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.



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