Chemo- and bio-informatics insight into anti-cholinesterase potentials of berries and leaves of Myrtus communis L., Myrtaceae: an in vitro/in silico study.

BACKGROUND: Myrtus communis L. (MC) has been used in Mesopotamian medicine. Here, the cholinesterase (ChE) inhibitory potential of its methyl alcohol extracts has been investigated and computationally dissected. METHOD: The ChE inhibition has been measured based on usual Ellman's colorimetric method compared to a canonical ChE inhibitor, eserine. Through a deep text mining, the structures of phytocompounds (= ligands) of MC were curated from ChemSpider, PubChem, and ZINC databases and docked into protein targets, AChE (PDB 1EVE) and BChE (PDB 1P0I) after initial in silico preparedness and binding affinity (BA; kcal/mol) reported as an endpoint. The calculation of ADMET (absorption, distribution, metabolism, excretion, and toxicity) features of phytocompounds were retrieved from SwissADME ( http://www.swissadme.ch/ ) and admetSAR software to predict the drug-likeness or lead-likeness fitness. The Toxtree v2.5.1, software platforms ( http://toxtree.sourceforge.net/ ) have been used to predict the class of toxicity of phytocompounds. The STITCH platform ( http://stitch.embl.de ) has been employed to predict ChE-chemicals interactions. RESULTS: The possible inhibitory activities of AChE of extracts of leaves and berries were 37.33 and 70.00%, respectively as compared to that of eserine while inhibitory BChE activities of extracts of leaves and berries of MC were 19.00 and 50.67%, respectively as compared to that of eserine. Phytochemicals of MC had BA towards AChE ranging from -7.1 (carvacrol) to -9.9 (ellagic acid) kcal/mol. In this regard, alpha-bulnesene, (Z)-gamma-Bisabolene, and beta-bourbonene were top-listed low toxic binders of AChE, and (Z)-gamma-bisabolene was a more specific AChE binder. Alpha-cadinol, estragole, humulene epoxide II, (a)esculin, ellagic acid, patuletin, juniper camphor, linalyl anthranilate, and spathulenol were high class (Class III) toxic substances which among others, patuletin and alpha-cadinol were more specific AChE binders. Among intermediate class (Class II) toxic substances, beta-chamigrene was a more specific AChE binder while semimyrtucommulone and myrtucommulone A were more specific BChE binders. CONCLUSION: In sum, the AChE binders derived from MC were categorized mostly as antiinsectants (e.g., patuletin and alpha-cardinal) due to their predicted toxic classes. It seems that structural amendment and stereoselective synthesis like adding sulphonate or sulphamate groups to these phytocompounds may make them more suitable candidates for considering in preclinical investigations of Alzheimer's disease.

An overview of the effect of medicinal herbs on pain.

This paper is typically intended to carefully collect and properly review the antinociceptive activities of medicinal plants. In this review article, by searching keywords of medicinal plants, pain, herbal medicine, antinociceptive, phytotherapy in databases of Web of Science, Scopus, Google Scholar, Springer, Wiley, Proquest, PubMed, Nature, Magiran, Emerald, SID, ISI, and some other indexing cites, or traditional books, desired articles were obtained until 2021. The title of medicinal plants was searched diligently in Persian and English. Ultimately, 270 articles were studied. The findings possibly indicated that several medicinal plants are among the most valuable plants that have antinociceptive activities. There efficiently are various antinociceptive compounds in medicinal plants. The antinociceptive activity of these specific compounds may be through their peculiar effects on the opioid system, cholinergic pathways, and stimulation of GABA receptors, with the peripheral and central antinociceptive mechanism. Antiinflammatory processes, inhibition of the synthesis, and the release of arachidonic acid, prostaglandins, phospholipase, nitric oxide, and cyclooxygenase-2 have been reported as analgesic mechanisms of some herbs. In a reasonable conclusion, our review thoughtfully provides a comprehensive summary of present data from some scientific studies on the common herbs with antinociceptive and antiinflammatory activities.

Activation of androgen receptors alters hippocampal synaptic plasticity and memory retention through modulation of L-type calcium channels.

AIMS: It has been revealed that membrane androgen receptor activation modulates avoidance memory and synaptic plasticity. In a previous study, we showed that Calcineurin, a calcium dependent phosphatase, could be a potential mediator of these AR effects. Also, it is reported that AR activation leads to L-type calcium channel activation. The aim of the current study is to test whether L-type calcium channels are downstream of AR and whether this signal pathway mediates the impairment effect of androgenic steroids on passive avoidance memory and synaptic plasticity. MATERIALS AND METHODS: We measured the effect of Nandrolone Decanoate (AR agonist), AR antagonist (Nilutamide) plus ND or L-type calcium channel inhibitor (Nifedipine) plus ND on passive avoidance performance of adolescent male rats. For extracellular field potential recordings hippocampal slices were perfused with ND, Nilutamide-ND or Nifedipine-ND. KEY FINDINGS: Our results clarified that AR activation by ND could impair avoidance behavior as step through latency decreased in ND-treated group while application of both Nilutamide and Nifedipine reestablished normal avoidance behavior. Also, LTP induction in the CA1 area of hippocampus was diminished by ND perfusion and both AR antagonist and L-type calcium channel inhibitor application lead to normal LTP. These findings support our hypothesis that activation of L-type calcium channels are involved in ARs mechanism effects on both avoidance behavior and hippocampal synaptic plasticity. SIGNIFICANCE: Understanding the biological effects of AR agonists on cognitive processes and its cellular mechanism may be a new/supplementary way to treating fear-related disorders.

The effects of Ibuprofen and 1, 8- cineol on anxiety and spatial memory in hyperammonemic rats.

In hepatic encephalopathy, hyperammonemia (HA) causes cognitive impairment and anxiety by causing neuroinflammation. Ibuprofen and 1,8- cineol have anti-inflammatory and antioxidant properties, respectively. The aim of this study was to evaluate the effects of ibuprofen alone and in combination with 1,8- cineol on anxiety and oxidative stress in a HA rat animal model. For this purpose, 36 rats were divided into six groups (n = 6) including the HA (received intraperitoneally (IP) ammonium acetate 2.5 mg/kg for four week), ibuprofen (induced HA rats that received 15 mg/kg, IP), cineol (induced HA rats that received 5 and 10 mg/kg, IP), Ib + cineol (induced HA rats that received 15 and 10 mg/kg, respectively, IP), and the control groups (received normal saline, IP). Except the HA group, all other groups received the aforementioned treatment for two weeks.. The Morris water maze and elevated plus maze were used to assess cognitive function and anxiety in the animals, respectively. Superoxide dismutase (SOD) activity was measured to evaluate oxidative stress. The mRNA expression levels of interleukin (IL)-6 and IL-1ß was assessed by real-time PCR in the animal's brain. The results showed a significant improvement in spatial memory and anxiety of the Ib group compared to the HA group (P < 0.01), but no significant change was observed in SOD activity (P > 0.05). There was a significant improvement in spatial memory and anxiety as well as a significant increase in SOD activity in the Ib + cineol group (P < 0.01) compared to the HA group. These results indicate that the Ib + cineol, not only improve cognitive function and reduce anxiety, also reduce oxidative stress, therefore, the simultaneous use of these two compounds may be useful in improving HA-induced cognitive disorders and anxiety.

In vitro cholinesterase inhibitory action of Cannabis sativa L. Cannabaceae and in silico study of its selected phytocompounds.

Cannabis sativa L. Cannabaceae, used for psychoactive rituals in Mesopotamia. Here, we investigated in vitro inhibitory activity of methyl alcohol extract derived from leaves and resin of cannabis against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Moreover, the binding affinity (BA; kcal/mol) of selected phytochemicals of cannabis to AChE and BChE has been predicted in silico. Phytochemicals of cannabis had acceptable BA towards AChE ranging from - 6.4 (beta-pinene) to - 11.4 (campesterol) and BChE ranging from - 5.5 (alpha-pinene) to - 9.8 (cannabioxepane). All cannabinoids, flavonoids (apigenin), terpenes, and phytosterols of cannabis were double inhibitors due they utilized hydrogen bonds and hydrophobically interacted with both catalytic triad and peripheral anionic site (PAS) of AChE and BChE. Campesterol is phytosterol docked with AChE and BChE via hydrogen bond and it will be a lead-like molecule for further drug design. Delta-9-Tetrahydrocannabinolic acid has been docked with AChE and BChE and it can be a candidate molecule for further drug design. To sum up, this study not only approved cholinesterase inhibitory effects of cannabis but also suggested an array of phytocompounds as hit small molecules for discovery or design of ecofriendly botanical antiinsectants or phytonootropic drugs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00075-0.

Molecular docking study of lignanamides from Cannabis sativa against P-glycoprotein.

P-glycoprotein (P-gp), which was first identified in cancer cells, is an ATP-dependent efflux transporter that expels a wide variety of cytotoxic compounds out of cells. This transporter can decrease the bioavailability of therapeutic drugs by preventing their sufficient intracellular accumulation. Over expression of P-gp in cancer cells lead to multidrug resistance (MDR) phenotype that is one of the main reasons for the failure of chemotherapy. Hence, P-gp inhibition is a favorable method to reverse MDR. In this study, the lignanamides from Cannabis sativa were docked against P-gp to recognize potential binding affinities of these phytochemicals. Tariquidar and zosuquidar, two well-known P-gp inhibitors, were selected as the control ligands. It was observed that cannabisin M and cannabisin N exhibited higher binding affinities (- 10.2 kcal/mol) to drug-binding pocket of P-gp when compared with tariquidar and zosuquidar that showed binding affinities of - 10.1 and - 9.6 kcal/mol, respectively. Based on these findings, cannabisin M and cannabisin N could be good drug candidates against P-gp.

Inflammation, oxidative stress, insulin resistance, and hypertension as mediators for adverse effects of obesity on the brain: A review.

Nowadays, the incidence of obesity is a global challenge and it is estimated that the total number of overweight and obese adults will increase up to 1.35 billion by 2030. Evidence obtained from clinical and experimental studies shows that obesity may be associated with cognitive performance and executive function impairments. Considering various evidence for the poor episodic memory tasks and verbal learning as well as the destruction of cortical gray matter in the obese individuals, here, we collected some causal pathways for contribution of inflammation, oxidative stress, insulin resistance, and hypertension in the development of brain disorders in obesity. The present study focuses on the providing an overview of the some negative effects of obesity on the brain. Different evidence mentioned in this review has thrown light on the obesity-associated complications which may predispose obese people to brain damage, dementia, and Alzheimer's disease.

Effects of Salvia officinalis L. (common sage) leaves tea on insulin resistance, lipid profile, and oxidative stress in rats with polycystic ovary: An experimental study.

OBJECTIVE: Oxidative stress conditions and metabolic complications are common among polycystic ovary syndrome (PCOS) patients. There are various reports about hypoglycemic and antioxidant effects of Salvia officinalis L. (common sage). This study evaluated the possible medicinal effects of sage tea drinking on oxidative status, lipid profile, and insulin resistance in rats with testosterone-induced PCOS. MATERIALS AND METHODS: Eighteen immature female Wistar rats (21-day old) were divided into 3 groups: 1) The Control group (n=6) that received no treatment. 2) The PCOS group (n=6) that received testosterone enanthate 10 mg/kg BW for 35 days subcutaneously. (3) The PCOS -sage tea group (n=6) to which after induction of PCOS by injection of testosterone enanthate, the sage tea was administered as a replacement of water for 14 days. The beverages were refreshed every day. The serum levels of total antioxidant capacity (TAC), malondialdehyde (MDA), glucose, insulin, HDL-C, total cholesterol, LDL-C, VLDL-C, total triglycerides, and atherogenic index were measured. RESULTS: Sage tea consumption increased serum TAC and decreased serum HDL-C, glucose, total cholesterol, LDL-C, and atherogenic index levels but it did not change the levels of MDA, insulin, total triglycerides, and VLDL-C. CONCLUSION: Results suggested that sage tea consumption may influence the oxidative status and reduce the blood glucose and atherogenic index and may have cardiovascular protective effects in PCOS women.

Computational insight to putative anti-acetylcholinesterase activity of Commiphora myrrha (Nees), Engler, Burseraceae: a lessen of archaeopharmacology from Mesopotamian Medicine I.

Commiphora spp., Burseraceae family and their resinous matter, myrrh, are used in Mesopotamian medicine as fragrance or antiinsectant. Based on in vitro, leaves, bark, and resin methyl alcohol extract of C. myrrha showed similar inhibitory effects of 17.00, 26.00, and 29.33% for acetylcholinesterase (AChE) as compared to eserine, respectively. The ADMET properties and putative anticholinesterase activity of phytochemicals of myrrh were computationally predicted using in silico tools. Phytochemicals of C. myrrha had acceptable binding affinity (BA) towards principal sites of AChE ranging from - 5.8 (m-cresol) to - 10.5 (abietic acid) kcal/mol. In this regard, all terpenoid compounds (25 out of 28) of myrrh were dual inhibitors since they hydrophobically interacted with both catalytic triad and peripheral anionic site (PAS) of AChE while alpha-terpineol, elemol, and eugenol employed hydrogen bonds with AChE. Cuscohygrine as a pyrrolidine alkaloid has been docked with AChE through hydrogen bonds with PAS and through hydrophobic interactions with catalytic triad thereby we initially proposed it as dual inhibitor of AChE. M-cresol as a methylphenol has been loosely docked with AChE via hydrogen bond and would be a hit molecule for further drug synthesis. This study not only confirmed archaeopharmacological applications of myrrh as antiinsectant or nootropics but also offered an array of terpenoid compounds, cuscohygrine, and m-cresol as a good starting point for hit-to-lead-to-drug optimization phase in synthesis of phyto-nootropics and ecofriendly insecticides.

Inhibition of Airway Contraction and Inflammation by Pomalidomide in a Male Wistar Rat Model of Ovalbumin-induced Asthma.

Asthma is a chronic inflammatory disease of the airways of the lungs. Pomalidomide (POM) a therapy for multiple myeloma has been stated to have an anti-inflammatory effect. The main goal of the present study was to assess its possible effect on airway contraction and inflammation in a rat model of ovalbumin-induced asthma. Different groups of rats received saline or pomalidomide (0.4, 0.8 mg/kg) or dexamethasone (0.6 mg/kg). The asthma was induced by ovalbumin (OVA). Trachea contraction was assayed by organ bath system. Airway histology was assessed using hematoxylin and eosin method. Serum Tumor necrosis factor alpha (TNF-α) level was analyzed by Enzyme-Linked Immunosorbent Assay and Platelet-derived growth factor (PDGFα) Gene expressions were evaluated by Real-time PCR. Pomalidomide prevented ovalbumin-induced airway contraction and histopathological damage. In addition serum, TNF-α level was significantly (p<0.05) decreased in POM treated animals compared to control (asthmatic animals that received POM vehicle). Results indicate that POM prevented the PDGF expression induced by ovalbumin. In conclusion, we found that pomalidomide ameliorated the symptoms, histopathological changes and inflammatory markers induced by ovalbumin in asthmatic rats and these effects might be related to its anti-inflammatory properties.

Impact of morphine dependency and detoxification by methadone on male's rat reproductive system.

BACKGROUND: One of the problems that addicts suffer from is decreased libido. Erectile dysfunction has been reported in men using opioids for treatment of heroin addiction. OBJECTIVE: The study was performed to investigate the effects of morphine and detoxification with methadone as causes of sexual dysfunction in addiction. METHODS AND METHODS: A total of 40 adult male rats (Wistar) were used. Animals were divided in to 4 groups. Control groups received saline for 30 days. Other 2 groups received 10 mg/kg morphine on day 1 and the morphine doses increased daily by 2 mg/kg increments per day until in day 30 a maximum of 68 mg/kg twice daily was achieved. Withdrawal syndrome sings were evaluated. At the end of period, one group of 2 morphine dependent groups was treated with methadone during 14 days. Animals in group 4 (saline solution+ methadone) received saline for 30 consecutive days and then detoxified with methadone during 14 days. Partial weights of seminal vesicles, testes, prostates, seminal vesicles content, concentrations of luteinizing hormone, follicle stimulating hormone, and testosterone in serum were determined. RESULTS: In the dependent group serum levels of testosterone (p<0.001), folicle stimulating hormone (p=0.0097) and luteinizing hormone (p=0.0031) as well as the weights of testes (p=0.0051), partial weights of prostates, seminal vesicles and seminal vesicles contents (p<0.001) were reduced as compared with control group. In the morphine dependent animals detoxified with methadone, testosterone concentrations and seminal vesicles contents remained lower than levels in the control group (p<0.001). CONCLUSION: The results suggest that morphine dependence may impair the reproductive function in male rats.

Effect of exogenous testosterone, finasteride, and castration on serum level of thyroxin.

BACKGROUND: The secretion of thyroxin (T4) as the main hormone of thyroid gland is regulated by androgens. The present study aimed to evaluate the effect of testosterone and finasteride administration and castration on serum levels of T4 and to show the effect of this regulation on total body weight, weight of testis, and the weight of prostate. METHODS: Male adult rats (n = 32) were divided into 4 groups (n = 8): Group 1 (control), Group 2 (castration), Group 3 (finasteride: 20 mg/kg/day) and Group 4 (testosterone: 5 mg/kg/day). At the end of the study (35 days), serum level of thyroxin, body weight, weight of testis, and prostate were determined. RESULTS: The data showed that the body weight increased in castrated (P = 0.04) and decreased in testosterone (P = 0.00) groups but did not differ in finasteride (P>0.05) group. There were not any differences in the weight of testis among control, finasteride, and testosterone groups but the weight of prostate increased in testosterone group (P = 0.00) and decreased in castrated (P = 0.03) and finasteride groups (P = 0.04). In addition, the serum level of T4 (nmo/ml) decreased in the three groups: finasteride (P = 0.03), testosterone (P = 0.04), and castrated (P = 0.00). CONCLUSION: Testosterone in both high and low levels decreased the amount of T4 with a time-dependent manner.

Exogenous testosterone, finasteride and castration effects on testosterone, insulin, zinc and chromium in adult male rats.

BACKGROUND: Although effects of trace elements on secretion of sex steroids and insulin have been studied, the effects of these hormones on serum level of trace elements have been rarely investigated. The aim of the present study was to evaluate the effect of testosterone and finasteride administration and castration on serum levels of testosterone, insulin, zinc and chromium. METHODS: Male adult rats (n = 32) were divided into 4 groups (n = 8). Group 1, control; Group 2, castration, castration was done at the first day of the study; Group 3, finasteride (20 mg/kg/day, dissolved in drinking water) and Group 4, testosterone (5 mg/kg/day, i.p.). At the end of the period of the study (35 days), serum testosterone, insulin, zinc and chromium levels were determined in the blood samples collected directly from the right atrium of the heart of the animals. RESULTS: The data indicated that the serum levels of testosterone, insulin and zinc were significantly increased (P<0.01) in testosterone-administrated and finasteride groups, but the level of chromium was decreased in both groups (P<0.01). Castrated group had the lowest serum levels of testosterone, insulin and zinc (P<0.05). Also, the levels of serum chromium in this group were increased. CONCLUSION: The study demonstrates that testosterone and finasteride increases insulin and zinc levels and decreases chromium levels in the serum of male adult rats. According to these data, it seems that testosterone may affect glucose cycle through effect on serum insulin levels and trace elements such as zinc and chromium.

The enhancing effects of alcoholic extract of Nigella sativa seed on fertility potential, plasma gonadotropins and testosterone in male rats.

BACKGROUND: The task force on plants for fertility regulation in men continued with its program to identify novel prototypes in plants alleged to have fertility regulating properties. Nigella Sativa seeds are frequently used in folk medicine in the Middle East and some Asian countries for the promotion of good health and treatment of many ailments. OBJECTIVE: To evaluated the role of alcoholic extract of Nigella sativa on fertility potential, Pituitary-testicular axis hormones and Testosterone in male rats. MATERIALS AND METHODS: 24 male rats were randomly divided into 3 groups; control, group A and group B, each group comprising of 8 rats. Animals in control group received 1 ml of normal saline and treatment groups (A and B) received (gavage) graded doses of 200 and 400 mg/kg body weight of alcoholic extract of Nigella sativa seeds on a daily basis for 60 days. At the end of treatment period, fertility parameters such as body and reproductive organs weight, sperm motility, viability and count, epididymal sperm reserve (ESR), daily sperm production (DSP), blood testosterone concentration, Gonadotropins levels and fertility index were measured. RESULTS: There was a significant difference in testes and epididymidis weight, sperm count, ESR, DSP, blood testosterone concentration, LH and fertility index in both the lower dose group and the higher group as compared to the control group. CONCLUSION: The results of this study showed that alcoholic extract of Nigella sativa seed especially in higher doses could increase fertility potential, LH and testosterone concentration in male rats.