIMS: Surgical resection still remains the best treatment for patients with periampullary tumors. This study aims to present the results of surgical treatment of this disease at our center. METHODOLOGY: Between January 1995 and December 2004, 216 periampullary tumors were treated by surgical resection. The mean age was 58 years with male to female ratio 2:1. The most common symptom was jaundice (97.7%). Abdominal pain occurred in 74% of patients. Pancreaticogastrostomy was done in 183 patients and pancreaticojejunostomy in 33 patients. RESULTS: Operative mortality occurred in 7 patients (3.2%). The median survival was 22.6 months for patients with ampullary tumors and 16.6 months for patients with pancreatic head tumors. Early operative complications occurred in 33% of patients; the most common one was wound infection (11.6%), pancreatic leak (10.6%), abdominal collection (10.6%) and delayed gastric emptying (8.8%). Factors associated with increased risk of developing complications were the type of pancreatico-enteric anastomosis (pancreatic leak was more frequent with pancraticojejunostomy), soft pancreatic texture and intraoperative blood transfusion of more than 4 units. Factors associated with better survival included tumor diameter (less than 3cm), origin (ampullary), differentiation (well differentiated) and margin status (negative resection margins). CONCLUSIONS: Postoperative complications of pancreaticoduodenectomy, especially with the adoption of pancreaticogastrostomy, occur with reasonable incidence. Survival largely depends on the origin of the tumor.

216 cases of pancreaticoduodenectomy: risk factors for postoperative complications.

BACKGROUND/AIMS: Surgical resection remains the best treatment for patients with periampullary tumors. Many series have been reported with low or zero mortality, however, high incidence of complications is the rule. This study aims to present the results of pancreaticoduodenectomy and factors predisposing to postoperative complications, especially pancreatic leak, at our center. METHODOLOGY: Between January 2000 and December 2006, 216 periampullary tumors were treated by Whipple pancreaticoduodenectomy. Pancreaticogastrostomy was done in 183 patients and pancreaticojejunostomy in 33 patients. Hospital mortality and surgical complications were recorded with special emphasis on pancreatic leak. All specimens were histologically examined for the presence and origin of malignant tissue. RESULTS: The mean age was 58 years and male to female ratio was 2:1. The commonest symptom was jaundice (97.7%) followed by abdominal pain (74%). Operative mortality in 7 patients (3.2%). 71 (33%) patients developed 1 or more complications, pancreatic leak occurred in 23 (10.6%) patients, abdominal collection in 23 patients (10.6%) and delayed gastric emptying in 19 (8.8%) patients. Factors that influenced the development of postoperative complications included type of pancreaticoenteric anastomosis, pancreatic texture and intraoperative blood transfusion of 4 or more blood units. Pancreatic leak was commoner with PJ (p=0.001), soft pancreatic texture (p=0.008), intraoperative blood transfusion of 4 or more units (p<0.0001). Periampullary adenocarcinoma was found in 204 (94.4%) patients, chronic pancreatitis in 9 (4.2%) patients, 2 patients with solid and papillary neoplasm, and 1 patient with NHL (Non-Hodgkin's Lymphoma). CONCLUSIONS: Surgery is the only hope for patients with periampullary tumors. Postoperative complications after pancreaticoduodenectomy depend largely on surgical technique and can be reduced reasonably with the adoption of pancreaticogastrostomy, which is safer and easier to learn than pancreaticojejunostomy.

The role of kallikrein in leukocyte migration inhibition.

Previous studies from this department have established the presence of leukocyte migration inhibition activity in acute nonimmune inflammatory rat pleural exudates, induced by different irritants, which involved coagulation phenomenon. In the present investigation we present evidence for a role of kallikrein in the leukocyte migration inhibition phenomenon exhibited by acute pleural exudate in rates depleted of kininogens by intravenous injection of cellulose sulfate.