Eryngium billardieri extract affects cardiac gene expression of master regulators of cardiomyaopathy in rats with high fatdiet-induced insulin resistance.

BACKGROUND: For years, numerous studies have focused on identifying approaches to increase insulin sensitivity by modifying the signaling factors. In the present study, we examined the effects of Eryngium billardieri extract, as an anti-diabetic herbal medication, on the heart mRNA level of Akt serine/threonine kinase (Akt), mechanistic target of rapamycin kinase (mTOR), peroxisome proliferator-activated receptor gamma (PPARγ), and Forkhead box o1 (Foxo1) in rats with high-fat diet (HFD)-induced insulin resistance (IR). We also assessed the anti-diabetic effects of E. billardieri extract in rats with insulin resistance. METHODS: Twenty-seven male Wistar rats were divided into two groups. Nine rats were fed a normal diet (control group), and 18 rats were fed an HFD for 13 weeks (HFD group). To confirm the induction of insulin resistance, the oral glucose tolerance test (OGTT) was performed and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. Then rats with IR were randomly divided into the following groups: the HFD group, which continued an HFD, and the group treated with E. billardieri extract, which received the extract at a concentration of 50 mg/kg for 30 days. On the 30th day, the animals were sacrificed and serum samples were collected for biochemistry analyses. Furthermore, the expression of Akt, mTOR, PPARγ, and Foxo1 was measured in heart tissue using the real-time polymerase chain reaction (PCR) method. RESULTS: Real-time PCR analyses revealed that an HFD can significantly decrease the expression level of Akt, mTOR, and PPARγ in the heart tissue. However, an HFD significantly increased the expression level of Foxo1 in the HFD group compared to the control group (P < 0.05). In addition, our data showed that the administration of E. billardieri extract significantly enhanced the mRNA levels of Akt, PPARγ, and mTOR in the heart tissue compared to the HFD group (P < 0.05), while it significantly decreased the Foxo1 mRNA levels (P < 0.01). CONCLUSION: Given that Akt, mTOR, PPARγ, and Foxo1 are critical factors in insulin resistance, the present study suggests that E. billardieri could probably be used as an alternative treatment for IR as a major feature of metabolic syndrome.

The effects of Lavandula angustifolia essential oil on analgesic effects and percutaneous absorption of naproxen sodium gel; an in vivo and in vitro study.

The percutaneous bioavailability of naproxen is low and several technologies have been utilized to overcome the problem. Although, some studies have reported the permeation-enhancing properties of natural essential oils, no research has reflected the effectiveness of Lavandula angustifolia essential oil (LAEO) on increasing the percutaneous absorption of naproxen sodium from a topical gel. Therefore, the present study was designed to investigate whether LAEO increased the percutaneous absorption and the analgesic effects of naproxen sodium topical gel. In the present study, naproxen topical gel was formulated using carbopol 940 (a gelling agent) and several vehicles such as PEG 400, ethanol, and water and the properties of gels were measured. Percutaneous absorption-enhancing properties of LAEO were measured too. Based on our data, the essential oil-containing formulation of naproxen represented greater penetration into (222.19 ± 24.87 vs. 107.65 ± 6.38 µg/cm2 ), and also across (22.07 ± 4.42 vs. 13.14 ± 2.87 µg/cm2 ) skin layers compared to the naproxen gel. Additionally, a significant analgesic property was observed in the naproxen topical gel containing 0.5% essential oil during both first and late phases of formalin test, as well as the late phase of tail-flick test. It could be concluded that LAEO significantly enhanced naproxen percutaneous absorption and also its analgesic effects.

Interaction effects of intracerebroventricular injection of crocin with the α2-adrenoceptors on memory deficit and hippocampal synaptic plasticity following chronic pain in rat.

Patients with chronic pain exhibit anxiety and deficits in memory. Additionally, α2-adrenoceptors that are wildly expressed in the brain have an important role in modulating both pain and memory formation. In the present study, we investigated the interaction effects of crocin with central α2-adrenoceptors on pain comorbidity and hippocampal synaptic plasticity changes following chronic constriction injury (CCI) of the sciatic nerve in rats. All the drugs (crocin, an antagonist (yohimbine) and agonist (clonidine) of α2-adrenergic receptors) were injected (via intracerebroventricular injection) from the day of CCI operation (day 0) and continued daily (once per day) until the 14th day post-CCI. The effects of drugs on the cold allodynia (using acetone test) and anxiety-like behaviors (using elevated plus maze, EPM and open field tests) were assessed. Spatial memory (using Barnes maze) was assessed on day 14 post-CCI operation. Hippocampal synaptic plasticity (using in-vivo extracellular field potential recording) was performed on day 14 post-CCI operation. We observed that crocin induced analgesic, anxiolytic and memory enhancer action following CCI surgery. Furthermore, crocin significantly increased long-term potentiation (LTP) (increased fEPSP slope and population spike amplitude). Furthermore, the co-injection of yohimbine effectively decreased analgesic, anxiolytic and enhancer action of crocin on the LTP parameters (fEPSP slope and population spike amplitude). Our study provided information that protective effects of crocin on pain/anxiety responses and synaptic plasticity were possibly mediated by central α2-adrenoceptor in the rats with chronic pain.

Analgesic effects of Terminalia chebula extract are mediated by the suppression of the protein expression of nerve growth factor and nuclear factor-κB in the brain and oxidative markers following neuropathic pain in rats.

BACKGROUND: Due to the complications related to the use of the current pharmacological approach for the alleviation of neuropathic pain, searching for effective compound with fewer complications is a requirement of the present era. It is well known that the pathophysiological mechanism of neuropathic pain is related to excessive inflammation in the nervous system. Hence, the present study focuses on whether the potential analgesic effects of Terminalia chebula (TC) extract are mediated by the changes in the protein expression of nerve growth factor (NGF) and nuclear factor-kappa B (NF-κB) in the brain in a rat model of sciatic nerve chronic constriction injury (CCI). METHOD AND RESULTS: Neuropathic pain was induced by the left sciatic nerve CCI. Male Wistar rats were assigned to three groups: sham, CCI, and CCI + TC (40 mg/kg). Animals received either normal saline (1 mL) or the aqueous-alcoholic extract of TC (40 mg/kg) for 30 days via gavage needles once a day. Cold allodynia and anxiety-like behaviors were examined one day before CCI surgery (day - 1), as well as days 2, 7, 14, and 30 following CCI. We also assessed the effects of the TC extract oxidative stress markers on day 30 following CCI. Moreover, a western blot analysis was performed on day 30 following CCI to evaluate the effects of the TC extract on the protein expression of NGF and NF-κB in the brain. Oral gavage of the TC extract significantly decreased cold allodynia on days 2 and 14 following CCI. Additionally, the CCI model of chronic pain significantly increased the protein expression of NGF and NF-κB in the brain on day 30 following CCI. Furthermore, the TC extract significantly decreased the protein expression of NGF and NF-κB in the brain. The TC extract also significantly increased the brain glutathione (GSH) content and decreased the malondialdehyde (MDA) content. CONCLUSION: It is suggested that the analgesic effects of the TC extract are mediated by the suppression of brain NGF, NF-κB, and by its antioxidant activity in the brain following neuropathic pain in rats.

Y chromosome is moving out of sex determination shadow.

Although sex hormones play a key role in sex differences in susceptibility, severity, outcomes, and response to therapy of different diseases, sex chromosomes are also increasingly recognized as an important factor. Studies demonstrated that the Y chromosome is not a 'genetic wasteland' and can be a useful genetic marker for interpreting various male-specific physiological and pathophysiological characteristics. Y chromosome harbors male­specific genes, which either solely or in cooperation with their X-counterpart, and independent or in conjunction with sex hormones have a considerable impact on basic physiology and disease mechanisms in most or all tissues development. Furthermore, loss of Y chromosome and/or aberrant expression of Y chromosome genes cause sex differences in disease mechanisms. With the launch of the human proteome project (HPP), the association of Y chromosome proteins with pathological conditions has been increasingly explored. In this review, the involvement of Y chromosome genes in male-specific diseases such as prostate cancer and the cases that are more prevalent in men, such as cardiovascular disease, neurological disease, and cancers, has been highlighted. Understanding the molecular mechanisms underlying Y chromosome-related diseases can have a significant impact on the prevention, diagnosis, and treatment of diseases.

The anti-cancer properties of neem (Azadirachta indica) through its antioxidant activity in the liver: its pharmaceutics and toxic dosage forms. A literature review.

OBJECTIVES: The neem (Azadirachta indica) have been used in herbal medicine for the treatment of multiple diseases, particularly cancer. The mechanism of anti-cancer properties of neem are far from clear. However, it is well accepted that anti-cancer effects of neem is mediated via its hepatic anti-oxidant activity. In the present review, we are going to classify in vitro and in vivo studies about anti-cancer activity of neem via its hepatic anti-oxidant activity. We also summarize its active ingredients and some therapeutic and toxic dosage forms. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for neem, A. indica, anti-cancer, anti-tumor, carcinogen, liver, antioxidant activity, neem ingredients, and glutathione. Electronic database searches combined and duplicates were removed. RESULTS: The neem plant have been used in herbal medicine for the treatment of various diseases, particularly cancer. The mechanisms of anti-cancer effects of neem are far from clear. Cancerous cells growth can induce imbalance the oxidant and anti-oxidant activity in various organs particularly in the liver. Therefore, it seems that neem have anti-cancer effects via restore of the antioxidant disturbances close to the control ones in the liver. Additionally, administration of neem extract can induce oncostatic potential via several mechanism including; suppression of the NF-κß pathway, increased expression of tumor suppressor (such as p53 and pTEN), decreased expression of oncogenes (such as c-Myc), and increased apoptosis in cancerous cells. The median lethal dose (LD50) value for extracts of neem was higher than 2,500 mg/kg. CONCLUSIONS: It is suggested that neem plays pivotal role in the prevention and treatment of cancer via its hepatic antioxidant activity. Indeed, application of neem extract can decreased tumor growth via restore of the antioxidant disturbances close to the control ones in the liver.

Anti-diabetic effects of fullerene C60 nanoparticle mediated by its anti-oxidant activity in the pancreas in type 1 diabetic rats

Abstract The present study aims to examine the anti-diabetic effects of fullerene C60 nanoparticle, as an anti-oxidant compound, on serum glucose level, body weight, food and water intake, and pancreatic oxidative stress in the rats with type 1 diabetes. Diabetes mellitus was induced by single intravenous injection of streptozotocine (45 mg/kg) into the tail vein of the rats. Four groups of rats were divided as follow: normal, normal treatment, diabetic, and diabetic treatment groups. Normal treatment and diabetic treatment groups received intra-orally fullerene (1 mg/ kg/daily) up to day 60 following streptozotocine injection. Oxidative stress markers in the pancreas were evaluated on day 60 after inducing diabetes mellitus. Injection of streptozotocine significantly increased serum glucose level as well as food and water intake on all experimental days; it decreased body weight on day 60. Streptozotocine increased MDA level and decreased GSH level and SOD activity in the pancreas. Fullerene significantly decreased food and water intake and increased body weight as compared with the diabetic group. Fullerene also could normalize the pancreatic MDA and GSH markers. The present study suggested that fullerene can decrease diabetic symptoms via its anti-oxidant activity in the pancreas in the rats with type 1 diabetes mellitus.

A Randomized Clinical Trial on Therapeutic Effects of Myrtus communis L. Cream on Chronic Skin Lesions and Quality of Life of Sulfur Mustard-exposed Veterans

Abstract: Sulfur mustard is one of the chemical warfare agent. It rapidly reacts with the cutaneous tissues and other tissues, leading to various devastating long-term effects on human health. Mustard-exposed veterans suffer from its chronic skin problems, including itching, burning sensation, and eczema. We aimed to evaluate the protective effects of Myrtus communis L. (myrtle) on chronic skin lesions and quality of life of sulfur mustard-exposed veterans. In this randomized, double-blind clinical trial, 60 sulfur mustard-exposed patients were evaluated. Thirty patients received myrtle essence 5% cream (case group) and 30 patients received Eucerin cream (placebo group) twice in a day for one month. Then, We assessed the chronic skin problems and itching-related parameters (such as the itching time, severity, distribution, frequency, and calculated itching score), duration of sleep, number of waking up at night, and quality of life in the both groups. Our analysis of data revealed that application of myrtle cream effectively decreased skin problems including; itching and burning sensation. Additionally, myrtle markedly decreased skin lesion symptoms such as excoriation in the case group as compared with before treatment. Noticeably, myrtle cream significantly improved quality of life of the patients in the case group. The present study provides more in-depth information regarding the protective role of myrtle on the sulfur mustard-induces skin complication. Also, myrtle effectively improved quality of life of the sulfur mustard-exposed veterans.

Intracerebroventricular injection of propranolol blocked analgesic and neuroprotective effects of resveratrol following L5 spinal nerve ligation in rat.

OBJECTIVES: Resveratrol as a natural polyphenolic agent can alleviate neuropathic pain symptoms. The mechanism of analgesic activity of resveratrol is far from clear. The current study examine whether analgesic activity of resveratrol is mediated by its neuroprotective and anti-oxidant activity in the neuropathic pain. We further examine whether analgesic activity of resveratrol is mediated by ß-adrenoceptors in the brain. METHODS: Neuropathic pain induced by L5 spinal nerve ligation (SNL). Male Wistar rats assigned into sham, SNL, SNL + resveratrol (40 µg/5 µL), and SNL + resveratrol + propranolol (a non-selective ß-adrenoceptor antagonist, 30 µg/5 µL) groups. Drugs injected intracerebroventricular (ICV) at day SNL surgery and daily for 6 days following SNL. Thermal allodynia and anxiety examined on days of -1, 2, 4, and 6 following SNL. Electrophysiological study performed on day 6 following SNL for evaluation of resveratrol effects on sciatic nerve conduction velocity (NCV). The activity of catalase (Cat) and superoxide dismutase (SOD) enzymes in the brain assessed on days 6 following SNL. RESULTS: Resveratrol significantly decreased thermal allodynia (and not anxiety) in all experimental days. Additionally, resveratrol significantly increased NCV, and also normalized the disrupted Cat and SOD activities following neuropathic pain. Furthermore, propranolol significantly blocked the analgesic and neuroprotective effects of resveratrol. CONCLUSIONS: It is suggested that the analgesic effects of resveratrol is mediated by its neuroprotective and antioxidant activities in the neuropathic rats. Furthermore, propranolol blocked the analgesic and neuroprotective effects of resveratrol.

Administering crocin ameliorates anxiety-like behaviours and reduces the inflammatory response in amyloid-beta induced neurotoxicity in rat.

Anxiety, hippocampus synaptic plasticity deficit, as well as pro-inflammatory cytokines, are involved in Alzheimer's disease (AD). The present study is designed to evaluate the possible therapeutic effect of crocin on anxiety-like behaviours, hippocampal synaptic plasticity and neuronal shape, as well as pro-inflammatory cytokines in the hippocampus using in vivo amyloid-beta (Aß) models of AD. The Aß peptide (1-42) was bilaterally injected into the frontal-cortex. Five hours after the surgery, the rats were given intraperitoneal (IP) crocin (30 mg/kg) daily up to 12 days. Elevated plus maze results showed that crocin treatment after bilateral Aß injection significantly increased the percentage of spent time into open arms, frequency of entries, and percentage of entries into open arms as compared with the Aß group. In the open field test, the Aß+crocin group showed a higher percentage of spent time in the centre and frequency of entries into central zone as compare with the Aß treated animals. Administering crocin increased the number of soma, dendrites and axonal arbores in the CA1 neurons among the rats with Aß neurotoxicity. Cresyl violet (CV) staining showed that crocin increased the number of CV-positive cells in the CA1 region of the hippocampus compared with the Aß group. Silver-nitrate staining indicated that crocin reduced neurofibrillary tangle formation induced by Aß. Crocin treatment attenuated the expression of TNF-α and IL-1ß mRNA in the hippocampus compared with the Aß group. Our results suggest that crocin attenuated Aß-induced anxiety-like behaviours and neuronal damage, and synaptic plasticity loss in hippocampal CA1 neurons may via its anti-inflammatory effects.

Pharmacological mechanism of immunomodulatory agents for the treatment of severe cases of COVID-19 infection.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1ß. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF. RESULTS: Here, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application. CONCLUSION: It is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.

The effects of Valerian on sleep spindles in a model of neuropathic pain.

INTRODUCTION: Valeriana officinalis is known to be one of the most famous herbal supplements for the treatment of anxiety and insomnia. Despite its widespread use in most countries all around the world, there is little scientific information and research on how this medication affects sleep patterns, and there are almost no studies on its effects on the characteristics of sleep spindles. MATERIAL AND METHODS: The present study was conducted to investigate the effects of Valerian extract (VAL) on sleep spindles and induced anxiety in chronic neuropathic pain model in rats. 24 male rats were divided into three groups: neuropathic group (n=9) in which the rats underwent chronic constriction injury (CCI), sham group (n=7) in which the sciatic nerves of the animals were exposed without any constriction and also fed with the vehicle, and the third group was under CCI condition and treated with Valerian (n=8). All the rats underwent electrode implant surgery so that we could record electroencephalogram and electromyography waves. In all the three groups, EEG and EMG recordings were recorded three times (150min each time). The initial recording was just prior to the CCI surgery and the rest were 3 and 6 days following CCI surgery. Moreover, cold allodynia and elevated plus maze tests were performed 3 and 6 days following the CCI surgery. RESULTS: Valerian treatment could repair the allodynia induced by neuropathy. On the other hand, by Valerian treatment (400mg/kg) during neuropathy, the REM sleep, decreased and the non-REM sleep increased. Moreover, there was an increment in sleep spindle density and spindle frequency even in neuropathic condition. DISCUSSION: This herbal supplement improves the quality of sleep in neuropathy conditions.

Evaluation of the GABAA Receptor Expression and the Effects of Muscimol on the Activity of Wide Dynamic Range Neurons Following Chronic Constriction Injury of Sciatic Nerve in Rats.

INTRODUCTION: The modality of γ-aminobutyric acid type a receptors (GABAA) controls dorsal horn neuronal excitability and inhibits sensory information. This study aimed to investigate the expression of the GABAA receptor and the effects of its agonist muscimol on Wide Dynamic Range (WDR) neuronal activity in the Chronic Constriction Injury (CCI) model of neuropathic pain. METHODS: Adult male Wistar rats weighing 200 to 250 g were used to induce CCI neuropathy. Fourteen days after surgery, muscimol (0.5, 1, and 2 mg/kg IP) was injected. Then, the behavioral tests were performed. After that, the animals were killed, and the lumbar segments of the spinal cords were collected for Western blot analysis of the GABAA receptor α1 subunit expression. The electrophysiological properties of WDR neurons were studied by single-unit recordings in separate groups 14 days after CCI. RESULTS: The outcomes indicated the development of thermal hyperalgesia and mechanical allodynia after neuropathy; nonetheless, the expression of the GABAA receptor α1 subunit did not change significantly. Moreover, the evoked responses of the WDR neurons to electrical, mechanical, and thermal stimuli increased considerably. Fourteen days after CCI, muscimol administration decreased thermal hyperalgesia, mechanical allodynia, and hyper-responsiveness of the WDR neurons in CCI rats. CONCLUSION: The modulation of the spinal GABAA receptors after nerve injury can offer further insights to design new therapeutic agents to reduce neuropathic pain symptoms.

Analgesic and anti-inflammatory activities of hydro-alcoholic extract of Lavandula officinalis in mice: possible involvement of the cyclooxygenase type 1 and 2 enzymes

Abstract Lavandula officinalis Chaix, Lamiaceae, extracts can inhibit inflammation and also pain induced by formalin in mice. This study evaluated the effects of L. officinalis hydro-alcoholic extract on pain induced by formalin and also cyclooxygenase (COX) type 1 and 2 activity in mice. To evaluate probable analgesic and anti-inflammatory effects of the extract, flowers were prepared by maceration and extraction in alcohol and their analgesic effects were studied in male mice, using formalin and hot plate tests. The effect of intraperitoneal hydro-alcoholic extracts of L. officinalis (100, 200, 250, 300, 400 and 800 mg/kg), subcutaneous morphine (10 mg/kg), dexamethasone (10 mg/kg; i.p.) and indomethacin (10 mg/kg; i.p.) on formalin induced pain were studied. Our results indicated that administration of the extract (100, 200, 250, 300, 400 and 800 mg/kg; i.p.) has inhibitory effects on inflammation induced by formalin injection into the animals hind paw. Moreover, this inhibitory effect was equal to the effects of morphine, dexamethasone and indomethacin. The extract in100, 200 and 300 mg/kg; significantly reduced heat-induced pain. The extract also reduced COX activity in dose dependent manner, where the inhibitory effect on COX1 activity was 33% and on COX2 activity was 45%. Here for the first time we show that L. officinialis extract can modulate pain and inflammation induced by formalin by inhibition of COX enzymes.