Ipidacrine (Axamon), A Reversible Cholinesterase Inhibitor, Improves Erectile Function in Male Rats With Diabetes Mellitus-Induced Erectile Dysfunction.

BACKGROUND: Management of diabetes mellitus-induced erectile dysfunction (DMED) is challenging because of its insufficient responses to phosphodiesterase type 5 inhibitors. AIM: To compare the effects of ipidacrine, a reversible cholinesterase inhibitor, and sildenafil on DMED in a rat model of streptozotocin (STZ)-induced diabetes. METHODS: Erectile dysfunction (ED) caused by STZ-induced diabetes mellitus was modeled in adult male Wistar rats, which were randomized to 4 groups: untreated diabetic rats, sildenafil (5 mg/kg), ipidacrine (3.6 mg/kg) and ipidacrine (6.7 mg/kg). The test drug (ipidacrine), comparator (sildenafil) or control substance (1% starch solution) were administered orally for 5 days or 14 days. Erectile function was assessed by the change in the maximum intracavernous pressure (ICPmax) following cavernous nerve electrical stimulation. The mean arterial pressure (MAP) was recorded, and the ICPmax/MAP ratio was calculated. Sexual behavior, cholinesterase activity and blood testosterone level tests assessed. MAIN OUTCOME MEASURE: The quantitative value of ICPmax/MAP 14 days after the start of administration of the test drug and the comparison drug. RESULTS: Animals with STZ-induced diabetes mellitus showed a significant decrease in ICPmax and ICPmax/MAP ratio compared to the intact control group. When ipidacrine was administered to rats with DMED for 14 days, an increase in these indicators was noted. It was proved that ipidacrine at a dose of 6.7 mg/kg has noninferiority compared to sildenafil on the DMED model. Significant increase in ICPmax compared to STZ-control after electrostimulation of the cavernous nerve was recorded following administration of ipidacrine at a dose of 6.7 mg/kg (P < .05) and sildenafil at a dose 5 mg/kg (P < .05). Neither the test drug, nor the comparator were associated with increase in testosterone levels in blood; as well both drugs did not promote activation of sexual behavior. CLINICAL IMPLICATIONS: Ipidacrine may be considered as an effective therapy for DMED but needs to be verified in human investigations. STRENGTHS & LIMITATIONS: The role of ipidacrine, was firstly demonstrated in rats with DMED. However, the results were obtained in animal experiments, and will be further tested in the study of receptor interactions and the determination of cellular targets. CONCLUSION: This is the first study to show that administration of ipidacrine, the reversible cholinesterase inhibitor, improved erectile function in diabetic rats and these results may be beneficial in further studies using ipidacrine for treatment of DMED, particularly in non-responders to PDE5 inhibitors. Bykov V, Gushchina E, Morozov S, et al. Ipidacrine (Axamon), A Reversible Cholinesterase Inhibitor, Improves Erectile Function in Male Rats With Diabetes Mellitus-Induced Erectile Dysfunction. Sex Med 2022;10:100477.

Comparison of biomarker and chromatographic analytical approaches to pharmacokinetic study of sitagliptin.

The pharmacokinetic profiling of active compounds is necessary for drug development and application. Approaches to a pharmacokinetic study based on biological markers are alternatives to traditional approaches based on chromatographic methods. The aim of the study was to compare two analytical approaches to pharmacokinetics investigation for an example of sitagliptin in rabbits after one dose oral administration. The method for sitagliptin quantification in rabbit plasma samples based on a correlation between its concentration and dipeptidyl peptidase IV activity was proposed, validated, and applied. The high-performance liquid chromatography (HPLC)-ultraviolet (UV) method was also validated and applied for the same sample analysis. The plasma pharmacokinetics of sitagliptin after oral administration to the rabbits in one dose was characterized after two analytical assays. The close values of the main pharmacokinetic parameters were obtained after two approaches. The nontraditional approach based on correlation of special marker activity and active substance concentration appears to be more sensitive than HPLC-UV. Thus, the sitagliptin concentrations determined by biomarker assay were higher than the lower limit of quantification (LLOQ) for a longer period (more timepoints) than after the HPLC-UV assay. This feature may influence the values of some calculated concentration-dependent (area under the curve [AUC]0-t , etc.) and time-dependent parameters (mean residence time [MRT], T1/2 , etc.). The values of Tmax obtained by the two approaches were similar and adequate for oral drug administration that confirms the correctness of biomarker selection for pharmacokinetics assessment. The obtained results on the example of sitagliptin confirms that the biomarker approach is adequate and applicable for a pharmacokinetics study. Similar approaches may be effective for individual compounds and complex mixtures when it is difficult or impossible to analyze them traditionally by chromatographic methods.

Universal Live-Attenuated Influenza Vaccine Candidates Expressing Multiple M2e Epitopes Protect Ferrets against a High-Dose Heterologous Virus Challenge.

The development of an influenza vaccine with broad protection and durability remains an attractive idea due to the high mutation rate of the influenza virus. An extracellular domain of Matrix 2 protein (M2e) is among the most attractive target for the universal influenza vaccine owing to its high conservancy rate. Here, we generated two recombinant live attenuated influenza vaccine (LAIV) candidates encoding four M2e epitopes representing consensus sequences of human, avian and swine influenza viruses, and studied them in a preclinical ferret model. Both LAIV+4M2e viruses induced higher levels of M2e-specific antibodies compared to the control LAIV strain, with the LAIV/HA+4M2e candidate being significantly more immunogenic than the LAIV/NS+4M2e counterpart. A high-dose heterosubtypic influenza virus challenge revealed the highest degree of protection after immunization with LAIV/HA+4M2e strain, followed by the NS-modified LAIV and the classical LAIV virus. Furthermore, only the immune sera from the LAIV/HA+4M2e-immunized ferrets protected mice from a panel of lethal influenza viruses encoding M genes of various origins. These data suggest that the improved cross-protection of the LAIV/HA+4M2e universal influenza vaccine candidate was mediated by the M2e-targeted antibodies. Taking into account the safety profile and improved cross-protective potential, the LAIV/HA+4M2e vaccine warrants its further evaluation in a phase I clinical trial.

High-Dimensional Brain in a High-Dimensional World: Blessing of Dimensionality.

High-dimensional data and high-dimensional representations of reality are inherent features of modern Artificial Intelligence systems and applications of machine learning. The well-known phenomenon of the "curse of dimensionality" states: many problems become exponentially difficult in high dimensions. Recently, the other side of the coin, the "blessing of dimensionality", has attracted much attention. It turns out that generic high-dimensional datasets exhibit fairly simple geometric properties. Thus, there is a fundamental tradeoff between complexity and simplicity in high dimensional spaces. Here we present a brief explanatory review of recent ideas, results and hypotheses about the blessing of dimensionality and related simplifying effects relevant to machine learning and neuroscience.

Therapeutic efficacy of arginine-rich exenatide on diabetic neuropathy in rats.

Diabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 µg/kg). One group of diabetic rats was treated with Byetta® (1 µg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IHC study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.

Metabolite profiling and mechanisms of bioactivity of snake autolysate - A traditional Uzbek medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Aqueous autolysate from the snake Eryx miliaris (SNA) has been used in traditional medicine of Uzbekistan as anti-inflammatory, hepatoprotective and immunomodulatory agent. However, little is known about the chemical composition and its mechanisms of activity. AIM OF THE STUDY: This is our first attempt to analyse the composition of snake autolysate using gas chromatography with mass spectrometry (GC-MS) and to investigate the mechanisms of anti-inflammatory and hyaluronidase activity of fingerprinted E. miliaris autolysate to support their use in the traditional Uzbek medicine. MATERIALS AND METHODS: Aqueous autolysate was evaporated and derivatised for GC-MS analysis of metabolites. For quantification, lipids were extracted from autolysate by solvent extraction and derivatised by esterification and silylation. Biological activity was evaluated with lipid peroxidation, cyclooxygenase (COX) inhibition and antihyaluronidase activity tests. RESULTS: GC-MS analysis of SNA enabled the identification of 27 compounds. Short chain fatty acids (SCFA, 21%), amino acid/derivatives 39% (incl. 2-piperidinone 19%), phenyl (7%), and OH-Phenyl (10%) derivatives covered 77%. Other derivatives (9%) included succinic acid and 3-indole acetic acid). Long chain fatty acids (C16-C18) accounted for 3%. The lipid concentration of SNA was 1.2 mg/mL (0.12%). Three concentration levels (1.0-20.0 µg/mL) did not inhibit COX-1 and COX-2 in vitro and malondialdehyde level was not decreased by SNA in lipid peroxidation model. However, SNA was a potent inhibitor of the hyaluronidase enzyme activity in a dose dependent manner with IC50 = 0.086 mL/mL. CONCLUSION: The results from GC-MS analyses of SNA lead us to the identification of a wide range of major chemical structures of the metabolites and their derivatives with several categories. Pharmacological studies support the traditional use of SNA and show one of its possible mechanisms of activity via inhibition of hyaluronidase.

Pharmacokinetic Study of Bioactive Glycopeptide from Strongylocentrotus droebachiensis After Intranasal Administration to Rats Using Biomarker Approach.

A glycopeptide fraction (GPF) from internal organs of green sea urchins (Strongylocentrotus droebachiensis Müller, Strongylocentrotidae) has been reported to be an effective bronchitis treatment. In this study, we evaluated the pharmacokinetic and tissue distribution of GPF, following single and repeated intranasal (i/n) administration over the course of seven days in rats. The method measuring lactate dehydrogenase as biomarker was used to analyse the plasma and tissue concentrations of GPF. GPF appears in the plasma 15 min after single i/n administration (100 µg/kg) and reaches its maximum at 45 min. The area under the curve (AUC)0-24 and Cmax were similar using both i/n and intravenous administration, while mean residence time (MRT) and T1/2 after i/n administration were significantly higher compared with intravenous (i/v) administration. The absolute bioavailability of GPF after i/n administration was 89%. The values of tissue availability (ft) provided evidence about the highest concentration of GPF in the nose mucosa (ft = 34.9), followed by spleen (ft = 4.1), adrenal glands (ft = 3.8), striated muscle (ft = 1.8), kidneys (ft = 0.5), and liver (ft = 0.3). After repeated dose administration, GPF exhibited significantly higher AUC0-24 and MRT, indicating its accumulation in the plasma.

Animal-derived medicinal products in Russia: Current nomenclature and specific aspects of quality control.

ETHNOPHARMACOLOGICAL RELEVANCE: Animal-derived medicinal products (ADMP) had been extensively used in Russia and became a part of officinal medicine in 1778. AIM OF THE STUDY: The aim of the current review was to analyse the ADMPs authorised in the Russian Federation and to identify specific aspects of quality evaluation of these medicinal products. MATERIALS AND METHODS: Information of ADMPs was extracted from the online State Register of Medicinal Products of the Russian Federation. At the next stage, we systematically searched library catalogues, E-library.ru, Medline/PubMed, Scopus, Web of Science and Google Scholar databases to find data related to ADMP quality evaluation, clinically proven efficacy and safety. RESULTS: For classification of ADMP, we propose an approach based on the raw material used: ADMPs derived from marine organisms, ADMPs from cattle and pigs and ADMPs from other terrestrial animals. The majority of ADMPs authorised in Russia are produced by local manufacturers. ADMPs are available in dosage forms of solution for parenteral administration (35% of all products) and lyophilisates for parenteral use (19%), tablets and capsules (17% and 11%, respectively), ointments (5%) and powders (3%). ADMPs belong to the following pharmacotherapeutic groups: medicines for tissue regeneration and repair stimulators (30%), digestive enzyme products (22%), anticoagulants (17%), proteolytic agents (6%) and medicines for the treatment of chronic prostatitis (5%). The most important approaches to standardisation of ADMPs are implementation of modern requirements for registration dossiers, development of risk-oriented approaches for evaluation of impurities, elaboration of advanced instrumental and in vitro test methods capable of replacing in vivo methods and harmonisation of the potency units used for standardisation. CONCLUSIONS: The key features of ADMPs that help them retain their leading position in the pharmaceutical market are as follows: (i) their unique composition usually represented by a complex of biologically active substances; (ii) a high degree of affinity of the active ingredient of an ADMP to the human body and (iii) proved safety and clinical efficiency. Variability in the quality of raw ingredients, epidemiological situation and other conditions pose additional challenges for the development of ADMPs and for the standardisation.

Two Live Attenuated Vaccines against Recent Low⁻and Highly Pathogenic H7N9 Influenza Viruses Are Safe and Immunogenic in Ferrets.

Influenza H7N9 virus is a potentially pandemic subtype to which most people are immunologically naïve. To be better prepared for the potential occurrence of an H7N9 pandemic, in 2017 the World Health Organization recommended developing candidate vaccine viruses from two new H7N9 viruses, A/Guangdong/17SF003/2016 (A/GD) and A/Hong Kong/125/2017 (A/HK). This report describes the development of live attenuated influenza vaccine (LAIV) candidates against A/GD and A/HK viruses and study of their safety and immunogenicity in the ferret model in order to choose the most promising one for a phase I clinical trial. The A/HK-based vaccine candidate (A/17/HK) was developed by classical reassortment in eggs. The A/GD-based vaccine candidate (A/17/GD) was generated by reverse genetics. Ferrets were vaccinated with two doses of LAIV or phosphate-buffered saline. Both H7N9 LAIVs tested were safe for ferrets, as shown by absence of clinical signs, and by virological and histological data; they were immunogenic after a single vaccination. These results provide a compelling argument for further testing of these vaccines in volunteers. Since the A/HK virus represents the cluster that has caused the majority of human cases, and because the A/HK-based LAIV candidate was developed by classical reassortment, this is the preferred candidate for a phase I clinical trial.

Pharmacokinetic and Tissue Distribution of Fucoidan from Fucus vesiculosus after Oral Administration to Rats.

Fucus vesiculosus L., known as bladderwrack, belongs to the brown seaweeds, which are widely distributed throughout northern Russia, Atlantic shores of Europe, the Baltic Sea, Greenland, the Azores, the Canary Islands, and shores of the Pacific Ocean. Fucoidan is a major fucose-rich sulfated polysaccharide found in Fucus (F.) vesiculosus. The pharmacokinetic profiling of active compounds is essential for drug development and approval. The aim of the study was to evaluate the pharmacokinetics and tissue distribution of fucoidan in rats after a single-dose oral administration. Fucoidan was isolated from F. vesiculosus. The method of measuring anti-activated factor X (anti-Xa) activity by amidolytic assay was used to analyze the plasma and tissue concentrations of fucoidan. The tissue distribution of fucoidan after intragastric administration to the rats was characterized, and it exhibited considerable heterogeneity. Fucoidan preferentially accumulates in the kidneys (AUC0–t = 10.74 µg·h/g; Cmax = 1.23 µg/g after 5 h), spleen (AUC0–t = 6.89 µg·h/g; Cmax = 0.78 µg/g after 3 h), and liver (AUC0–t = 3.26 µg·h/g; Cmax = 0.53 µg/g after 2 h) and shows a relatively long absorption time and extended circulation in the blood, with a mean residence time (MRT) = 6.79 h. The outcome of this study provides additional scientific data for traditional use of fucoidan-containing plants and offers tangible support for the continued development of new effective pharmaceuticals using fucoidan.

A new tridecapeptide with an octaarginine vector has analgesic therapeutic potential and prevents morphine-induced tolerance.

A growing body of evidence suggests that peptides may possess analgesic effects without tolerance development. The synthetic tetrapeptide Tyr-d-Arg-Phe-Gly-NH2 was modified with the inclusion of a (d-Arg)8 vector to prevent the action of endopeptidase and to increase the duration of the analgesic action of the tetrapeptide when administered orally. The aim of this study was to estimate the analgesic efficacy of the tetrapeptide with (d-Arg)8 (tridecapeptide, TDP) in experimental models of acute and chronic pain. The analgesic effects of TDP were estimated using a model of acute visceral pain in mice (writhing test) and a model of chronic neuropathic pain (chronic constriction injury (CCI) of the sciatic nerve) in rats. The intravenous administration of morphine (0.32-1mg/kg) and TDP (0.32-1.8mg/kg) produced significant dose-related antinociceptive effects in the writhing test. The potency of TDP after i.g. administration was lower than that after i.v. administration but comparable with that of i.g. morphine. In the CCI model, TDP (0.1, 1 and 10mg/kg, i.g.) induced marked analgesia with repeated administration without any signs of tolerance. The single administration of TDP after morphine treatment (7days) produced a significant analgesic effect in morphine-tolerant rats, indicating the absence of cross-tolerance between these two drugs. The combined administration of TDP and morphine resulted in the reduction of analgesic tolerance to morphine. The absence of cross-tolerance to morphine and the ability to prevent morphine tolerance allows this compound to be a prospective candidate for chronic pain therapy. In order to find the target receptors for TDP, a docking study was performed. It was found that the molecule can bind to the NMDA receptor using electrostatic, hydrogen bonding and hydrophobic interactions.

Traditional and Current Food Use of Wild Plants Listed in the Russian Pharmacopoeia.

Historically Russia can be regarded as a "herbophilious" society. For centuries the multinational population of Russia has used plants in daily diet and for self-medication. The specificity of dietary uptake of medicinal plants (especially those in the unique and highly developed Russian herbal medical tradition) has remained mostly unknown in other regions. Based on 11th edition of the State Pharmacopoeia of the USSR, we selected 70 wild plant species which have been used in food by local Russian populations. Empirical searches were conducted via the Russian-wide applied online database E-library.ru, library catalogs of public libraries in St-Petersburg, the databases Scopus, Web of Science, PubMed, and search engine Google Scholar. The large majority of species included in Russian Pharmacopoeia are used as food by local population, however, aerial parts are more widely used for food. In this review, we summarize data on medicinal species published in Russia and other countries that are included in the Russian Pharmacopoeia and have being used in food for a long time. Consequently, the Russian Pharmacopoeia is an important source of information on plant species used traditionally at the interface of food and medicine. At the same time, there are the so-called "functional foods", which denotes foods that not only serves to provide nutrition but also can be a source for prevention and cure of various diseases. This review highlights the potential of wild species of Russia monographed in its pharmacopeia for further developing new functional foods and-through the lens of their incorporation into the pharmacopeia-showcases the species' importance in Russia.

Chemical Profiling and Bioactivity of Body Wall Lipids from Strongylocentrotus droebachiensis.

The lipids from gonads and polyhydroxynaphthoquinone pigments from body walls of sea urchins are intensively studied. However, little is known about the body wall (BW) lipids. Ethanol extract (55 °C) contained about equal amounts of saturated (SaFA) and monounsaturated fatty acids (MUFA) representing 60% of total fatty acids, with myristic, palmitic and eicosenoic acids as major SaFAs and MUFAs, respectively. Non-methylene-interrupted dienes (13%) were composed of eicosadienoic and docosadienoic acids. Long-chain polyunsaturated fatty acids (LC-PUFA) included two main components, n6 arachidonic and n3 eicosapentaenoic acids, even with equal concentrations (15 µg/mg) and a balanced n6/n3 PUFA ratio (0.86). The UPLC-ELSD analysis showed that a great majority of the lipids (80%) in the ethanolic extract were phosphatidylcholine (60 µg/mg) and phosphatidylethanolamine (40 µg/mg), while the proportion of neutral lipids remained lower than 20%. In addition, alkoxyglycerol derivatives-chimyl, selachyl, and batyl alcohols-were quantified. We have assumed that the mechanism of action of body wall lipids in the present study is via the inhibition of MAPK p38, COX-1, and COX-2. Our findings open the prospective to utilize this lipid fraction as a source for the development of drugs with anti-inflammatory activity.

Comparative stability of dimeric and monomeric pigments extracted from sea urchin Strongylocentrotus droebachiensis.

Ultraviolet-visible spectroscopy and UPLC-DAD-MS were used for analysis of stability of ethanol solutions of ethylidene-6,6'-bis(2,3,7-trihydroxynaphthazarin) (ENZ), spinochrome dimer (SDM) and spinochrome D (SD) that were isolated from Strongylocentrotus droebachiensis. In the freshly prepared solution, the concentration of ENZ at pH 6.0 was at 6 fold less comparing to pH 1.6. The increase of pH up to 4.0 resulted to increase of SD concentration and to decrease of SDM concentration. After 48 h storage, both dimers showed the highest stability at pH 1.6, while the elevation of the pH solution up to 6.0 activates degradation of SDM and ENZ at 1.3 and 3.6 fold correspondingly. The concentration of SD after 48 h storage at the pH 1.6 was at two-fold less comparing to the initial concentration, and at the pH 6.0 - at 4 fold less. This study contributes to increasing the knowledge on the stability of the spinochrome pigments.

Pharmacokinetics and Tissue Disposition of Nanosystem-Entrapped Betulin After Endotracheal Administration to Rats.

BACKGROUND AND OBJECTIVES: Betulin is a triterpene extracted from the cork layer of the outer bark of Betula spp. It has a wide spectrum of pharmacological activities, including being lung protective; however, its bioavailability is low. To increase its bioavailability, betulin was entrapped in a nanosystem (BN). In this study, we investigated the pharmacokinetics and tissue distribution of nanosystem-entrapped betulin after single dose endotracheal administration to rats. METHOD: Betulin was nanosystem-entrapped using a solvent exchange technique. The surface morphology and size of the nanosystem were characterized by transmission electron microscopy and dynamic light scattering. The plasma and tissue concentrations of betulin were determined using a validated high-performance liquid chromatography method. RESULTS: The highest concentration of betulin was found in lungs and liver, and the lowest in the heart. Betulin did not penetrate highly vascularized tissues or tissue with an average degree of vascularization, nor did it cross the blood-brain barrier. Tissue availability in the lungs was 1.3 times higher for BN than for free betulin. Betulin was detected in the bloodstream at 15 min after administration of BN compared with only at 1 h after administration of free betulin. Penetration of betulin in the liver tissue was characterized by a high degree of intensity both for BN and free betulin. Betulin in the heart tissue was detected in much smaller quantities than in the liver. CONCLUSION: Entrapment of betulin in nanosystem form shows promise as a novel strategy in the treatment of pulmonary diseases.

Aralia elata var. mandshurica (Rupr. & Maxim.) J.Wen: An overview of pharmacological studies.

PURPOSE: Aralia elata var. mandshurica (Rupr. & Maxim.) J.Wen syn. A. mandshurica Rupr. & Maxim is evaluated for its medicinal application. The aim of this study is to analyze pharmacological studies on A. elata var. mandshurica published until December 2015. METHODS: The information regarding the chemistry, safety, effectiveness, and pharmacological and clinical effects of A. elata was systematically collected from the scientific literature through library catalogs; online services such as E-library.ru, Medline/PubMed, Scopus, Web of Science, and Google Scholar. RESULTS: A. elata is often considered an example of a medicinal plant used in Chinese, Korean, and Japanese traditional medicine. However, the contemporary applications of Aralia in officinal medicine result primarily from a large number of pharmacological and clinical investigations carried out in the former USSR in the mid-20th century. Since the 1950s, medicinal preparations from radices of A. elata and radices of A. mandshurica have secured an established position within Russian/USSR medicine as evidenced by the inclusion of the drug in recent editions of the National Pharmacopoeia of the USSR and in the Register of Medicinal Preparations of Russia. Pharmacological studies on animals have shown that Aralia increases physical working capacity and affords a stress-protective effect against a broad spectrum of harmful factors including cold stress, immobilization, UV irradiation, and low air pressure. The phytoadaptogen exerts an effect on the central nervous, reproductive, immune, respiratory, and gastrointestinal systems; the metabolic syndrome including hypolipidemic and antidiabetic effects; and blood coagulation. Together with general properties of adaptogens, Aralia has its own specificity, which manifests in cardioprotective and antiarrhythmic activities. Studies on isolated organs, cells, and enzymes have revealed that Aralia preparations exhibit antioxidant activities and enhance sarcoplasmic reticulum Ca2+-ATPase activity, inhibit endoplasmic reticulum stress-associated apoptosis markers (GRP78, CHOP, Caspase-12, and JNK), and increase phosphorylation of STAT3 and Bcl2/Bax ratio; they also show cytotoxic activities against some tumor cell lines; affect NF-κB and PPARs activities; and regulate biosynthesis of pro-inflammatory cytokines and inflammation-related protein expression, tissue respiration, and oxygen consumption. In healthy subjects, Aralia increases mental performance, working capacity, and endurance of movement. Numerous clinical trials have shown the efficiency of Aralia preparations in patients with traumatic brain injury (accompanied with asthenic syndrome and neurotic reactions, depression, neurasthenia, and psychasthenia), neurological diseases (accompanied with astheno-depressive and astheno-hypochondriasis syndromes), myasthenia syndrome (accompanied with chronic post-influenza arachnoiditis), and arterial hypotension. Aralia tincture and "Saparal" are useful as antiviral remedies. Radioprotective properties of Aralia have been reported in pregnant women. Synergistic antiobesity effect was reported for the combination of A. mandshurica and Engelhardtia chrysolepis extracts and antidiabetic effect for the combination of Aralia and glipizide. Promising stress-relieving effects of Aralia are reported for professionals whose work requires a high level of attention. Its proposed ability to moderate stress-induced damage and dysfunction in the cardiovascular tissue might make Aralia the adaptogen of choice among patients with higher risk for cardiovascular diseases. Because Aralia extract administration appears to affect plasma glucose level and hepatic lipid accumulation and ameliorate hyperinsulinemia, it might also provide benefits and be the adaptogen of choice for patients with obesity and diabetes. CONCLUSION: This review describes the considerable diversity of pharmacological effects of A. elata reported in numerous studies carried out in the former USSR and other countries, which have been confirmed over >47 years of use of the plant as an official medicinal remedy. The knowledge discussed in this review can be applied to the expansion of the use of this high-value plant in the pharmacotherapy of European and other countries and for the further discovery of new drugs based on the secondary metabolites of this plant. Modern approaches in mechanisms of action, including a study of gene expression profiling, suggest the most up-to-date challenges for the future research of Aralia.

Bergenia crassifolia (L.) Fritsch--pharmacology and phytochemistry.

PURPOSE: Bergenia crassifolia (L.) Fritsch, a species in the Bergenia genus belongs to the family Saxifragaceae, is valuated for its medicinal application. The review focuses on the medicinal uses, phytochemistry, and the biological activities of B. crassifolia to explore its benefits and potential uses. METHODS: In this review, we summarized data, published in Russia and in other countries related to B. crassifolia. RESULTS: Rhizomes and leaves of this plant are in use as traditional remedies for the treatment of different disorders in the folk medicine systems of Russia and Asia. The plant is a potential source of tannins, benzanoids, flavonoids, polysaccharides and other active compounds. Due to the presence of a multitude of bioactives, a wide array of pharmacological activities have been ascribed to different parts of this herb and individual compounds, which include adaptogenic, antiinflammatory, antihypertensive, antimicrobial, antioxidant, antiobesity, antitussive, cerebro-protective, hepatoprotective, immunomodulating, and diuretic. CONCLUSION: The review highlights the potential of B. crassifolia for further development of herbal medicines on its base.

Oplopanax elatus (Nakai) Nakai: chemistry, traditional use and pharmacology.

Oplopanax elatus (Nakai) Nakai, a member of the ancient angiosperm plant family Araliaceae, is used for the treatment of different disorders in the medicine systems of China, Russia, and Korea, and was designated in Russia as a classical adaptogen. Despite extensive studies of classical adaptogens, there are comparatively few reports concerning the chemical composition and pharmacological effects of O. elatus in English. The plant is a potential source of saponins, flavonoids, anthraquinones, terpenes, and other active compounds. Experimental studies and clinical applications have indicated that O. elatus possesses a number of pharmacological activities, including adaptogenic, anti-convulsant, anti-diabetic, anti-fungal, anti-inflammatory, anti-oxidant, blood pressure modulating, and reproductive function effects. In this review, the chemistry, safety, and therapeutic potential of O. elatus are summarized and highlighted to encourage the further development of this plant.

Rapid profiling of phenolic compounds of green and fermented Bergenia crassifolia L. leaves by UPLC-DAD-QqQ-MS and HPLC-DAD-ESI-QTOF-MS.

Bergenia crassifolia L., Saxifragaceae, is an evergreen perennial plant known in traditional medicine of Russia, Mongolia and China. Polyphenols are responsible for the number of pharmacological effects of Bergenia. UPLC-DAD-QqQ-MS and LC-DAD-ESI-QTOF-MS were used for the rapid profiling of phenolic compounds, mainly hydrolysable tannins. Green leaves consisted of 55% ellagitannins, 29% gallic acid derivatives and 11% flavonoids, with the remaining gallic acid, arbutin, bergenin and caffeoyl quinic acid. In fermented leaves, 31% of gallic acid was found, followed with 28% ellagitannins, 18% gallic acid derivatives and 18% flavonoids, with the remaining caffeoyl quinic acid, bergenin and arbutin. Tellimagrandin I, pedunculagin, caffeoyl quinic acid, monogalloyl quinic acid, 1-O-galloylglucose and 1,2,6-tri-O-galloylglucose were identified for the very first time.

Characterization of volatile and semi-volatile compounds in green and fermented leaves of Bergenia crassifolia L. by gas chromatography-mass spectrometry and ID-CUBE direct analysis in real time-high resolution mass spectrometry.

Chemical compositions of volatile and semi-volatile components in green and fermented leaves of Bergenia crassifolia L. were studied. Leaf components were identified using gas chromatography with low resolution mass spectrometry and direct analysis in real time (DART) high resolution mass spectrometry with an ID-CUBE ion source. Phytol, nerolidol, geraniol, linalool, alpha-bisabolol, alpha-bisabololoxide B, alpha-cadinol, delta-cadinene, alpha-terpineol and several other marker compounds of special interest were defined, for which the process of fermentation significantly changed their content in the leaves. Low resolution El GC-MS and ID-CUBE DART-HRMS were found to be complementary methods, as they provide different information, helpful to increase the confidence of identification.