Cannabis sativa L. (var. indica) Exhibits Hepatoprotective Effects by Modulating Hepatic Lipid Profile and Mitigating Gluconeogenesis and Cholinergic Dysfunction in Oxidative Hepatic Injury

Cannabis sativa L. is a crop utilized globally for recreational, therapeutic, and religious purposes. Although considered as an illicit drug in most countries, C. sativa until recently started gaining attention for its medicinal application. This study sought to investigate the hepatoprotective effect of C. sativa on iron-mediated oxidative hepatic injury. Hepatic injury was induced ex vivo by incubating hepatic tissues with Fe2+, which led to depleted levels of reduced glutathione, superoxide dismutase, catalase and ENTPDase activities, triglyceride, and high-density lipoprotein–cholesterol (HDL-C). Induction of hepatic injury also caused significant elevation of malondialdehyde, nitric oxide, cholesterol, and low-density lipoprotein–cholesterol (LDL-C) levels while concomitantly elevating the activities of ATPase, glycogen phosphorylase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, amylase, and lipase. Treatment with the hexane, dichloromethane (DCM), and ethanol extracts of C. sativa leaves significantly (p < 0.05) reversed these levels and activities to almost near normal. However, there was no significant effect on the HDL-C level. The extracts also improved the utilization of glucose in Chang liver cells. High-performance liquid chromatography (HPLC) analysis showed the presence of phenolics in all extracts, with the ethanol extract having the highest constituents. Cannabidiol (CBD) was identified in all the extracts, while Δ-9-tetrahydrocannabinol (Δ-9-THC) was identified in the hexane and DCM extracts only. Molecular docking studies revealed strong interactions between CBD and Δ-9-THC with the β2 adrenergic receptor of the adrenergic system. The results demonstrate the potential of C. sativa to protect against oxidative-mediated hepatic injury by stalling oxidative stress, gluconeogenesis, and hepatic lipid accumulation while modulating cholinergic and purinergic activities. These activities may be associated with the synergistic effect of the compounds identified and possible interactions with the adrenergic system.

A Systematic Review on the Role of Adrenergic Receptors in Angiogenesis Regulation in Health and Disease

Angiogenesis is essential during development or when tissue restoration and oxygenation is required. Limited or excessive formation of blood vessels is a hallmark of several pathologies, and many angiogenesis-related pathways are being studied to highlight potential targets for effective angiogenesis-stimulating or inhibiting therapeutic approaches. A few studies point to the adrenergic system as a significant regulator of angiogenesis, directly or indirectly. Functional adrenergic receptors are expressed on endothelial cells and affect their response to the adrenergic system. The latter can also upregulate the release of growth factors by mural cells of the vessel wall, blood cells or cancer cells, thus subsequently affecting endothelial cell functions and angiogenesis. In the present study we summarize up-to-date literature on the known effects of the adrenergic receptors on physiological and pathological angiogenesis.

The role of the autonomic nervous system in stress cardiomyopathy

Aim. To identify the role of the autonomic nervous system in stress cardiomyopathy in an experimental model of Takotsubo syndrome.Materials and methods. The study was carried out on 120 female Wistar rats. Stress modeling was performed by immobilizing animals on the back for 24 hours. Intact rats were used as controls. The rats were decapitated after termination of immobilization under general anesthesia with ether. Stress cardiomyopathy (SCM) was quantified by accumulation of 99mTc pyrophosphate radiopharmaceutical (99mTc PP) in the myocardium. The pharmacological agents used included the ganglionic blocker hexamethonium, administered five times at a dose of 20 mg / kg; guanethidine (50 mg / kg) administered subcutaneously once a day for three days, the last injection was performed 24 hours before immobilization; the muscarinic receptor antagonist atropine methyl nitrate (1 mg / kg); the α1-AR (adrenergic receptor) antagonist prazosin (2 mg / kg); the α2-AR antagonist yohimbine, administered at a dose of 2 mg / kg; the β1-AR antagonist nebivolol (1.2 mg / kg); the β2-AR antagonist ICI 118,551 (0.3 mg / kg); and the β3-AR antagonist L-748337 (0.1 mg / kg).Results. Three-day administration of guanethidine caused a decrease in the degree of 99mTc-PP accumulation in the heart by 35.9%. Hexamethonium did not affect the degree of SCM. The blockade of the muscarinic receptor caused an increase in accumulation of 99mTc-PP by 26.5%. Inhibition of α1-AR did not affect SCM. The blockade of α2-AR caused a 2.2-fold increase in the accumulation compared with stress control. The blockade of β1-AR reduced 99mTc-PP accumulation by 2.5 times. The blockade of β2-AR by ICI 118,551 increased the degree of 99mTcPP accumulation by 34.6%. Inhibition of β3-AR had no effect on SCM.Conclusion. The adrenergic system and β1-adrenergic receptor play an important role in the development of SCM. The parasympathetic nervous system ensures resistance of the heart to stress.

Serotonin after β-Adrenoreceptors’ Exposition: New Approaches for Personalized Data in Breast Cancer Cells

Serotonin is an important monoamine in the human body, playing crucial roles, such as a neurotransmitter in the central nervous system. Previously, our group reported that β-adrenergic drugs (ICI 118,551, isoprenaline, and propranolol) influence the proliferation of breast cancer cells (MCF-7 cells) and their inherent production of adrenaline. Thus, we aimed to investigate the production of serotonin in MCF-7 cells, clarifying if there is a relationship between this production and the viability of the cells. To address this question, briefly, we treated the MCF-7 cells with ICI 118,551, isoprenaline, and propranolol, and evaluated cellular viability and serotonin production by using MTT, Sulforhodamine B (SRB) and Neutral Red (NR) assays, and HPLC-ECD analysis, respectively. Our results demonstrate that isoprenaline promotes the most pronounced endogenous synthesis of serotonin, about 3.5-fold greater than control cells. Propranolol treatment also increased the synthesis of serotonin (when compared to control). On the other hand, treatment with the drug ICI 118,551 promoted a lower endogenous synthesis of serotonin, about 1.1-fold less than what was observed in the control. Together, these results reveal that MCF-7 cells can produce serotonin, and the drugs propranolol, isoprenaline and ICI 118,551 influence this endogenous production. For the first time, after modulation of the β-adrenergic system, a pronounced cellular growth can be related to higher consumption of serotonin by the cells, resulting in decreased levels of serotonin in cell media, indicative of the importance of serotonin in the growth of MCF-7 cells.

Takotsubo syndrome: hyperthyroidism, pheochromocytoma, or both? A case report

Background Takotsubo syndrome (TTS) is a transient left ventricular dysfunction usually with apical akinesia (classical pattern). Other less frequent variants have been described: the mid-ventricular pattern is characterized by hypokinesia of the mid-left ventricle and hypercontractile apical and basal segments; the inverted or basal pattern is characterized by basal and mid-ventricular segment hypokinesia or akinesia with preserved contractility or hypercontractility of apical segments and finally the focal pattern. There are also biventricular variants and forms with exclusive involvement of the right ventricle. There is a correlation between endocrine disorders and TTS, the one most frequently described is with pheochromocytoma. Catecholamine-mediated myocarditis, focal and diffuse myocardial fibrosis, and myocardial dysfunction are described in pheochromocytoma. Case summary We describe a case of a 69-year-old patient with a recent diagnosis of hypertension and Graves’ disease, hospitalized for persistent chest pain, hypertensive crisis, tachycardia, dyspnoea, and diaphoresis. Thyroid hormones, antibodies to TSH receptors, and hs-troponin I were increased. Electrocardiogram showed sinus tachycardia at 130 b.p.m., first-degree atrioventricular block, signs of left ventricular hypertrophy with inverted T wave in V4–V6. Echocardiogram demonstrated left ventricular apical and para-apical akinesia. Coronary angiography ruled out an obstructive coronary artery disease. Computed tomography angiogram aortic dissection ruled out aortic dissection but incidentally revealed a left adrenal mass compatible with a pheochromocytoma. Plasma and urinary metanephrines were increased. A TTS secondary to pheochromocytoma and hyperthyroidism was diagnosed. Pharmacological treatment included nitrates, urapidil and esmolol IV and methimazole at high doses. Type 2 multiple endocrine neoplasia has been excluded. After a complete haemodynamic stability on 20th day of hospitalization, the patient underwent an adrenalectomy. Discussion High levels of catecholamines in pheochromocytoma can lead to myocardial dysfunction. Similarly, an excess of thyroid hormones with up-regulation of adrenergic system can lead to myocardial dysfunction. These two conditions, if both present, define a high haemodynamic risk profile. How do catecholamines interact with the thyroid gland? The clinical case is of interest as a relationship has been hypothesized between the incretion of plasma catecholamines and Graves’ disease. We suppose an imbalance of the immune system with a predominance of the T helper-type 2 (Th2)-mediated response. Predominance of Th2-mediated immune response may induce humoral immunity causing Graves’ disease. In addition Th2 cytokines are strong inducers of M2 macrophages (alternatively activated) that are involved in autoimmune diseases, myocarditis, and myocardial fibrosis. Knowing the interaction between the cardiovascular system, immune response, and endocrine glands can help define the patient's risk class, possible complications, and follow-up.

Associative studies of polymorphic variants of adrenergic receptor genes and tardive dyskinesia in schizophrenia

Адренергическая система, наряду с дофаминергической, серотонинергической и глутаматергической системами, играет важную роль в патофизиологии шизофрении и ответе на применяемую фармакотерапию. Тардивная или поздняя дискинезия (ТД) относится к серьезным побочным эффектам и может развиваться у больных шизофренией на фоне длительного использования антипсихотиков. Важная роль в патогенезе ТД принадлежит генетическим факторам. Целью настоящего исследования явился поиск возможных ассоциаций полиморфных вариантов генов ADRβ1 и ADRA1A с развитием ТД у больных шизофренией, получающих антипсихотическую терапию. Выборка составила 449 пациентов из русской популяции Сибирского региона с верифицированным диагнозом шизофрения, из которых 121 пациент соответствовал критериям ТД. Генотипирование полиморфных вариантов rs1801253, rs2036108, rs472865 генов ADRβ1 и ADRA1A проведено методом ПЦР в реальном времени амплификатором QuantStudio 5 с использованием наборов TaqMan. Ассоциативный анализ частот генотипов и аллелей оценивался с помощью критерия χ2 в программе R 3.6.2 с использованием базовых функций и дополнительного пакета SNPassoc. Распределение частот генотипов и аллелей для полиморфного варианта rs2036108 гена ADRA1A значимо отличается в группах пациентов с ТД и без побочного эффекта (для генотипов р = 0,028; для аллелей р = 0,040). Впервые была выявлена ассоциация полиморфного варианта rs2036108 гена ADRA1A с ТД у больных шизофренией. Необходимы дальнейшие исследования роли генов адренергических рецепторов в развитии ТД для разработки фармакогенетических подходов к персонализации терапии. The adrenergic system, along with the dopaminergic, serotonergic and glutamatergic systems, plays an important role in the pathophysiology of schizophrenia and response to the applied pharmacotherapy. Tardive or late dyskinesia (TD) is a serious side effect and can develop in schizophrenic patients with prolonged use of antipsychotics. An important role in the pathogenesis of TD belongs to genetic factors. The aim of this study was to search for possible associations of polymorphic variants of the ADRβ1 and ADRA1A genes with the development of tardive dyskinesia in schizophrenic patients receiving antipsychotic therapy. We examined 449 patients from Russian population of Siberian region with verified diagnosis of schizophrenia. 121 patients from whole group met the criteria for tardive dyskinesia. Genotyping of the polymorphic variants rs1801253, rs2036108, rs472865 of the ADRβ1 and ADRA1A genes was performed by real-time PCR using a QuantStudio 5 amplifier using TaqMan kits. The associative analysis of the frequencies of genotypes and alleles was assessed using the χ2 test in the R 3.6.2 program using basic functions and an additional SNPassoc package. The distribution of genotype and allele frequencies for the rs2036108 polymorphic variant of the ADRA1A gene significantly differs in the groups of patients with tardive dyskinesia and without side effects (for genotypes p = 0.028; for alleles p = 0.040). For the first time, the association of the rs2036108 polymorphic variant of the ADRA1A gene with tardive dyskinesia in schizophrenic patients was revealed. Further studies of the role of adrenergic receptor genes in the development of tardive dyskinesia are required to develop pharmacogenetic approaches to personalizing therapy.