Pharmacognosy

Androgen Receptor (NR3C4) regulator potential of Ceratonia siliqua extract and its signaling pathways Fehmi Kigili, Fatih Ozen, Tunc Catal, Belkıs Atasever Arslan Pharmacognosy Magazine 2019 15(62):1-4 Aim/Background: Androgen receptor (AR/NR3C4) regulates growth, development, reproduction, metabolism, and homeostasis. Since it has multifunctional properties, disrupting of the functions can cause many diseases such as cancer and neurodegenerative diseases. Therefore, AR modulators and blockers are very important therapy of androgen-dependent diseases. Furthermore, mechanisms and signaling pathways of AR on the diseases are unclear. Ceratonia siliqua was shown to have preventative effects against digestive system disorders, diabetes mellitus, asthma-bronchitis, and oxidative stress in various studies. Materials and Methods: In the present study, its AR regulator potential was investigated in AR-deficient HEK293 cells. Results: While C. siliqua extract increased >2 folds of NR3C4 gene expression in the cells, it induced a decrease in AKT1 and kynureninase genes expression levels. On the other hand, it increased p38 gene expression, but it did not change FUS gene expression. These results support a regulating role on the receptor and also that the compounds specifically affect NR3C4 signaling pathways. Conclusion: Determination of the molecules and their various combinations with each other can contribute to discover new therapeutic agents for diseases dependent on AR signaling pathways.

Antihyperglycemic activity of the leaves from annona diversifolia Safford. and farnesol on normal and alloxan-induced diabetic mice* Fernando Calzada, Miguel Valdes, Normand Garcia-Hernandez, Claudia Velázquez, Elizabeth Barbosa, Celia Bustos-Brito, Leovigildo Quijano, Emmanuel Pina-Jimenez, Jesica Elena Mendieta-Wejebe Pharmacognosy Magazine 2019 15(62):5-11 Background: Diabetes mellitus (DM) is a chronic disease characterized by high blood glucose levels resulting from insulin resistance or inadequate insulin secretion. In the world, DM is one of the most frequent non-contagious diseases that affect more than 371 million people. Objective: This study aimed to evaluate the antihyperglycemic properties of the ethanol extract, subsequent fractions, and farnesol obtained from the leaves of Annona diversifolia on alloxan-induced diabetic and normal mice. Materials and Methods: Bioassay-guided fractionation of the ethanol extract of the leaves of A. diversifolia (EELAd) was performed on alloxan-induced Type 2 diabetic and normoglycemic (NM) mice. Oral glucose tolerance test (OGTT), oral sucrose tolerance test (OSTT), and oral lactose tolerance test (OLTT) were performed in fast NM mice (FNM). Results: The EELAd, CHCl3 fraction, and farnesol induced a significant reduction of postprandial hyperglycemia in acute and subchronic tests using AITD mice. When EELAd, CHCl3 fraction, and farnesol were tested on NM in subchronic assays, these did not affect glycemic levels. In the case of acute test on NM, only CHCl3 fraction induced a hypoglycemic effect at 2 h after the treatment. OLTT and OSTT showed that the EELAd, CHCl3 fraction, and farnesol induced a significant reduction of hyperglycemia levels in FNM at 2 h after a lactose or sucrose load comparable to acarbose. In the case of OGTT was observed a significant reduction of hyperglycemia levels in FNM mice at 2 h after a glucose load comparable to canagliflozin. Conclusion: The EELAd and farnesol induced a significant reduction of postprandial hyperglycemia on AITD mice in acute and subchronic assays. Our results suggest that the control of postprandial hyperglycemia may be mediated by the regulation of absorption of glucose and inhibition of disaccharide digestion such as sucrose and lactose. Finally, the results explained the use of A. diversifolia in Mexican traditional medicine as an antihyperglycemic agent.

Anti-tuberculosis drug-induced oxidative stress in kidneys: Role of brahmi as an antioxidant supplement Sabina Evan Prince, Sherry Joseph Martin, B Udhaya Lavinya, Kavitha Selvanathan, A Geetha Pharmacognosy Magazine 2019 15(62):12-16 Purpose: Nephrotoxicity is a known, but rare complication of anti-tuberculosis (TB) therapy and is known to be due to induction of oxidative stress and immune reaction to the drugs. In the current study, we have made an attempt to evaluate the effect of Brahmi in attenuating the oxidative stress caused by isoniazid (INH) and rifampicin (RIF) in the kidneys of Wistar rats. Materials and Methods: The animals were administered INH and RIF with concomitant supplementation of Brahmi for 28 days. The levels of urea, uric acid, creatinine, and acid phosphatase were measured to evaluate kidney function along with catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, and lipid peroxidation to assess the kidney antioxidant status. In addition, the levels of cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, and the cytokine tumor necrosis factor (TNF-α) were also measured. The protective efficacy of Brahmi was compared to that of Silymarin. Results: Brahmi caused a statistically significant (P < 0.05) restoration of kidney function along with an increase in the antioxidant status. This was accompanied by a reduction of TNF-α level to near normal. A histopathological study of the kidney tissues confirmed the protective effect of Brahmi against INH- and RIF-induced oxidative stress in the kidneys. Conclusion: It is evident that Brahmi plays a protective role against anti-TB drug-induced oxidative stress in the kidneys.

In vivo and in vitro antidiabetic and antioxidant activity of spirulina Patrick Nwabueze Okechukwu, Sophia Ogechi Ekeuku, Mridula Sharma, Chong Pei Nee, Hor Kuan Chan, Norazlina Mohamed, Gabriele Ruth Anisah Froemming Pharmacognosy Magazine 2019 15(62):17-29 Objective: This study aims to evaluate the effect of spirulina, a biomass produced by cyanobacteria, on the level of plasma glucose, oxidative stress, and other biochemical parameters in diabetes in streptozocin (STZ) 50 mg/kg-induced diabetic-induced rat model. Materials and Methods: The in vitro antioxidant property of spirulina was assessed by measuring its ability to scavenge free radicals and reactive oxygen species (ROS) such as superoxide anion, nitric oxide, and hydroxyl and lipid peroxyl radicals. The inhibition of diabetic link enzymes alpha-glucosidase, alpha-amylase, and dipeptidyl peptidase-4 inhibitor (DPP-IV) were tested in vitro. Thirty female Sprague-Dawley rats weighing 150–250 g were divided into five groups: normal, diabetes (negative control), metformin in single dose of 300 mg/kg, spirulina in a single dose of 300 mg/kg and spirulina combined with metformin at dose of 150 mg/kg, and spirulina at dose of 150 mg/kg (spirulina + metformin 300 mg/kg) (n = 6). After an acclimation period of 2 weeks, diabetes was induced in the rats through STZ intraperitoneal injection. Spirulina (300 mg/kg) was dissolved in water and was administered orally for 12 weeks, and the rats' that plasma glucose level reached ≥11 mmol/L after 12 weeks treatment was selected for the study. After the treatment, the blood and liver were used for the evaluation of antioxidant enzyme activities, lipid, liver, kidney, and hematology profile. Results: Spirulina was able to reduce hyperglycemia-induced oxidative stress by reducing plasma glucose levels and scavenging or reducing the production of ROS and free radicals. It was also able to inhibit the activities of the alpha-glucosidase, alpha-amylase, and DPP-IV. With this, it significantly reduced the effect of STZ on the liver and kidney at the organ level and on antioxidant enzymes at the cellular level. Conclusion: Spirulina is able to reduce the lipid, liver, and kidney disease markers in STZ-induced rats and therefore is a potential supplement for diabetic patients. The antidiabetic effect of spirulina may be based on the antioxidant effect of the biomass as a whole, or it is based on specific bioactive components present in spirulina.

In vitro evaluation of the effects of lycopene on caspase system and oxidative DNA damage in high-glucose condition Bunyamin Bazyel, Semiha Dede, Sedat Cetin, Veysel Yuksek, Mehmet Taşpinar Pharmacognosy Magazine 2019 15(62):30-33 Aim and Background: The present study was planned to investigate the effects of lycopene, on the caspase-dependent apoptosis in high-dose glucose (HG)-treated PC12 cell line. PC12 cells were cultured in vitro. Materials and Methods: HG was prepared as G (250 mM), and lycopene was prepared as L1 (10 μM), L2 (20 μM), and L3 (40 μM). After 6 h of incubation, the cells were exposed to trypsin, and the samples were obtained with freeze/thaw method. Caspase 3, 8, 9; 8-hydroxy-2-deoxyguanosine (8-OHdG); and M30 were determined (enzyme-linked immunosorbent assay). Results: 8-OHdG increased in L3 (P ≤ 0.001), whereas L1 caused a decrease in HG group (P ≤ 0.001). Caspase-3 decreased significantly in L1, L2, and L3G compared to control (P ≤ 0.001) group. Caspase-8 increased significantly in L1, L1G, L2G, and all L3 glucose groups (P ≤ 0.001). There was no difference for Caspase-9. M30 was not affected by L and HG, which decreased significantly (P ≤ 0.001). Conclusion: As a result, it was determined that, when PC12 cell line was treated with HG, lycopene application had effects on caspase enzymes and DNA damage.

In vitro antileishmanial activity of methanolic extracts for some selected medicinal plants Ahmed Gomaa Gomaa Darwish, Mamdouh Nabil Samy, Sachiko Sugimoto, Katsuyoshi Matsunami, Hideaki Otsuka Pharmacognosy Magazine 2019 15(62):34-37 Objective: The aim of this study is to evaluate the antileishmanial activity of selected medicinal plants; ten well-known medicinal plants cultivated and growing under African environmental conditions were studied. Materials and Methods: The methanolic extracts of these plants were screened for their antileishmanial activity against Leishmania major using 3-(4.5-dimethylthiazol-2yl)-2.5-diphenyltetrazolium bromide assay. Results: The methanol extract of Colchicum autumnale and Alpinia officinarum showed potent antileishmanial activity at inhibition% value of 98.29% ± 0.75% and 97.25 ± 1.63%, respectively, while Silybum marianum exhibited inhibition% value of 90.97% ± 1.13%, compared with the standard amphotericin B (89.31% ± 2.08%). Conclusion: Considering these results, medicinal plants from African environment could constitute a developer source for antileishmanial compounds.

Cloning, identification, and in silico analysis of terpene synthases involved in the competing pathways of artemisinin biosynthesis pathway in Artemisia annua L Umara Nissar Rafiqi, Irum Gul, Monica Saifi, Nazima Nasrullah, Javed Ahmad, Prasanta Dash, Malik Zainul Abdin Pharmacognosy Magazine 2019 15(62):38-46 Background: Endoperoxide sesquiterpene lactone, artemisinin, is a widely used antimalarial drug. Artemisia annua L. synthesizes this terpenoid and is the only source of artemisinin. In plants, the content of artemisinin is low (0.1–0.8% by dry weight). One of the best approaches to increase artemisinin production is metabolic engineering. Methods: Both the genes were amplified and cloned in Topo vector. Using computational approach, full gene sequencing and a detailed in silico analysis was performed to check the functional and structural properties of these enzymes. Expression patterns of both the genes were assessed at different developmental stages (vegetative, preflowering, flowering, and postflowering stage) of the plant reverse transcription polymerase chain reaction. Results: Deduced amino acid sequence of these genes possessed two important and highly conserved aspartate-rich motifs, and lacks an N-terminal signal peptide, a characteristic of sesquiterpene synthases. Physiochemical properties demonstrated are thermostable. Low hydropathy values ascertain them to be hydrophobic and are active at neutral pH. Structural analysis disclosed that both the proteins possess more α-helices followed by random coils. Ramachandran analysis showed a C-score of −0.35, TM-score of 0.67 ± 0.13 for β caryophyllene synthase model while as C-score of −0.21, TM-score of 0.69 ± 0.12 for β-Farnesene synthase model. Both the proteins contain enormous nitrosylation sites suggesting their functional link through nitrosylation. Gene expression pattern of both the enzymes were upregulated during preflowering and flowering stage. Conclusion: A thorough analysis of these two putative genes in A. annua L paves way to essential insights concerning terpene biosynthesis in general and regulation in artemisinin production in particular. This study also strongly indicates that these two enzymes are developmentally controlled and may have the regulatory effects on the terpene biosynthesis.

Cytoprotective effect of Cactus cladode (Opuntia ficus-indica) against chlorpyrifos induced reactive oxygen species in rat hepatocytes: Involvement of heat shock protein 70 and CYP1A1/2 proteins Hafiz Antar Makeen, Saida Ncibi, Syam Mohan, Abdullah Farasani, Roger Rahmani, Mohammed Al Bratty, Hassan A Alhazmi Pharmacognosy Magazine 2019 15(62):47-53 Background: Organophosphorus insecticides are well known to induce hepatotoxicity. One among this is chlorpyrifos (CPF), which is an insecticide inducing various toxicities including in liver. Objective: This investigation focused on CPF-induced oxidative damage in rat hepatocytes primary culture and the protective effect of Cactus cladode aqueous extract. Materials and Methods: Hepatocytes were treated with CPF (50, 75, and 150 μM) and cactus aqueous extract. On treatment for 48 h, mortality within these cells was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide test, reactive oxygen species (ROS) levels were measured by H2DCFDA test. Furthermore, heat shock protein 70 (HSP70) and CYP1A1/2 levels were determined using western blot analysis. Annexin V and 4',6-diamidino-2-phenylindole analysis was run to determine the level of cell death and cytoprotection exerted by CPF and extracts, respectively. Results: The results showed that CPF increases the levels of H2O2 and HSP70 and induces CYP1A1/2 and mortality within these cells. In the other side of this study, the co-treatment of these cells with CPF and Cactus cladode aqueous extract showed a recovery of these parameters. It also has been found that the Cactus cladode aqueous extract has the potential to do cytoprotective effect by preventing necrosis induced by CPF. Conclusion: Taken together, these findings suggest that the toxicity exerted by CPF in hepatocytes are involved with the generation of ROS and the regulation of well-controlled programmed cell death, which could be well protected by the Cactus cladode extract pretreatment.

Improvement of sexual behavior and ejaculatory parameters by the methanolic extract of Guibourtia tessmannii (Caesalpiniaceae) in high-fat-diet-fed sexually sluggish male rats Patrick Brice Defo Deeh, Pierre Watcho, Kamalesh K Gulia Pharmacognosy Magazine 2019 15(62):54-61 Background: Guibourtia tessmannii (GT) (Caesalpiniaceae) is claimed as a plant having aphrodisiac property as per the African traditional medicine. Objective: This study evaluated the effects of the methanolic extract of GT on sexual behavior and fictive ejaculation in high-fat diet (HFD)-induced sexually sluggish male rats. Materials and Methods: Male Wistar rats fed either on HFD or standard diet (SD) for 16 weeks were monitored for their growth rate and Lee index. At the end of this period, three consecutive copulatory tests were conducted and HFD-induced sexually sluggish rats were selected. Besides Group 1 as time control (SD), drugs or vehicle (veh) were administered orally everyday into three groups of rats as Group 2: HFD (veh), Group 3: HFD + GT (220 mg/kg), and Group 4: HFD + sildenafil citrate (5 mg/kg). Their copulatory activities were tested on day 1, 7, 14, and 21 and the electromyography of bulbospongiosus muscles was assessed for fictive ejaculation on day 22. Results: Treatment with the methanolic extract of GT facilitated sexual behavior by decreasing (P < 0.001) ejaculatory latency within 14 days of treatment that sustained till day 21 compared to the control (HFD) and improving sex drive scores (P < 0.01). The fictive ejaculation parameters were more pronounced in HFD + GT group compared with the HFD group. For instance, after urethral stimulation, the contraction of the bulbospongiosus muscles was significantly increased in HFD + GT group (12.26 ± 7.25) compared to the control group (6.75 ± 0.25). Conclusion: These findings provide robust evidence for the GT treatment in the management of sexual deficits pertaining to obesity.

The contribution of ionotropic gabaergic and N-methyl-D-Aspartic acid receptors in the antidepressant-like effects of hispidulin Abeer Abdelhalim, Imran Khan, Nasiara Karim Pharmacognosy Magazine 2019 15(62):62-70 Background: Salvia triloba, commonly known as sage belongs to Lamiaceae family, is conventionally used as a brain-enhancing tonic. The purpose of this study was to evaluate hispidulin, a flavonoid isolated from S. triloba for its antidepressant-like effects and to identify its possible mechanisms of action. Materials and Methods: Mouse models of the forced swimming test (FST) and tail-suspension test (TST) were used to assess the antidepressant-like effects of hispidulin. Results: The results showed that hispidulin at the doses level of 1–10 mg/kg, intraperitoneal (ip) exerted significant antidepressant-like effects in both FST and TST. Pretreatment of animals with bicuculline (4 mg/kg, ip; a competitive γ-aminobutyric acid (GABA) antagonist) and N-methyl-D-aspartic acid (NMDA) (75 mg/kg, ip, glutamate receptor agonist) significantly blocked the reduction in immobility time of mice treated with hispidulin (3 mg/kg, ip) in FST. Furthermore, brain GABA levels were significantly decreased by coadministration of hispidulin with bicuculline, whereas glutamate levels were increased with combined administration of hispidulin and NMDA. Moreover, coadministration of sub-effective doses of hispidulin (0.5 mg/kg, ip) and ketamine (0.3 mg/kg, ip) or MK 801 (0.1 mg/kg, ip) also exerted significant antidepressant-like effects in FST. Conclusion: Taken together, these findings suggest that hispidulin possess significant antidepressant-like effects mediated most likely through GABAergic and glutamatergic mechanisms.

Cytokine & Growth Factor

The role of the IL-33/ST2 axis in autoimmune disorders: Friend or Foe? Publication date: Available online 3 April 2019 Source: Cytokine & Growth Factor Reviews Author(s): Xiuxing Liu, Yichen Xiao, Yuan Pan, Li He, Song Guo Zheng, Su Wenru Abstract Autoimmune diseases (ADs), which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T effector (Th)1/Th17 cells and T regulatory cells. Interleukin (IL)-33, a member of the IL-1 family, induces inflammatory disease development by mediating type 2 immune responses. Recently, IL-33/ST2 axis was reported to induce autoimmunity involving Th1 and Th17 cells. In this review, we focus on the expression, regulation and function of IL-33/ST2 pathway in the context of autoimmune disorders. We discuss the clinical potential of this signaling pathway in predicting disease activity and severity and offer possible future therapeutic alternatives. Graphical abstract

An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis Publication date: Available online 2 April 2019 Source: Cytokine & Growth Factor Reviews Author(s): Sabateeshan Mathavarajah, Jayme Salsman, Graham Dellaire Abstract Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis. Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms. One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE). In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.

The mesenchymal stem cell secretome: A new paradigm towards cell-free therapeutic mode in regenerative medicine Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Praveen Kumar L., Sangeetha Kandoi, Ranjita Misra, Vijayalakshmi S., Rajagopal K., Rama Shanker Verma Abstract Mesenchymal Stem Cells (MSCs) have been shown to be a promising candidate for cell-based therapy. The therapeutic potential of MSCs, towards tissue repair and wound healing is essentially based on their paracrine effects. Numerous pre-clinical and clinical studies of MSCs have yielded encouraging results. Further, these cells have been shown to be relatively safe for clinical applications. MSCs harvested from numerous anatomical locations including the bone marrow, adipose tissue, Wharton's jelly of the umbilical cord etc., display similar immunophenotypic profiles. However, there is a large body of evidence showing that MSCs secrete a variety of biologically active molecules such as growth factors, chemokines, and cytokines. Despite the similarity in their immunophenotype, the secretome of MSCs appears to vary significantly, depending on the age of the host and niches where the cells reside. Thus, by implication, proteomics-based profiling suggests that the therapeutic potential of the different MSC populations must also be different. Analysis of the secretome points to its influence on varied biological processes such as angiogenesis, neurogenesis, tissue repair, immunomodulation, wound healing, anti-fibrotic and anti-tumour for tissue maintenance and regeneration. Though MSC based therapy has been shown to be relatively safe, from a clinical standpoint, the use of cell-free infusions can altogether circumvent the administration of viable cells for therapy. Understanding the secretome of in vitro cultured MSC populations, by the analysis of the corresponding conditioned medium, will enable us to evaluate its utility as a new therapeutic option. This review will focus on the accumulating evidence that points to the therapeutic potential of the conditioned medium, both from pre-clinical and clinical studies. Finally, this review will emphasize the importance of profiling the conditioned medium for assessing its potential for cell-free therapy therapy.

Insulin-like growth factor binding proteins and angiogenesis: from cancer to cardiovascular disease Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Thomas Slater, Natalie J Haywood, Connor Matthews, Harneet Cheema, Stephen B Wheatcroft Abstract Angiogenesis is a tightly regulated activity that is vital during embryonic development and for normal physiological repair processes and reproduction in healthy adults. Pathological angiogenesis is a driving force behind a variety of diseases including cancer and retinopathies, and inhibition of angiogenesis is a therapeutic option that has been the subject of much research, with several inhibitory agents now available for medical therapy. Conversely, therapeutic angiogenesis has been mooted as having significant potential in the treatment of ischemic conditions such as angina pectoris and peripheral arterial disease, but so far there has been less translation from lab to bedside. The insulin-like growth factor binding proteins (IGFBP) are a family of seven proteins essential for the binding and transport of the insulin-like growth factors (IGF). It is being increasingly recognised that IGFBPs have a significant role beyond simply modulating IGF activity, with evidence of both IGF dependent and independent actions through a variety of mechanisms. Moreover, the action of the IGFBPs can be stimulatory or inhibitory depending on the cell type and environment. Specifically the IGFBPs have been heavily implicated in angiogenesis, both pathological and physiological, and they have significant promise as targeted cell therapy agents for both pathological angiogenesis inhibition and therapeutic angiogenesis following ischemic injury. In this short review we will explore the current understanding of the individual impact of each IGFBP on angiogenesis, and the pathways through which these effects occur.

The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Gunnhildur Ásta Traustadóttir, Lene Vig Lagoni, Lea Bo Sønderlund Ankerstjerne, Hanne Cathrine Bisgaard, Charlotte Harken Jensen, Ditte Caroline Andersen Abstract Delta like non-canonical Notch ligand 1 (Dlk1) is an imprinted gene, mainly known for its involvement in adipogenesis, although it has been associated with many other stem cells/progenitors and is known to be widely expressed during organism development and tissue regeneration. In a systematic manner, we have outlined the overall expression pattern of Dlk1 in both man and mouse, and found Dlk1 to be expressed in tissues from all three germ layers. Yet, Dlk1 expression decreases along with increased differentiation as gestation proceeds and in most tissues Dlk1 is absent around birth. Thus, in adults, expression of Dlk1 is restricted to a few tissues and progenitor cells, but is re-expressed during disease and regeneration. Although diffferences exist, we found an overall conservation of Dlk1 expression between mouse and man, and conclude in that sense that the mouse is an appropiate model to study Dlk1. In agreement with the observed Dlk1 expression pattern, we found that the majority of published Dlk1 studies, report Dlk1 to have an inhibitory effect on both cell proliferation and differentiation, but the levels of the different DLK1 isoforms may be critical and have an impact on the overall outcome. This may also be an issue during tissue regeneration where several studies have reported Dlk1′s impact during skeletal muscle and liver regeneration without establishing the exact role. Likewise, the underlying mechanism of Dlk1 action is unknown, and seems to depend on both Notch dependent and independent pathways. However, from our data it is intriguing to speculate that the actual role of DLK1 may be to function as a checkpoint to slow down proliferation while forcing cells into the process of differentiation, and thus switch the cell/organ to a state of growth and hypertrophy. This may fit well with its reported impact on growth restiction and body size. Thus, our study which for the first time summarizes reported knowledge on Dlk1 in tissue development and regeneration as well as on the Dlk1 mechanism may provide novel insight to the general role of this remarkable imprinted gene in controlling cell growth, from which new hypotheses can be made in the field of stem cell biology and regenerative medicine. Graphical abstract

The regulation of circadian clock by tumor necrosis factor alpha Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Mustafa Gokhan Ertosun, Gamze Kocak, Osman Nidai Ozes Abstract All organisms display circadian rhythms which are under the control of the circadian clock located in the hypothalamus at the suprachiasmatic nucleus, (SCN). The circadian rhythms allow individuals to adjust their physiological activities and daily behavior for the diurnal changes in the living environment. To achieve these, all metabolic processes are aligned with the sleep/wake and fasting/feeding cycles. Subtle changes of daily behavior or food intake can result in misalignment of circadian rhythms. This can cause development of variety of metabolic diseases and even cancer. Although light plays a pivotal role for the activation of the master clock in SCN, the peripheral secondary clocks (or non-SCN), such as melatonin, growth hormone (GH), insulin, adiponectin and Ghrelin also are important in maintaining the circadian rhythms in the brain and peripheral organs. In recent years, growing body of evidence strongly suggest that CA2+ signaling, tumor necrosis factor alpha (TNFα) and transforming growth factor beta (TGFβ) also play very important roles in the regulation of circadian rhythms by regulating the transcription of the clock genes. Graphical abstract

Elabela and Apelin actions in healthy and pathological pregnancies Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Delphine Eberlé, Lucie Marousez, Sandy Hanssens, Claude Knauf, Christophe Breton, Philippe Deruelle, Jean Lesage Abstract Pregnancy is a dynamic and precisely organized process during which one or more baby develops. Embryonic development relies on the formation of the placenta, allowing nutrient and oxygen exchange between the mother and the fetus. Dysfunction of placental formation lead to pregnancy disorders such as preeclampsia (PE) with serious deleterious consequences for fetal and maternal health. Identifying factors involved in fetoplacental homeostasis could inform better diagnostic and therapeutic strategies for these pathological pregnancies. Here, we summarize actions of elabela, apelin and their common receptor APJ in the fetoplacental unit. Studies indicate that elabela is crucial for embryo cardiovascular system formation and early placental development, while apelin acts in mid/late gestation to modulate fetal angiogenesis and energy homeostasis. Most of these findings, drawn from animal models, indicate a key role of elabela/apelin-APJ system in the fetoplacental unit. This review also provides an overview of clinical studies investigating elabela/apelin-APJ system in pathological complicated pregnancies such as PE and gestational diabetes mellitus (GDM). While elabela-deficient mice display all the features of PE, current clinical studies show no difference in circulating elabela levels between PE and control patients which does not support a role in PE development. Conversely, apelin levels are increased during PE, but the use of apelin as an early PE marker remains to be fully investigated.

Editorial Board Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s):

Exploitation of phage display for the development of anti-cancer agents targeting fibroblast growth factor signaling pathways: New strategies to tackle an old challenge Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Behzad Jafari, Maryam Hamzeh-Mivehroud, Michael B. Morris, Siavoush Dastmalchi Abstract A tumor is defined as a group of cancer cells and 'surrounding' stromal bio-entities. Alongside the extracellular matrix (ECM) in the tumor microenvironment (TME), the stromal cells play key roles in cancer affliction and progression. Carcinoma-associated fibroblasts (CAFs) in the area of the tumor, whether activated or not, dictate the future of tumor cells. The CAFs and corresponding secreted growth factors (GFs), which mediate the crosstalk within the TME, can be targeted in therapies directed at the stroma. The impact of the fibroblast growth factor-fibroblast growth factor receptor (FGF-FGFR) signaling pathway in different kinds of tumors has been explored. Several tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and ligand traps targeting the formation of FGF-FGFR complex are in preclinical or early development phases. Moreover, there are numerous studies in the literature reporting the application of phage display technology for the development of peptides and proteins capable of functioning as FGF mimetics or traps, which are able to modulate FGF-related signaling pathways. In this review, prominent research in relation to phage display-assisted ligand identification for the FGF/FGFR system is discussed. Graphical abstract

Corrigendum to "New vaccination strategies in liver cancer" [Cytokine Growth Factor Rev. 36 (2017) 125–129] Publication date: April 2019 Source: Cytokine & Growth Factor Reviews, Volume 46 Author(s): Luigi Buonaguro, Andrea Mayer-Mokler, Christian Flohr, Carsten Reinhardt, Harpreet Singh-Jasuja, Roberto Accolla, Giovanna Tosi, Yuk T. Ma, David Adams, Danila Valmori, Regina Heidenreich, Ulrike Gnad-Vogt, Alfred Königsrainer, Markus Löffler, Hans-Georg Rammensee, Bruno Sangro, Sven Francque, Maria Tagliamonte, Annacarmen Petrizzo, Maria Lina Tornesello

Ethnopharmacology

Cytotoxic effect of aqueous ethanolic extract of Luffa cylindrica leaves on cancer stem cells CD44+/24- in breast cancer patients with various molecular sub-types using tissue samples in vitro Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Ibrahim Mohamed Abdel-Salam, A.A. Abou-Bakr, Mohamed Ashour Abstract Ethnopharmacological relevance: Luffa cylindrica (L.) M.Roem is a climbing plant its parts have been used as traditional medicine for the treatment of different types of diseases including diarrhea, inflammation, cancer and viral infections. The parts used include fruit, seeds and leaves. Aim of the study: Our study aims to investigate the effect of the aqueous-ethanol extract of Luffa cylindrica leaves on breast cancer stem cells CD44+/24- and other cell sub-populations using clinical samples with different molecular sub-types of breast cancer in vitro. Materials and Methods: Breast tissues were obtained from patients undergoing surgery for the removal of breast tumors after complete clinical and pathological investigations. Tissue samples were processed to cell suspensions and treated with the extract in the tissue culture laboratory. Percentages of cell sub-populations within tumors and viability were measured by flowcytometry using clusters of differentiation as cell markers. Results Our results revealed that there were decreases in the total cell viability, CD44+/24- and total CD24+ cell sub-populations percentages after treatment with the extract, this may be an important indication of using Luffa leaves extract in the treatment of breast cancer or in combination with the traditional treatments. Conclusion: Luffa cylindrica has proven to have anticancer activity on three different subtypes of breast cancer including luminal A, luminal B and Her2/neu enriched more over it has cytotoxic effect on both bulk tumor cells as well as cancer stem cells sub population CD44+/24- which possess high tumorigenic potency, these results were confirmed by measuring their viable number after treatment and sphere formation assay results. Graphical abstract

The new buzz: Investigating the antimicrobial interactions between bioactive compounds found in South African propolis Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): K. Kharsany, A. Viljoen, C. Leonard, S. van Vuuren Abstract Ethnopharmacological relevance Propolis, a resinous substance produced by the Apis mellifera bee, contains a number of flavonoids sourced from plants found in the surrounding region. Whilst bees use this substance to seal off and protect the beehive, humans have used propolis therapeutically for centuries, making use of its antibacterial, antiseptic, antipyretic and wound healing properties, among others. South African propolis is rich in the flavonoids pinocembrin, galangin, and chrysin and very little previous research has been conducted on the antimicrobial effects of these compounds. Aim of the study To obtain an understanding of the antimicrobial activity of the compounds pinocembrin, galangin, and chrysin, both independently and in combination. Materials and methods The compounds pinocembrin, galangin and chrysin were investigated for interactive antimicrobial activity by determining the minimum inhibitory concentrations (MIC), minimum bactericidal concentrations (MBC), anti-quorum sensing activity, biofilm studies, and toxicity studies (brine shrimp lethality assay). Results Minimum inhibitory concentration results demonstrated that combinations of compounds showed better inhibitory activity than single compounds. When the flavonoids were tested in combination using the MIC assay, synergy was noted for 22% of the 1:1 ratio combinations and for 66% of the triple 1:1:1 ratio combinations. Similarly, MBC results showed bactericidal activity from selected combinations, while the compounds on their own demonstrated no cidal activity. Quorum sensing studies showed that compound combinations are more effective at inhibiting bacterial communication than the individual compounds. Biofilm assays showed that the highest percentage inhibition was observed for the triple combination against E. coli at 24 h. Finally, brine shrimp lethality studies revealed that combinations of the three compounds had reduced cytotoxicity when compared to the individual compounds. Conclusion The results obtained in this study demonstrate that the compounds found in South African propolis work synergistically to achieve an optimal antimicrobial effect, whilst simultaneously minimizing cytotoxicity. Graphical abstract

Self-reported prevalence and severity of opioid and kratom (Mitragyna speciosa korth.) side effects Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Azlin Saref, Sharifah Suraya, Darshan Singh, Oliver Grundmann, Suresh Narayanan, Marc T. Swogger, Walter C. Prozialeck, Edward Boyer, Nelson Jeng Yeou Chear, Vicknasingam Balasingam Abstract Ethnopharmacological relevance Mitragyna speciosa (Korth.) is a traditional medicinal plant widely used in Southeast Asia for its opioid-like effects. Although kratom produces analgesia through binding of mitragynine and other alkaloids at the mu-opioid receptor (MOR), the association of long-term kratom use with adverse opioid-like effects remains unknown. Aim of the study: To determine the self-reported prevalence and severity of opioid-related adverse effects after kratom initiation in a cohort of illicit opioid users. Materials and methods A total of 163 illicit opioid users with current kratom use history were recruited through convenience sampling from the northern states of Peninsular Malaysia. Face-to-face interviews were conducted using a semi-structured questionnaire. Results Respondents were all males, majority Malays (94%, n = 154/163), with a mean age of 37.10 years (SD = 10.9). Most were single (65%, n = 106/163), had 11 years of education (52%, n = 85/163) and employed (88%, n = 144/163). Half reported using kratom for over >6 years (50%, n = 81/163), and 41% consumed >3 glasses of kratom daily (n = 67/163). Results from Chi-square analysis showed kratom initiation was associated with decreased prevalence of respiratory depression, constipation, physical pain, insomnia, depression, loss of appetite, craving, decreased sexual performance, weight loss and fatigue. Conclusions Our findings indicate that kratom initiation (approximately 214.29 mg of mitragynine) was associated with significant decreases in the prevalence and severity of opioid adverse effects. Graphical abstract

Comprehensive chemical profiling of monascus-fermented rice product and screening of lipid-lowering compounds other than monacolins Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Jin-Xiu Liang, Qun-Qun Zhang, Yan-Fei Huang, Han-Qing Pang, Xin-Guang Liu, Wen Gao, Ping Li, Hua Yang Abstract Ethnopharmacological relevance Monascus-fermented rice product (MFRP) has been regarded as a dietary supplement and traditional medicine with circulation-promoting effects in China and other countries for centuries. Aim of the study This study was carried out to profile the chemical components in MFRP, and provide available information for elucidating the potential lipid-lowering compounds other than monacolins. Materials and methods High-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF MS) and gas chromatography coupled with mass spectrometry (GC-MS) methods were applied to comprehensive analysis of chemical components in MFRP. Potential small molecules were identified by comparing with reference standards, or tentatively characterized by comparing their retention time and high-resolution mass spectral data with previous literature. The lipid-lowering properties of ten major non-monacolin compounds were evaluated in cholesterol-fed zebrafish larvae. And one with optimum lipid-lowering activity was subsequently evaluated in high fat diet-fed C57BL/6 J mice, with the dyslipidemia and ectopic lipid deposition being investigated. Results A total of 99 compounds were characterized in MFRP, including 38 monacolins, 5 decalins, 6 isoflavones, 13 pigments, 8 azaphilonoids, 11 amino acids, 4 nucleosides, 9 lipid acids, 4 phytosterols and glycerol. The preliminary screening showed that ergosterol remarkably reduced cholesterol levels in zebrafish larvae. Moreover, ergosterol delayed body weight gain and decreased circulating total cholesterol, triglyceride, low density lipoprotein cholesterol levels in high fat diet-fed mice. Ectopic lipid accumulation was also ameliorated in the liver and heart of obese mice. Conclusion Global analysis of chemical components and screening of lipid-lowering non-monacolin compounds in MFRP have improved our understanding of its therapeutic material basis. Graphical abstract

Ameliorative effect of Atractylodes macrocephala essential oil combined with Panax ginseng total saponins on 5-fluorouracil induced diarrhea is associated with gut microbial modulation Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Jing Wang, Wuwen Feng, Shiyang Zhang, Lu Chen, Yongcheng Sheng, Fei Tang, Junlin He, Xin Xu, Hui Ao, Cheng Peng Abstract Ethnopharmacological relevance Traditional Chinese medicine (TCM) holds that deficiency of spleen-Qi is the major pathogenesis of chemotherapy-induced diarrhea (CID). Herb pair of Atractylodes macrocephala Koidz. (AM) and Panax ginseng C. A. Mey. (PG) has good effects of supplementing Qi and strengthening spleen. Aim of the study To investigate therapeutic effects and mechanism of Atractylodes macrocephala essential oil (AMO) and Panax ginseng total saponins (PGS) alone and in combination (AP) on 5-fluorouracil (5-FU) chemotherapy induced diarrhea in mice. Materials and methods The mice were administered with AMO, PGS and AP respectively for 11 days, and intraperitoneally injected with 5-FU for 6 days since the 3rd day of the experiment. During the experiment, the body weights and diarrhea scores of mice were recorded daily. Thymus and spleen indexes were calculated after sacrifice of the mice. Pathological changes in ileum and colonic tissues were examined by hematoxylin-eosin (HE) staining. And the content levels of intestinal inflammatory cytokines were measured by enzyme-linked immmunosorbent assays (ELISA). 16S rDNA Amplicon Sequencing was used to analyze and interpret the gut microbiota of fecal samples. Results AP significantly inhibited body weights loss, diarrhea, reductions of thymus and spleen indexes, and pathological changes of ileums and colons induced by 5-FU. Neither AMO nor PGS alone significantly improved above-mentioned abnormalities. Besides, AP could significantly suppressed the 5-FU-mediated increases of the intestinal inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-1β and IL-17), while AMO or PGS only inhibited some of them after 5-FU chemotherapy. Gut microbiota analysis indicated that 5-FU induced overall structural changes of gut microbiota were reversed after AP treatment. Additionally, AP significantly modulated the abundances of different phyla similar to normal values, and restored the ratios of Firmicutes/Bacteroidetes (F/B). At genus level, AP treatment dramatically decreased potential pathogens like Bacteroides, Ruminococcus, Anaerotruncusand Desulfovibrio. AP also antagonized the abnormal effects of AMO and PGS alone on certain genera like Blautia, Parabacteroides and Lactobacillus. Neither AMO nor PGS alone inhibited changes of gut microbial structure caused by 5-FU. Conclusions AP, combination of AMO and PGS, not AMO or PGS alone, significantly ameliorated diarrhea, inhibited intestinal pathology, and modulated gut microbial structure in 5-FU induced mice. AP also antagonized abnormal effects of AMO or PGS on certain genera. The results illustrated that gut microbiota was involved in the combined effects of AP on 5-FU induced diarrhea. Graphical abstract

Analgesic and anti-inflammatory effects and molecular mechanisms of Kadsura heteroclita stems, an anti-arthritic Chinese Tujia ethnomedicinal herb Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Huang-he Yu, Ye Lin, Rong Zeng, Xin Li, Ting Zhang, Shumaila Tasneem, Cong Chen, Yi-xing Qiu, Bin Li, Jin Liao, Yu-hong Wang, Xiong Cai, Wei Wang Abstract Ethnopharmacological relevance Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by failure of spontaneous resolution of inflammation. The stem of Kadsura heteroclite (KHS) is a well-known anti-arthritic Tujia ethnomedicinal plant, which named Xuetong in folk, has long been used for the prevention and treatment of rheumatic and arthritic diseases. Aim of the study The analgesic and anti-inflammatory effects and the potential mechanisms behind such effects of KHS would be investigated by using different animal models. Materials and methods The abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid and the tail-flick response induced by radiant heat stimulation were used to evaluate the analgesic effect of KHS. The number of abdominal writhing episodes of mice and the latency of tail-flick in rats were measured and recorded. In acute inflammatory models, the ear edema of mice was induced by applying xylene on the ear surface, while the paw edema of male and female rats was induced by subcutaneous injection of carrageenan into the right hind paws of animals. The carrageenan-induced paw swelling in rats were selected as an anti-acute inflammatory mechanism of KHS. Serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) were measured by ELISA, and protein expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were detected by Western blot. Results The maximal tolerated single dose of KHS was determined to be 26 g/kg in both sexes of mice. Pharmacological studies showed that KHS at the dose of 200 mg/kg significantly prolonged the reaction time of rats to radiant heat stimulation and suppressed abdominal writhing episodes of mice induced by intraperitoneal injection of acetic acid. KHS at the dose of 200, 400, and 800 mg/kg, showed dose-dependent inhibition of xylene-induced ear swelling in mice. KHS at the dose of 100, 200, 400, and 800 mg/kg demonstrated dose- and time-dependent suppression of paw edema induced by subcutaneous injection of carrageenan in both all rats. Mechanistic studies revealed that the anti-inflammatory effect of KHS was associated with inhibition of the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and effectively decreased the expression of COX and iNOS proteins in the carrageenan-injected rat serum, paw tissues and inflammatory exudates. The positive reference drug, rotundine at a dosage of 100 mg/kg and indomethacin at a dosage of 10 mg/kg were used in both mice and rat models. Conclusion These results suggested that KHS has significant effects on analgesia and anti-inflammation with decreasing the pro-inflammation cytokines of IL-1β, IL-6, and TNF-α and inhibiting the proteins expression of COX-2 and iNOS. Graphical abstract

The effect of Xiang-Sha-Liu-Jun-Zi tang (XSLJZT) on irritable bowel syndrome: A randomized, double-blind, placebo-controlled trial Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Yi-Sing Shih, Chang-Hai Tsai, Tsai-Chung Li, Hsueh-Chou Lai, Kun-Teng Wang, Wen-Ling Liao, Ching-Liang Hsieh Abstract Background Irritable bowel syndrome (IBS) is characterized by chronic, recurrent abdominal pain or abdominal discomfort and changes in defecation habits. Xiang-Sha-Liu-Jun-Zi tang (XSLJZT) is a traditional Chinese medical formula that can modulate gastrointestinal disturbance. Purpose To investigate the therapeutic effect of XSLJZT on IBS. Materials and methods This study was designed as a double-blind, randomized, controlled preliminary study. Eighty patients with IBS were assigned to a control group (CG, 40 patients) that received oral administration of an XSLJZT 10% comparator (3.0 g three times daily) for 28 days or to a treatment group (TG, 40 patients) that received XSLJZT. The primary outcome measure was changes in scores on the Gastrointestinal System Rating Scale-IBS. The secondary outcome measures were changes in scores on the irritable bowel syndrome-quality of life (IBS-QOL) and World Health Organization-quality of life-brief. Results A total of 63 patients completed the study (n = 31 for the CG; n = 32 for the TG). The TG were discovered to have significantly lower diarrhea scores than the CG at V2 (second assessment) compared with V1 (first assessment, baseline) (mean change ± SD: CG: 0.19 ± 1.33 vs. TG: −0.38 ± 0.91, p = 0.05). The scores for Item 28 on the IBS–quality of life (QOL) scale ("I feel frustrated that I cannot eat when I want because of my bowel problems") were lower in the CG at V3 (third assessment) compared with V1 but slightly higher in the TG (CG: −0.48 ± 0.89 vs. TG: 0.03 ± 0.65, p = 0.01). Conclusion Oral administration of XSLJZT (3.0 g) for 28 days lowered the mean diarrhea score in patients with IBS, indicating that the patients in the TG had greater diarrhea improvement than those in the CG. The present study used 10% XSLJZT as a comparator, and the different items of the Gastrointestinal System Rating Scale–IBS, IBS-QOL, and World Health Organization Quality of Life–Brief were scored separately. Therefore, the selection of an appropriate comparator or placebo and score assessment are crucial issues for future study. Graphical abstract

Lonicera japonica extract increases metformin distribution in the liver without change of systemic exposed metformin in rats Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Seung Yon Han, Hee-Sung Chae, Byoung Hoon You, Young-Won Chin, Hojun Kim, Han Seok Choi, Young Hee Choi Abstract Ethnopharmacological relevance Flower and flower bud of Lonicera japonica, Lonicerae Flos, have been popularly used as medicinal plant for the treatment of clearing heat and thirst, thereby improving diabetic or diabetic associated symptoms (thirst and poor eyesight). Aim of the study Organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) are known to play important roles in metformin transport in the liver and kidneys. Thus, there might be interactions between Lonicerae Flos and metformin via OCTs and MATEs. Also treatment period has been issued in transporter-mediated drug interactions. The objective of this study was to determine the effect of Lonicerae Flos ethanol extract (LJ) on metformin pharmacokinetics and its glucose lowering activity in different treatment periods. Materials and methods Effect of LJ on metformin uptake was evaluated in vitro HEK-293 cells expressing human OCTs or MATEs. Treatment period-dependent impact of LJ on systemic exposure and hepatic distribution of metformin as well as its glucose tolerance activity were assessed in in vivo rats. Results LJ substantially inhibited MATE1-mediated metformin uptake in vitro. In evaluating treatment period effects of LJ and metformin, 1-, 7-, and 28-day co-treatments of LJ with metformin did not change systemic exposure of metformin compared to those in metformin alone. Whereas, 28-day co-treatment of LJ with metformin increased metformin concentration in liver as a pharmacological target site of metformin. It could be due to the reduced MATE1-mediated metformin efflux from hepatocytes to bile by MATE1 inhibition in liver. Glucose tolerance activity was also enhanced by 28-day co-treatment of LJ and metformin compared to metformin alone. Conclusions In 28-day co-treatment of LJ and metformin, LJ increased metformin concentration in liver and improved glucose tolerance activity without systemic exposure change of metformin, suggesting the importance to consider treatment period effect and both systemic exposure and tissue distribution in drug interactions. Graphical abstract

Dahuang Zhechong Pill suppresses colorectal cancer liver metastasis via ameliorating exosomal CCL2 primed pre-metastatic niche Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Chunhui Chen, Xueqing Yao, Yihua Xu, Qingyuan Zhang, Hao Wang, Liang Zhao, Ge Wen, Yawei Liu, Linlin Jing, Xuegang Sun Abstract Ethnopharmacological relevance Dahuang Zhechong Pill (DZP) is a classical formula from "Synopsis of Prescriptions of the Golden Chamber". It has been used for treatment of abdominal masses (including tumorous diseases) for thousands of years. Aim of the study Our previous work showed that DZP suppresses CCl-4 induced hepatic fibrosis by downregulating the expression of interleukin-13. We aimed to test if DZP suppresses the metastasis of colorectal cancer (CRC) by ameliorating the fibrosis status of the future metastatic organ. Materials and methods Liver metastasis was observed by injection of MC38-EGFP cells with stably expressing enhanced green fuorescence protein beneath the splenic capsule of C57BL/6J mice. MC38-EGFP-derived exosomes were analyzed by Label-free comparative proteomics. mRNA expression was determined by Quantitative PCR. Protein expression was determined by immunohistochemistry, immunofuorescence and Western blot. Collagen deposition was determined by Masson staining. All data were statistically analyzed using SPSS. Results DZP drastically reduced the metastatic tumor number and fluorescence intensity in a splenic liver metastasis model. It also lowered the expression of mature TGF-β1 and decreased the fibronectin contents & collagen deposition. Exosome proteomics showed that the upregualted CC chemokine ligand-2 (CCL2) was repressed by DZP treatment. Importantly, DZP markedly lowered the expression of CCL2 and its receptor CCR2 in the liver. Exosomal CCL2 activated macrophage recruitment and shifted the M1/M2 paradigm to a M2 phenotype. DZP reduced the macrophage infiltration and attenuated the M2 polarizaion in tumor-bearing mice liver. It decreased the F4/80 positive areas and specifically reduced the ratio of CCR2+ positive macrophage. Anti-fibrosis and inhibition of CCR2 suppress the growth and metastasis of CRC. Conclusions DZP inhibits the liver metastasis of CRC by suppressing CCL2 mediated M2-skewing paradigm and ameliorating the pro-fibrotic microenvironment. Graphical abstract

Long-term administration of Aspalathus linearis infusion affects spatial memory of adult Sprague-Dawley male rats as well as increases their striatal dopamine content Publication date: 28 June 2019 Source: Journal of Ethnopharmacology, Volume 238 Author(s): Justyna Pyrzanowska, Izabela Fecka, Dagmara Mirowska-Guzel, Ilona Joniec-Maciejak, Kamilla Blecharz-Klin, Agnieszka Piechal, Ewa Wojnar, Ewa Widy-Tyszkiewicz Abstract Ethnopharmacological relevance Everyday use of the herbal tea rooibos, produced from Aspalathus linearis (Brum.f) Dahlg. (Fabaceae) is customary in South Africa, a continuation of its historical use by indigenous people. Although evidence of its traditional indications is anecdotal, rooibos tea is regarded as a general health tea. Aims of the study Available contemporary research indicates to broad cell protective activity of rooibos focusing on its antioxidative, anti-inflammatory, anti-hyperglycaemic and antithrombotic features affecting metabolic syndrome, cardiovascular risk and neuroprotection. Nevertheless little is known about its impact on brain functions. The present experiment aimed to evaluate the possible behavioural and neurochemical effects of long-term oral administration of "fermented"" rooibos herbal tea (FRHT) infusions to adult male Sprague-Dawley rats. Materials and methods Infusions, prepared using 1, 2 and 4 g of "fermented"" (oxidised) A. linearis leaves for 100 ml of hot water, were characterised in terms of flavonoid content by ultra-high and high performance liquid chromatography (UHPLC-qTOF-MS, HPLC-DAD) and administered to rats as sole drinking fluid for 12 weeks. Spatial memory behaviour was assessed in a modified version of the Morris water maze. Dopamine, noradrenaline, serotonin and their metabolite levels (DOPAC, 3-MT, HVA, MHPG, 5-HIAA) were quantified in prefrontal cortex, hippocampus and striatum by HPLC-ECD. Body weight and blood glucose level were additionally estimated. Results All FRHT-treated rats showed improvement of long-term spatial memory defined as increased number of crossings over the previous platform position in SE quadrant of the water maze. It was not accompanied by excessive motor activity. Striatal dopamine and its metabolite 3-MT (3-methoxytyramine) levels were increased in treated rats. There were no differences in body weight gain between control and treated animals but blood glucose level was significantly lower in the latter ones. Conclusion The improvement of long-term memory in FRHT-treated rats and stimulating impact of FRHT on their dopaminergic striatal transmission support the wellness enhancing effect of rooibos tea, contributing to a better understanding of the neurological background of traditional habitual consumption of this herbal tea. Graphical abstract

Anthropological Archaeology

Dimensions of inequality. Comparing the North Atlantic and the US Southwest Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Orri Vésteinsson, Michelle Hegmon, Jette Arneborg, Glen Rice, Will G. Russell Abstract Analysis of three different realms of inequality in two pairs of small-scale pre-industrial societies in two very different and culturally unconnected regions – Hohokam and Mimbres in the US Southwest and Greenland and Iceland in the North Atlantic – suggests that inequality can be successfully used as a yardstick to compare societies in the past. The study finds that there were significant inequalities in these small-scale farming societies – often described in previous studies as "egalitarian" – but that proxies for economic inequality like access to productive resources and to exotic goods do not fully reflect the range and nature of these inequalities. Access to ritual space is found to be a more sensitive measure of actual inequalities as experienced by members of these societies.

Reconsidering sex and gender in relation to health and disease in bioarchaeology Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Molly K. Zuckerman, John Crandall Abstract As an interdisciplinary field that integrates historical, ethnographic, archaeological, and biological data, bioarchaeology is well positioned to contribute to understandings of the health of past peoples in their socio-cultural contexts. Recently, following a longstanding trend in archaeology, many bioarchaeologists have begun to productively engage with concepts of sex, gender, and to a lesser extent, sexuality, particularly in relation to issues of health and disease. In response, this review interrogatively and synthetically surveys recent bioarchaeological work on this nexus, querying how bioarchaeologists theorize sex and gender, how they operationalize these concepts relative to health and disease, and the relative merits of these approaches. Within this, the review focuses on studies addressing metabolic disease, trauma and violence, infectious disease, and overall health (e.g., frailty). Throughout, the review highlights how theoretically informed bioarchaeological data can be used to further elucidate the biosocial factors that shape past patterns of health. It also highlights the distinct insights generated from this scholarship, as well as the unresolved questions, methodological difficulties, and theoretical tensions facing it. The aim throughout is to give future scholars novel, social theory-informed, and operationalized theoretical frameworks and interpretive devices that can be used to answer these questions and resolve these conflicts within bioarchaeology.

Supply and demand in prehistory? Economics of Neolithic mining in northwest Europe Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Peter Schauer, Stephen Shennan, Andrew Bevan, Gordon Cook, Kevan Edinborough, Ralph Fyfe, Tim Kerig, Mike Parker Pearson Abstract The extent to which non-agricultural production in prehistory had cost-benefit motivations has long been a subject of discussion. This paper addresses the topic by looking at the evidence for Neolithic quarrying and mining in Britain and continental northwest Europe and asks whether changing production through time was influenced by changing demand. Radiocarbon dating of mine and quarry sites is used to define periods of use. These are then correlated with a likely first-order source of demand, the size of the regional populations around the mines, inferred from a radiocarbon-based population proxy. There are significant differences between the population and mine-date distributions. Analysis of pollen data using the REVEALS method to reconstruct changing regional land cover patterns shows that in Britain activity at the mines and quarries is strongly correlated with evidence for forest clearance by incoming Neolithic populations, suggesting that mine and quarry production were a response to the demand that this created. The evidence for such a correlation between mining and clearance in continental northwest Europe is much weaker. Here the start of large-scale mining may be a response to the arrival by long-distance exchange of high-quality prestige jade axes from a source in the Italian Alps.

The persistence of place: Hunter-gatherer mortuary practices and land-use in the Trent Valley, Ontario Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Samantha Walker Abstract Hunter-gatherer mortuary practices identified in the Trent Valley region, ON are highly patterned for the Middle Woodland period (400 BCE-700 CE), but the importance of many of these mortuary sites can be recognized as far back as the Late Archaic period (2500–1000 BCE). A geospatial modelling approach is used to predict the distribution of mortuary sites based on ecological factors that may have influenced land use strategies. The assessment reveals that Late Archaic and Middle Woodland mortuary sites were primarily located near aerobic wetlands that were likely rich in emergent plant life. The predicted suitably of mineral soil horizons, when compared with Trent Valley floodplain behaviour, suggests that wild rice may have been a particularly abundant resource near mortuary sites. The position of wild rice in Anishinaabe traditional stories is discussed to contextualize its potential early food value to Indigenous occupants of the Trent Valley, prior to the resource's documented historic importance. The highly selective positioning of mortuary sites and their continuity within the Trent Valley region shed light on how ancestral ties to key places were established and maintained in precolonial hunter-gatherer societies.

Biocultural consequences of the Late Woodland transition at Forbush Creek, North Carolina (AD 800-1200) Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Steph M. Berger, Dale L. Hutchinson Abstract After several centuries of cultural continuity, the Late Woodland transition (AD 600-1000) in the Southeastern Woodlands involved a significant intensification of existing lifeways. This study examines the biocultural consequences of the Late Woodland transition at Forbush Creek (AD 800-1200), a Yadkin River Valley site from the Piedmont region of North Carolina. Twelve percent of individuals recovered from the site sustained violence-related trauma, including five individuals with healed blunt force trauma, two individuals with perimortem cranial trauma, and a single projectile point injury. Secondary burial individuals exhibited significantly more trauma (n = 10, 42%) and nutrient deficiencies (n = 12, 50%) than primary burial individuals (n = 1, 4%; and n = 5, 19%, respectively). The Forbush Creek remains provide new evidence of the biological impacts of cultural transitions and suggest that uncertainty, scarcity, and conflict arising from changing lifeways contributed to inequality in the Forbush Creek community. Secondary bundle burial inclusion may represent marginalization and an increased vulnerability to morbidity and mortality risks. The emergence of social inequality in the Late Woodland period likely shaped long-term cultural dynamics that preceded the complex sociopolitical hierarchies of the later Mississippian period.

Southeast Asian early Maritime Silk Road trading polities' hinterland and the sea-nomads of the Isthmus of Kra Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Bérénice Bellina, Aude Favereau, Laure Dussubieux Abstract In Southeast Asia, archaeological research has recently shown that the earliest centralised polities qualifying as incipient States emerged by the late 5th and early 4th c. BCE (Kim, 2013; Stark, 2015; Bellina, 2017, 2018). Understanding of their hinterland is still very limited. This essay presents the results of a regional study conducted since 2005 in the Isthmus of Kra in the Thai-Malay Peninsula, a narrow piece of land located between the Bay of Bengal and the South China Sea. It argues that in this region, Maritime Silk Road incipient trading states' emergence went along economic specialisation, cultural differentiation and cooperation between different groups participating in local and long-distance networks. Amongst these so-called "marginal" groups emerge "sea nomads". Like those described in historical and ethnographic sources some of which are referred to here, these early sea nomads appeared to have already played a crucial economic and political role as part of these maritime trading polities hinterland. Along with an archaeology of sea nomadism, this study opens perspectives on reconstructing a more complete narrative of Southeast Asia and beyond of the Maritime Silk Road, a narrative that integrates marginal groups.

Meat outside the freezer: Drying, smoking, salting and sealing meat in fat at an Epipalaeolithic megasite in eastern Jordan Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Anna Spyrou, Lisa A. Maher, Louise A. Martin, Danielle A. Macdonald, Andrew Garrard Abstract Even though pivotal for understanding many aspects of human behaviour, preservation and storage of animal resources has not received great attention from archaeologists. One could argue that the main problem lies in the difficulties of demonstrating meat storage archaeologically due to the lack of direct evidence. This paper represents an attempt to refine zooarchaeological methods for the recognition of meat preservation and storage at prehistoric sites. Drawing on the faunal assemblage from Kharaneh IV, an Early/Middle Epipalaeolithic aggregation site in eastern Jordan, this study demonstrates that a combination of taphonomic and contextual analyses alongside ethnographic information may indeed lead archaeologists to insights not directly available from the archaeological record. The empirical evidence presented here contributes to the archaeological visibility of meat preservation and storage, providing a clearer concept of the nature of these practices in pre-agricultural societies.

Toward archaeological predictive modeling in the Bosutswe region of Botswana: Utilizing multispectral satellite imagery to conceptualize ancient landscapes Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Carla Klehm, Adam Barnes, Forrest Follett, Katie Simon, Christopher Kiahtipes, Sarah Mothulatshipi Abstract Geospatial technologies such as GIS, remote sensing, and GNSS are transforming landscape archaeology, particularly in research areas that are hard to access due to geographical size, environmental challenges, lack of infrastructure, and/or political instability. In the following article, we explore the potential of high-resolution, multispectral satellite imagery for building a predictive model of the settlement pattern of the Iron Age polity of Bosutswe (700–1650 CE) in Botswana. While the case study lies in Africa, the problems that Africanists experience extend far beyond the continent. With limited funding, poor access to survey regions, and countless others, predictive modelling has the potential to identify more robust archaeological landscapes. Using ArcGIS 10.6, ENVI 5.4, and WorldView 2 and 3 imagery, we catalog 22 prospective archaeological sites within a 5 km radius of Bosutswe (100 sq. km), demonstrating the potential for image classification to identify sites difficult to locate in a traditional pedestrian survey. The discovery of these new, often small sites has implications for past environmental utilization and for regional sociopolitical dynamics. We describe our test excavation at one new site, Letlalolanoga, to demonstrate how it may contribute towards a growing body of literature that favors heterarchical power relations within African complex societies.

Isotopic perspectives on pastoralist mobility in the Late Bronze Age South Caucasus Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Hannah Chazin, Gwyneth W. Gordon, Kelly J. Knudson Abstract Isotopic methods of studying the geographic and seasonal movements of herd animals provide new data pertinent to ongoing scholarly re-consideration of the relationships between pastoralist mobility and the development of new forms of political organization. Radiogenic strontium and mass-dependent oxygen and carbon isotope analysis on a large sample of herd animals (sheep, goats, and cattle) from Late Bronze Age (1500–1100 BC) sites in the Tsaghkahovit Plain, Armenia indicate that long-distance movements across geological zones were not common, but that animals were drinking from a range of water sources. Connecting this variation to movement is complicated by limited intra-tooth variation in δ13C values. Data from the study provide preliminary evidence for foddering. These results reveal a gap between the emphasis on mobility in theoretical models of pastoralism and political organization and the way that animal diets mediate isotopic proxies for movement. These interpretive difficulties emphasize the need to consider herds' seasonal and geographic movement within a wider range of pastoralist practices. These findings also highlight the need for large sample sizes in isotopic investigations of pastoralist mobility, in order to accurately identify and evaluate the diversity in both geographic and seasonal movements within a single ancient pastoralist system.

Navigating the ancient Tigris – insights into water management in an early state Publication date: June 2019 Source: Journal of Anthropological Archaeology, Volume 54 Author(s): Stephanie Rost Abstract This paper offers the first detailed investigation of water management in pre-classical antiquity based on primary sources. The importance of water management for ancient societies can hardly be overstated, as many of the earliest civilizations emerged in large river valleys (Nile, Euphrates and Tigris, Indus, Yellow and Yangtze river). More importantly many of those early civilizations occupied the reach of the river, which was located in the arid/semi-arid zone, by which rivers vital sources of water, in particular for irrigation. Many studies on ancient water management have focused on irrigation, often failing to recognize the full extent to which rivers were managed and utilized. The water management scheme of late 3rd millennium Southern Mesopotamia, described in this paper, was designed to not only serve irrigation, but equally navigation and flood control. It combined the manipulation of water levels with the diligent observation and maneuvering of water masses of the ancient Tigris, by which the otherwise conflicting demands of irrigation, navigation and flood control could be reconciled. The written sources used in this study allowed to describe this water control system in great detail and is a testimony to remarkable ancient hydraulic engineering as early as the 3rd Millennium BC.

Voice

Effect of Dysphonia and Cognitive-Perceptual Listener Strategies on Speech Intelligibility Publication date: Available online 25 April 2019 Source: Journal of Voice Author(s): Connie K. Porcaro, Paul M. Evitts, Nicole King, Cassandra Hood, Erin Campbell, Layla White, Jacqueline Veraguas ABSTRACT There is a high prevalence of dysphonia among professional voice users and the impact of the disordered voice on the speaker is well documented. However, there is minimal research on the impact of the disordered voice on the listener. Considering that professional voice users include teachers and air-traffic controllers, among others, it is imperative to determine the impact of a disordered voice on the listener. To address this, the objectives of the current study included: (1) determine whether there are differences in speech intelligibility between individuals with healthy voices and those with dysphonia; (2) understand whether cognitive-perceptual strategies increase speech intelligibility for dysphonic speakers; and (3) determine the relationship between subjective voice quality ratings and speech intelligibility. Sentence stimuli were recorded from 12 speakers with dysphonia and four age- and gender-matched typical, healthy speakers and presented to 129 healthy listeners divided into one of three strategy groups (ie, control, acknowledgement, and listener strategies). Four expert raters also completed a perceptual voice assessment using the Consensus Assessment Perceptual Evaluation of Voice for each speaker. Results indicated that dysphonic voices were significantly less intelligible than healthy voices (P≤ 0.001) and the use of cognitive-perceptual strategies provided to the listener did not significantly improve speech intelligibility scores (P = 0.602). Using the subjective voice quality ratings, regression analysis found that breathiness was able to predict 41% of the variance associated with number of errors (P = 0.008). Overall results of the study suggest that speakers with dysphonia demonstrate reduced speech intelligibility and that providing the listener with specific strategies may not result in improved intelligibility.

The Effectiveness of Vocal Hygiene Education for Decreasing At-Risk Vocal Behaviors in Vocal Performers Publication date: Available online 25 April 2019 Source: Journal of Voice Author(s): Fran Pomaville, Kristi Tekerlek, Anthony Radford Summary This study examined the knowledge gained and behavioral changes made by vocal performers after attending a vocal hygiene education program. A single-group, pretest-posttest research design was utilized to examine the improvement of voice care knowledge and decrease of phonotraumatic behaviors in vocal performers. Data analysis involved a comparison of pretest and posttest responses from an online questionnaire. A paired sample t test revealed a statistically significant improvement in the participants' knowledge regarding the larynx, voice production, and vocal hygiene. In addition, a behavioral inventory revealed improved hydration habits, decreased caffeine and alcohol intake, and healthier responses to symptoms of throat irritation or vocal fatigue. The findings from this study will contribute to evidence regarding the benefits of having vocal performers attend a vocal hygiene education program in order to increase their knowledge about voice production and care, decrease at-risk vocal behaviors, and improve healthy vocal practices.

Normative Value of SVHI-10. Systematic Review and Meta-Analysis Publication date: Available online 25 April 2019 Source: Journal of Voice Author(s): Maria Sobol, Ewelina M. Sielska-Badurek, Anna Rzepakowska, Ewa Osuch-Wójcikiewicz Summary Objective The study aimed to determine the normative value of SVHI-10. Study Design The study is a systematic review and a meta-analysis. Methods A systematic literature search was performed using PubMed and ScienceDirect to access relevant databases and to locate outcome studies. Eligibility criteria included type of publication, participant characteristics, and report of outcomes. Data analysis was conducted using the meta-analysis method. Results Six articles were included for the final analysis. The normative values for the SVHI-10 for a group of 528 subjects were 8.38 with confidence levels of 7.43–9.34 (age range 16–83). Conclusions Based on the results of the meta-analysis the SVHI-10 can be used as a screening tool for a group of singers. In the future, it would be worthwhile to carry out a subordinate analysis to determine the SVHI-10 range for mild voice disorders or severe voice disorders in singing.

Morphology, Vibratory Function, and Vascular Pattern for Predicting Malignancy in Vocal Fold Leukoplakia Publication date: Available online 19 April 2019 Source: Journal of Voice Author(s): Anna Rzepakowska, Maria Sobol, Ewelina Sielska-Badurek, Kazimierz Niemczyk, Ewa Osuch-Wójcikiewicz Summary Background The study evaluates clinical features of vocal fold (VF) leukoplakia in predicting its benign or malignant nature. Materials 57 patients with 84 lesions were evaluated before undergoing laryngeal microsurgery. The texture, color, thickness and size of the leukoplakia, along with an assessment of the surrounding mucosa vascularization using narrow-band imaging (NBI), and VF vibratory function were analyzed. Receiver-operating characteristic curves were constructed to determine the predictive value of each feature and area under the curve (AUC) was calculated. Results Histopathological examination revealed high-grade dysplasia or invasive cancer in 13 of VF leukoplakia. Seventy-one lesions were nondysplastic or low-grade dysplasia. Nonhomogenous color, irregular texture, and prominent thickness predicted malignancy with statistical significance (P < 0.05). AUC was 0.793, 0.793, and 0.679, respectively. Absence of a mucosal wave on laryngovideostroboscopy was significant for the detection of malignancy (P < 0.001) with an AUC of 0.927. The NBI diagnosis of horizontal vessel loops was significant with the highest AUC of 0.993. Conclusions The comprehensive clinical evaluation of VF leukoplakia with laryngovideostroboscopy and NBI creates the opportunity to differentiate between low- and high-risk malignancy lesions. The perpendicular vascular pattern and the limited or absent mucosal wave appear to be the most powerful indicators of malignancy.

A Very Rare Complication of Hyaluronic Acid Injection for Medialization Laryngoplasty: A Case With Laryngeal Abscess Publication date: Available online 17 April 2019 Source: Journal of Voice Author(s): Necati Enver, Orhan Asya, Ghazi Abuzaid, Ece Gürol Summary Hyaluronic acid injection for medialization laryngoplasty is a safe procedure performed on patients with glottic incompetence. Laryngeal abscess formation as a complication of injection laryngoplasty is a very rare complication, and, as we know from the literature, there has been only one case of laryngeal abscess after injection laryngoplasty in a patient with a type-I laryngeal cleft. We document for the first time a laryngeal abscess resulting from hyaluronic acid injection laryngoplasty for unilateral vocal fold paralysis. Prompt evaluation of the patient was necessary. Our patient was treated with antibiotics and corticosteroids without a need for intubation. One year after injection, the patient's Voice Handicap Index-10 score was still good and within the range of normal values.

Efficacy of Videostroboscopy and High-Speed Videoendoscopy to Obtain Functional Outcomes From Perioperative Ratings in Patients With Vocal Fold Mass Lesions Publication date: Available online 17 April 2019 Source: Journal of Voice Author(s): Maria E. Powell, Dimitar D. Deliyski, Steven M. Zeitels, James A. Burns, Robert E. Hillman, Terri Treman Gerlach, Daryush D. Mehta Summary Objectives A major limitation of comparing the efficacy of videostroboscopy (VS) and high-speed videoendoscopy (HSV) is the lack of an objective reference by which to compare the functional assessment ratings of the two techniques. For patients with vocal fold mass lesions, intraoperative measures of lesion size and depth may serve as this objective reference. This study compared the relationships between the pre- to postoperative change in VS and HSV visual-perceptual ratings to intraoperative measures of lesion size and depth. Design Prospective visual-perceptual study with intraoperative measures of lesion size and depth. Methods VS and HSV samples were obtained preoperatively and postoperatively from 28 patients with vocal fold lesions and from 17 vocally healthy controls. Two experienced clinicians rated amplitude, mucosal wave, vertical phase difference, left-right phase asymmetry, and vocal fold edge on a visual-analog scale using both imaging techniques. The change in perioperative ratings from VS and HSV was compared between groups and correlated to intraoperative measures of lesion size and depth. Results HSV was as reliable as VS for ratings of amplitude and edge, and substantially more reliable for ratings of mucosal wave and left-right phase asymmetry. Both VS and HSV had mild-moderate correlations between change in perioperative ratings and intraoperative measures of lesion area. Change in function could be obtained in more patients and for more parameters using HSV than VS. Group differences were noted for postoperative ratings of amplitude and edge; however, these differences were within one level of the visual-perceptual rating scale. The presence of asynchronicity in VS recordings renders vibratory features either uninterpretable or potentially distorted and thus should not be rated. Conclusions Amplitude and edge are robust vibratory measures for perioperative functional assessment, regardless of imaging modality. HSV is indicated for evaluation of subepithelial lesions or if asynchronicity is present in the VS image sequence.

Acoustic Voice Quality Index and Acoustic Breathiness Index: Analysis With Different Speech Material in the Brazilian Portuguese Publication date: Available online 17 April 2019 Source: Journal of Voice Author(s): Marina Englert, Livia Lima, Mara Behlau Summary Objective To analyze the Acoustic Voice Quality Index (AVQI) and the Acoustic Breathiness Index (ABI) concurrent validity and diagnostic accuracy with different speech materials. Methods Voices of 53 subjects (40 dysphonic; 13 vocally health) were recorded: vowel /a/ + counting numbers 1–20 (42 syllables) + reading text (138 syllables). Numbers and text were edited in order to achieve 3 seconds of voiced segments, such as the vowel /a/ (average of 18.81 and 32.49 syllables; confidence interval of 1.87 and 2.30). The audio files were edited to have 17 syllables for numbers and 32 for text. Three voice specialists perceptually judge the overall voice quality (G) and the breathiness (B). AVQI's and ABI's precision and concurrent validity were assessed. Results The intra- and inter-rater reliability were high. Reading text presented higher concurrent validity (r) than automatic speech and excellent area under the receiver-operating characteristic curve for AVQI (0.963) and ABI (0.929). Counting numbers presented good area under the receiver-operating characteristic curve for AVQI (0.870) and excellent for ABI (0.924). Counting numbers produced higher sensitivity for ABI (95.2%) and reading text higher specificity for both indexes (AVQI = 100%; ABI = 90.90%). Reading text presented higher AVQI and ABI scores than numbers, therefore, reading seems to reveal more vocal deviations; however, perceptual judgment can be similar in both samples. Conclusions Different speech materials may impact acoustic outcomes and certain voice characteristics may not be evident. Reading text offers higher diagnostic accuracy. Clinician and/or researchers must select and standardize the speech sample according to their goals.

Association Between Subglottic Pressure and Pulmonary Function in Individuals With Parkinson's Disease Publication date: Available online 16 April 2019 Source: Journal of Voice Author(s): Adrián Castillo, Javiera Castillo, Alvaro Reyes Summary Introduction In individuals with Parkinson's disease (PD), pulmonary complication such as weakness and rigidity of respiratory muscles and reduced cough airflow may be associated with reduced voice production due to limited pulmonary capacity and reduced airflow needed to vibrate the vocal folds. It is not clear, however, which pulmonary function parameter is determinant in the association with peak subglottic pressure (SGP). Therefore, the purpose of this study was to determine the association between peak SGP and pulmonary function parameters in individuals with PD. Methods Forty-two individuals with diagnosis of idiopathic PD of both genders were recruited in the study. Mean and peak SGP, spirometric indices, maximum inspiratory pressure, maximum expiratory pressure (MEP), and peak cough flow (PCF) during reflex and voluntary cough were measured on all participants. Results The analysis revealed that peak SGP had a moderate but significant linear association with MEP (r = 0.38; P = 0.013), voluntary (r = 0.31; P = 0.051), and reflex PCF (r = 0.40; P = 0.012), but not with maximum inspiratory pressure (r = 0.23; P = 0.145). Higher values in peak SGP were associated with higher values in MEP, voluntary PCF, and reflex PCF. No linear association was detected between peak SGP and spirometric indices. Conclusions Peak SGP has a direct association with voluntary and reflex PCF, and expiratory muscle strength, but not with inspiratory muscle strength. The association with peak SGP is higher for reflex PCF than for voluntary PCF.

Longitudinal Case Study of Transgender Voice Changes Under Testosterone Hormone Therapy Publication date: Available online 13 April 2019 Source: Journal of Voice Author(s): Gabriel J. Cler, Victoria S. McKenna, Kimberly L. Dahl, Cara E. Stepp Abstract The purpose of this study was to comprehensively evaluate voice and speech changes in one healthy 30-year-old transgender male undergoing testosterone therapy for transition. Testing occurred at three timepoints before cross-sex hormone therapy and every 2 weeks thereafter for 1 year. Data collected included measures of acoustics, aerodynamics, and laryngeal structure and function via flexible laryngoscopy. Analysis included acoustic correlates of pitch, loudness, voice quality, and vocal tract length, as well as perceptual measures of voice quality and gender. Speaking fundamental frequency (fo) lowered from 183 Hz to 134 Hz. Phonatory frequency range (ie, minimum and maximum singing range) shifted from a range of D#3–E6 to a range of A2–A5. Perceptual measures of voice quality indicated no negative changes. Naïve listeners reliably rated the participant's speech samples as male after 37 weeks on testosterone. Few studies document in detail the variety of voice changes that occur during cross-sex hormone therapy, focusing instead on fo alone. This study adds to the literature a comprehensive case study of speech and voice changes experienced by one transmasculine participant undergoing testosterone therapy.

The Prevalence of Dysphonia and Dysphagia in Patients with Vitamin D Deficiency Publication date: Available online 12 April 2019 Source: Journal of Voice Author(s): Abdul-Latif Hamdan, Elie Khalifee, Nader Al Souky, Bakr Saridar, Pierre Richard Abi Akl, Anthony Ghanem, Sami Azar Abstract Objective To investigate the prevalence of phonatory and swallowing symptoms in patients with hypovitaminosis D. Methods/Design All patients presenting to the endocrinology clinic and investigated for vitamin D deficiency between January 2018 and April 2018 were asked to participate in this study. Demographic data included age, gender, allergy, and history of smoking. Patients filled Voice handicap Index (VHI-10) and Eating Assessment Tool (EAT-10). Results A total of 136 consecutive subjects presenting to the endocrinology clinic for vitamin D testing were included: 60 with hypovitaminosis D and 76 with no hypovitaminosis D. The mean vitamin D level in the study group and controls was 13.25 ng/mL and 31.91 ng/mL, respectively. There was no significant difference in the mean score of VHI-10, nor in the mean score of EAT-10 in patients with hypovitaminosis D versus those with no hypovitaminosis D (P value >0.05). Conclusion There was no significant difference in the prevalence of phonatory and dysphagia symptoms using VHI-10 and EAT-10 questionnaires between subjects with hypovitaminosis D and those with normal serum vitamin D levels.