Harmine Hydrochloride Research Articles

A Phase 1 single ascending dose study of pure oral harmine in healthy volunteers.

Harmine is a component of the hallucinogenic brew, Ayahuasca, which also contains the psychoactive compound, N, N-dimethyltryptamine. Whether pharmaceutical-grade harmine hydrochloride (HCl) has psychoactive effects, the doses at which these might occur, and the dose-response relationship to side effects and safety in humans are unknown. We conducted a Phase 1, open-label single ascending dose trial in healthy adults with normal body mass index and no prior psychiatric illness. The primary goal was to determine the maximum tolerated dose (MTD) of oral pharmaceutical-grade harmine HCl and to characterize safety and tolerability. A secondary goal was to ascertain whether any oral dose has psychoactive effects. Thirty-four adult participants, aged 18-55 years, were screened for study eligibility. Twenty-five participants met eligibility criteria and were randomized to a single dose of 100, 200, 300, or 500 mg of harmine HCl, respectively, using a continuous reassessment method. The most common adverse events (AEs) observed were gastrointestinal and/or neurological, dose-related, and of mild to moderate severity. The MTD was determined to be between 100 and 200 mg and is weight-based, with 90% of those participants receiving >2.7 mg/kg experiencing a dose-limiting toxicity. No serious AEs of harmine HCl were identified. Harmine HCl can be orally administered to healthy participants in doses <2.7 mg/kg with minimal or no AEs. Doses >2.7 mg/kg are associated with vomiting, drowsiness, and limited psychoactivity. This study is the first to systematically characterize the psychoactive effects of pharmaceutical quality harmine in healthy participants.

Increased Myocardial MAO-A, Atrogin-1, and IL-1β Expression in Transgenic Mice with Pancreatic Carcinoma-Benefit of MAO-A Inhibition for Cardiac Cachexia.

Cancer cachexia (CC) continues to challenge clinicians by massively impairing patients' prognosis, mobility, and quality of life through skeletal muscle wasting. CC also includes cardiac cachexia as characterized by atrophy, compromised metabolism, innervation and function of the myocardium through factors awaiting clarification for therapeutic targeting. Because monoamine oxidase-A (MAO-A) is a myocardial source of H2O2 and implicated in myofibrillar protein catabolism and heart failure, we presently studied myocardial MAO-A expression, inflammatory cells, and capillarization together with transcripts of pro-inflammatory, -angiogenic, -apoptotic, and -proteolytic signals (by qRT-PCR) in a 3x-transgenic (LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre) mouse model of orthotopic pancreatic ductal adenoarcinoma (PDAC) compared to wild-type (WT) mice. Moreover, we evaluated the effect of MAO-A inhibition by application of harmine hydrochloride (HH, 8 weeks, i.p., no sham control) on PDAC-related myocardial alterations. Myocardial MAO-A protein content was significantly increased (1.69-fold) in PDAC compared to WT mice. PDAC was associated with an increased percentage of atrogin-1+ (p < 0.001), IL-1β+ (p < 0.01), COX2+ (p < 0.001), and CD68+ (p > 0.05) cells and enhanced transcripts of pro-inflammatory IL-1β (2.47-fold), COX2 (1.53-fold), TNF (1.87-fold), and SOCS3 (1.64-fold). Moreover, PDAC was associated with a reduction in capillary density (-17%, p < 0.05) and transcripts of KDR (0.46-fold) but not of VEGFA, Notch1, or Notch3. Importantly, HH treatment largely reversed the PDAC-related increases in atrogin-1+, IL-1β+, and TNF+ cell fraction as well as in COX2, IL-1β, TNF, and SOCS3 transcripts, whereas capillary density and KDR transcripts failed to improve. In mice with PDAC, increased myocardial pro-atrophic/-inflammatory signals are attributable to increased expression of MAO-A, because they are significantly improved with MAO-A inhibition as a potential novel therapeutic option. The PDAC-related loss in myocardial capillary density may be due to other mechanisms awaiting evaluation with consideration of cardiomyocyte size, cardiac function and physical activity.

Harmine Hydrochloride Induces G2/M Cell Cycle Arrest and Apoptosis in SK-Hep1 Hepatocellular Carcinoma Cells by Regulating Mitogen-Activated Protein Kinases and the PI3K/AKT Pathway.

Liver cancer is a globally common form of cancer. Thus, novel drugs derived from natural products are needed to reduce the side effects of chemotherapy. The present study aimed to analyze the anticancer properties and effects of harmine hydrochloride (HMH), a water-soluble metabolite of harmine that can be easily absorbed into tissues, in treating liver cancer cells. HMH dose-dependently inhibited cell growth, migration, invasion, and colony formation in SK-Hep1 cells. It also induced G2/M arrest by reducing the expression of p-cdc2, cyclin B1, and Rb (G2/M phase regulatory proteins) in a dose-dependent manner. HMH treatment reduced the expression of caspase-9, caspase-3, PARP, and Bcl-2 and increased the expression of Bax (a proapoptotic protein). Moreover, it increased the production of reactive oxygen species and decreased the intracellular uptake of rhodamine 123 due to mitochondrial dysfunction because of oxidative stress. HMH treatment also upregulated the phosphorylation of JNK, p38, and FOXO3a in SK-Hep1 cells and downregulated the PI3K/AKT signaling pathway. Our findings suggest that HMH may activate the compounds responsible for anticancer effects in hepatocellular carcinoma cells.

A screening identifies harmine as a novel antibacterial compound against Ralstonia solanacearum.

Ralstonia solanacearum, the causal agent of bacterial wilt, is a devastating plant pathogenic bacterium that infects more than 450 plant species. Until now, there has been no efficient control strategy against bacterial wilt. In this study, we screened a library of 100 plant-derived compounds for their antibacterial activity against R. solanacearum. Twelve compounds, including harmine, harmine hydrochloride, citral, vanillin, and vincamine, suppressed bacterial growth of R. solanacearum in liquid medium with an inhibition rate higher than 50%. Further focus on harmine revealed that the minimum inhibitory concentration of this compound is 120 mg/L. Treatment with 120 mg/L of harmine for 1 and 2 h killed more than 90% of bacteria. Harmine treatment suppressed the expression of the virulence-associated gene xpsR. Harmine also significantly inhibited biofilm formation by R. solanacearum at concentrations ranging from 20 mg/L to 60 mg/L. Furthermore, application of harmine effectively reduced bacterial wilt disease development in both tobacco and tomato plants. Collectively, our results demonstrate the great potential of plant-derived compounds as antibacterial agents against R. solanacearum, providing alternative ways for the efficient control of bacterial wilt.

Matrix Assisted Laser Desorption Ionization – Tandem Time-of-Flight – Mass Spectrometry (MALDI-TOF/TOF-MS) Characterization of Oligosaccharides: Structural Identification and Differentiation

Mass spectrometry (MS) has been developed for high-sensitivity structural determination of carbohydrates. Due to the similarity of oligosaccharide structures, there is still insufficient information about the correlation between carbohydrate chemical structure and mass spectra. A series of trisaccharides containing different glycosidic linkages (1→2, 1→3, 1→4, 1→6, 2→1 and 2→6), anomeric configuration (α and β), and monosaccharide (pentose, hexose and hexuronic acid), as well as two cyclodextrins (α- and β-cyclodextrin) were systematically investigated using matrix assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI TOF/TOF MS) in positive and negative ion modes using super-DHB (2,5-dihydroxybenzoic acid) and harmine hydrochloride as matrices, respectively. Cross-ring cleavage generated by A-types ions with neutral losses of 48, 60, 78, 90, or 120 Da were observed in the negative ion MS/MS spectra, and neutral losses of 60, 90, or 120 Da were observed in the positive ion MS/MS spectra. Glycosidic cleavages were observed in both modes. The linkage isomers were unambiguously identified by those diagnostic fragment ions with their relative intensities. Furthermore, the correlation between linkage pattern and characteristic ions successfully allowed the characterization of polysaccharides with different structural features.

Harmine Hydrochloride Triggers G2/M Cell Cycle Arrest and Apoptosis in HCT116 Cells through ERK and PI3K/AKT/mTOR Signaling Pathways.

Colorectal carcinoma (CRC) is one of the most common and aggressive malignant carcinomas. There is a pressing need to develop naturally derived novel drugs with minimal side effects for treatment of CRC. In this study, we aimed to investigate the anticancer effects of harmine hydrochloride (HMH), a hydrophilic and stable substance that is easily absorbed by tissues and similar to harmine, and the underlying mechanism of action in human CRC HCT116 cells. HMH inhibited the growth, colony formation, and migration ability of HCT116 cells. Additionally, HMH induced G2 cell cycle arrest by reducing expression of p-cdc2, cdc2, and cyclin B1, proteins that regulate the G2/M phase, and expression of Rb, a protein that regulates cell proliferation, in a dose-dependent manner. HMH mediated apoptosis by downregulating expression of apoptotic proteins (such as caspase-3, caspase-9, and PARP) and the anti-apoptotic protein Bcl-2 and by inducing expression of Bax, a pro-apoptotic protein. Furthermore, HMH reduced the levels of p-ERK, p-PI3K, p-AKT, and p-mTOR in HCT116 cells, and significantly inhibited p-ERK and p-AKT expression in cells treated with of HMH and PD98059, an ERK inhibitor, or LY294002, an AKT inhibitor (P<0.05 and P<0.01). These results demonstrate the inhibi-tory effect of HMH on cell proliferation and migration through inducing apoptosis by inhibiting ERK and PI3K/AKT/mTOR signaling pathways, indicating its potential therapeutic applications in CRC.

Harmine Hydrochloride Mediates the Induction of G2/M Cell Cycle Arrest in Breast Cancer Cells by Regulating the MAPKs and AKT/FOXO3a Signaling Pathways.

Breast cancer (BC) is one of the most common causes of death among women worldwide. Recently, interest in novel approaches for BC has increased by developing new drugs derived from natural products with reduced side effects. This study aimed to treat BC cells with harmine hydrochloride (HMH) to identify its anticancer effects and mechanisms. HMH treatment suppressed cell growth, migration, invasion, and colony formation in MCF-7 and MDA-MB-231 cells, regardless of the hormone signaling. It also reduced the phosphorylation of PI3K, AKT, and mTOR and increased FOXO3a expression. Additionally, HMH treatment increased p38 phosphorylation in MCF-7 cells and activated c-Jun N-terminal kinase (JNK) phosphorylation in MDA-MB-231 cells in a dose-dependent manner, where activated p38 and JNK increased FOXO3a expression. Activated FOXO3a increased the expression of p53, p21, and their downstream proteins, including p-cdc25, p-cdc2, and cyclin B1, to induce G2/M cell cycle arrest. Furthermore, HMH inhibited the PI3K/AKT/mTOR pathway by significantly reducing p-AKT expression in combination with LY294002, an AKT inhibitor. These results indicate that mitogen-activated protein kinases (MAPKs) and AKT/FOXO3a signaling pathways mediate the induction of cell cycle arrest following HMH treatment. Therefore, HMH could be a potential active compound for anticancer bioactivity in BC cells.

Alkaloids of Peganum harmala L. and their Pharmacological Activity

Peganum harmala L. contains 17 alkaloids of quinazoline and indole structure types. Of these, harmaline, harmine, harmalol and L-peganin (vazicin) are pharmacologically active. It was established that of the alkaloids contained in the seeds, 50-95% is dominated by harmaline, harmine is dominated in the roots (67-74% of the total of extractive substances), and in the aerial part, the main mass is peganin (up to 78% of the total of alkaloids). Beta-carboline alkaloids of Peganum harmala L. inhibit monoamine oxidase, thereby exerting a neuroprotective effect.&#x0D; This article is devoted to the results of studies of the neurotropic action of harmine hydrochloride, when compared with the activity of the reference drug “Amitriptyline”. It was shown that the use of harmine hydrochloride helps to reduce the level of anxiety in animals under conditions of experimental psychoemotional chronic stress with prolonged administration. In the study of acute and chronic toxicity, it was determined that harmine hydrochloride belongs to the category of moderately toxic substances (hazard class II). According to the results of molecular docking, the presence of strong bonds in harmine hydrochloride with the serotonin 5-HT2C receptor, dopamine D2 receptor, as well as monoamine oxidase A and B was revealed, which indicates the implementation of the mechanism of neurotropic action of harmine hydrochloride at the level of synaptic neurotransmission of monoamines (dopamine, serotonin and others). It was also established that harmine hydrochloride eliminates haloperidol-induced catalepsy in rats, reduces oligokinesia and rigidity in the Parkinson’s test, has antihypoxic activity in the hypobaric hypoxia test, and exhibits pronounced antidepressant activity in the Porsolt’s test. In the course of the study of pharmacokinetics and bioavailability, it was revealed that with the administration of harmine hydrochloride, the quantitative content is quickly achieved and the concentration of the active substance in the blood significantly increases. The relative bioavailability of harmine hydrochloride is 112.7%.

The experimental study of the antihypoxic properties of harmine hydrochloride

A derivative of the beta-carboline alkaloid harmine — the drug harmine hydrochloride was studied for the presence of antihypoxic properties in models of hypobaric hypoxia and normobaric hypoxia with hypercapnia. It was found that harmine hydrochloride does not have a signifi cant compensatory effect in the normobaric hypoxia test with hypercapnia. At the same time, harmine hydrochloride in small doses (2.5 and 5 mg/kg) has antihypoxic activity in the hypobaric hypoxia test, which is expressed in a statistically signifi cant increase in the life expectancy of animals treated with the drug, compared with the control, in conditions of hypoxia. According to the antihypoxic effect, harmine hydrochloride at doses of 2.5 and 5 mg/kg was found to be comparable with the reference drug (mexidol, 100 mg/kg).

An experimental study of the systemic bioavailability of the drug "Harmin hydrochloride, capsules" in comparison with native garmin on chinchilla rabbits

An experimental comparative study of the relative bioavailability of plant alkaloid harmine (native, in the form of a base) in comparison with its derivative harmine hydrochloride was carried out on chinchilla rabbit. Both substances was administered in capsules, containing an equimolar amount of harmine (50 mg, p.o.). Harmin hydrochloride was shown to have some pharmacokinetic advantages in comparison with native harmin due to a relatively rapid achievement of the maximal plasma concentration (T max ) and a significantly higher maximum concentration of the active substance in the blood. At the same time, there was shown that the chemical modification of harmine does not significantly affect on such pharmacokinetics parameter as the area under the curve (AUC), which indicates the absence of a difference in the degree of absorption in the compared dosage forms.

OPTIMIZATION OF EXTRACTION TECHNOLOGY OF PEGANUM HARMALA L. ROOTS

The aim of this work is to develop an effective and economical technology for extracting the sum of extractive substances from raw materials of Peganum harmala L. roots by percolation method.&#x0D; The plant material is the roots of Peganum harmala L., collected in October 2017 in the vicinity of the village of Akshi (Almaty region, Kazakhstan). Maceration was carried out on the pilot unit ERSND-1 (Karaganda, Kazakhstan). Percolation was carried out on extractor P-250 (Tomsk, Russia). Quantitative analysis of the content of harmine in the amount of extractive substances was determined by HPLC with a UV-detector method.&#x0D; Various factors affecting the efficiency of extracting the sum of alkaloids from the roots of Peganum harmala L. by maceration and percolation method are reviewed and compared in this work. It has been established that percolation is the preferred extraction method for the sum of extractive substances, which makes it possible to reduce the extraction process by 5 times compared to maceration. The optimal processing parameters and grinding of raw materials of Peganum harmala L. roots, as well as the technological parameters of extraction, providing a quantitative yield of the sum of alkaloids were established.&#x0D; The studies show the promise of using the percolation method and the need for further work on the implementation of the developed technology for the extraction of Peganum harmala L. alkaloids in the production of the substance of the neurotropic drug "Harmine hydrochloride".

The Level of Reactive Carbonyl Derivatives of Proteins, Malondialdehyde, and Catalase Activity in the Brain of Rats after Therapy Following Chronic Unpredictable Moderate Stress

BACKGROUND: Understanding the mechanisms of the behavioral disorders’ emergence under the influence of chronic stress is the most important aspect of the subsequent development of a strategy for its therapy and prevention. Changes in the oxidative metabolism processes can be decisive in the development of the pathogenetic cascade in the brain. Information about these processes can be obtained by studying protein carbonylation, lipid peroxidation, and catalase activity (CA). The complexity of the therapeutic impact in various behavioral disorders implies the search for new pharmacological substances and the study of the previously known drugs’ effects based on the available scientific data.&#x0D; AIM: The aim of the study was to study the reactive carbonyl derivatives of proteins (RCDP), malondialdehyde (MDA), and CA in the brain of rats after therapy following chronic unpredictable moderate stress (CUMS).&#x0D; METHODS: Forty male outbred rats weighing 450–500 g were used in this study. For 21 days, all animals were exposed to the diverse stress factors for developing the CUMS. The animals were divided into four groups of 10 rats, each using randomized selection. The rats of one group were euthanized by decapitation with subsequent brain harvesting (Group 4). Remaining three groups of rats were treated with placebo (Group 1), harmine hydrochloride (Group 2), and amitriptyline (Group 3) for 21 days. Upon completion of therapy, all rats were also euthanized by decapitation with subsequent brain harvesting. The levels of RCDP, MDA, and CA were studied in their brain, and after that, we compared the multiple studied indicators in four groups.&#x0D; RESULTS: The results of the rat brain examinations in four groups showed that RCDP level in Group 2 was significantly lower than in Group 4 (p = 0.000). Similarly, in Group 1, it was lower than in Group 4 (p = 0.021), plus, it did not differ statistically from the harmine hydrochloride group (p = 1,000). Indicators of Groups 3 and 4 did not have any significant differences in RCDP level, too, (p = 0.799); however, the RCDP level in Group 2 was significantly lower than in Group 3 (p = 0.040). MDA indicators did not show significant differences; however, a tendency for lower values was revealed in Group 1 (p = 0.233) and Group 2 (p = 0.151). CA in Group 4 was lower than that in Group 1 (p = 0.000), Group 2 (p = 0.001), and Group 3 (p = 0.003) contemporaneously, while all treatment groups were comparable (p = 1.000).&#x0D; CONCLUSION: The result of exposure to chronic stress can be reproduced with the best quality in the CUMS model. The neurobiological foundations of the model make it possible to assess biochemical markers of oxidative metabolism and evaluate the possibilities of pharmacological correction of stress-induced behavioral disorders. To assess the mechanisms of autoregulation of oxidative metabolism, this study included a placebo group (Group 1), the level of RCDP in which was significantly higher in comparison with Group 3 and Group 4 and slightly lower than in Group 2. In this study, harmine hydrochloride demonstrated activity exceeding amitriptyline, particularly limiting the process of protein carbonylation, not noted for amitriptyline. According to the results of the RCDP assessment in the CUMS model, the process of protein carbonylation can be considered to be one of the significant factors in the deactivation of neurotransmitters. The CA levels determined in all groups allowed us to consider this marker as the most sensitive to the effects of stress, which possibly has an inhibitory effect on catalase, as its activity in all groups after therapy was more than two-fold higher than in animals right after CUMS. We can assume that CA plays an important role in starting the processes of autoregulation of oxidative metabolism. The study was carried out as a part of the implementation of the scientific and technical program No. BR05236584 “Development of new herbal preparations and their pharmacological and clinical studies” (O.0820). (2018–2020) in the priority area, “Life and Health Sciences.”

High Content Screening Using New U2OS Reporter Cell Models Identifies Harmol Hydrochloride as a Selective and Competitive Antagonist of the Androgen Receptor.

Prostate cancer is the most commonly diagnosed malignancy in men. Its growth mainly relies on the activity of the androgen receptor (AR), justifying the use of androgen deprivation therapy as a gold standard treatment for the metastatic disease. Inhibition of the androgen axis using second generation antagonists has improved patients’ survival, but is systematically confronted to resistance mechanisms, leading to a median survival that does not exceed 5 years. Counteracting this resistance has been the object of a large number of investigations, with a particular emphasis towards the identification of new AR inhibitors, whether they antagonize the receptor by a competitive or a non-competitive binding. To this end, many high content screens have been performed, to identify new non-steroidal AR antagonists, using a variety of approaches, but reported somewhat controversial results, depending on the approach and on the cell model that was used for screening. In our study, we used the U2OS osteosarcoma cells stably transfected with AR or ARv7 and a luciferase reporter as a previously validated model to screen the Prestwick Phytochemical library. The results of our screen identified ellipticine, harmol, and harmine hydrochloride as confirmed hits. Surprisingly, we could demonstrate that harmol hydrochloride, previously identified as a non-competitive inhibitor of AR or a weak inhibitor of androgen signaling, was actually a competitive antagonist of AR, which inhibits the growth of VCaP prostate cancer line, at concentrations for which it did not affect the growth of the AR negative DU145 and PC3 cells. Interestingly, we also report for the first time that harmol hydrochloride was selective for AR, as it could not alter the activity of other nuclear receptors, such as the glucocorticoid receptor (GR), the progesterone receptor (PR), or the mineralocorticoid receptor (MR). Additionally, we demonstrate that, conversely to enzalutamide, harmol hydrochloride did not show any agonistic activity towards the pregnane X receptor (PXR), a master regulator of drug metabolism. Together, our results shed light on the importance of the cellular context for the screening of new AR antagonists. They further indicate that some of the potential hits that were previously identified may have been overlooked.

The impact of Harmine hydrochloride on growth, apoptosis and migration, invasion of gastric cancer cells

It has been reported that Harmine hydrochloride (HH) has an inhibitory effect on tumor cells, but the effect and mechanism of HH on gastric cancer cells remains unclear. The aim of this study was to investigate the effect and mechanism of HH on human gastric cancer cell line. In present study, results showed that HH could inhibit AGS, SGC7901 and HGC-27 cells in a time-dose-dependent manner (P < 0.01). Furthermore, this study demonstrated that more cells were arrested in G0/G1 phase, and apoptosis rate of AGS cells was significantly increased after HH treatment (P < 0.01). In addition, the study results showed that the mRNA and proteins of CyclinE, CyclinD1, PCNA declined dramatically, while p27, p21 increased significantly (P < 0.01). The results in this research also showed that the mRNA and proteins of Survivin and Bcl-2 decreased, while the expression of Bax, caspase-3, Bad increased significantly (P < 0.01). Also, the results of this study showed that invasion and migration of AGS cells decreased significantly after HH treatment (P < 0.01), with the expression of MMP-2, HIF-1 α and PRDX1 decreasing on observation after HH treatment (P < 0.01). In conclusion, HH has the property to inhibit GC cells via regulating GC cells’ proliferation, apoptosis, invasion and migration.

Experimental study of antiparkinsonian action of the harmine hydrochloride original compound.

The effects of chemical products on the nervous system have been studied by various scientists. In this work, the antiparkinsonian action of a water-soluble form of harmine hydrochloride was studied. The present studies aim to research antiparkinsonian action of the harmine hydrochloride original compound. To achieve the objective of the study, the authors used haloperidol-induced catalepsy and a method of Parkinson's syndrome (PS) induced by the MPTP (the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxin. The experiments were performed on rats and mice which were divided into groups of 10 animals. It was established that harmine hydrochloride (HH), at a certain dose, eliminated haloperidol-induced catalepsy in rats and reduced oligokinesia and rigidity in the parkinsonism test in mice. Seven days after the experiment, the authors found the presence of rigidity in animals which had received the neurotoxin. It manifested itself in a shortened stride length compared to this parameter in intact controls. During the study the efficacy of harmine hydrochloride was equivalent to the effects of levodopa at a certain dose, which suggested that harmine hydrochloride compensated dopamine deficiency in the brain.

Synergistic Effects and Mechanisms of Combined Treatment With Harmine Hydrochloride and Azoles for Resistant Candida albicans.

Several studies have demonstrated the significant antiviral, antimicrobial, antiplasmodial, antioxidative, antifungal, antimutagenic, and antitumor properties of harmine hydrochloride (HMH). The main objective of the present study was to investigate the antifungal effects and underlying mechanisms of HMH when combined with azoles to determine whether such combinations act in a synergistic manner. As a result, we found that HMH exhibits synergistic antifungal effects in combination with azoles against resistant Candida albicans (C. albicans) planktonic cells, as well as resistant C. albicans biofilm in the early stage. Antifungal potential of HMH with fluconazole was also explored in vivo using an invertebrate model. Our results suggest that HMH combined with azoles is synergistic against resistant C. albicans in vitro and in vivo. No synergy is seen with azole sensitive C. albicans strains nor with other Candida species. Such synergistic mechanisms on resistance C. albicans are involved in increasing intracellular azoles, inhibiting hyphal growth, disturbing cytosolic calcium concentration, and inducing apoptosis of resistant C. albicans cells.

Experimental research of Harmine hydrochloride effect on internal organs

Objective. The purpose of thisstudy was to determine the chronic toxicity of the drug “Harmine hydrochloride, capsules” for preclinical evaluation of its safety.&#x0D; Materials and methods.The experiment was performed on 48 CD-1 rats. Harmine hydrochloride was injectedto the animals intragastrically at doses of 2.5 mg / kg/per day, 5 mg / kg/per day, 9 mg / kg/per day, 10 mg / kg/per day for 3 months. After 3 months, the animals were withdrew from the experiment, internal organs (brain, heart, spleen, adrenals) were weighed and set in 10% neutral formalin. Histological specimenswere mounted in accordance with standard procedures.&#x0D; Results and Discussion. All morphological, histopathological changes, in addition to mortality and bodyweight changes were recorded.Microtome cuts, 5 micrometers thick, were stained with hematoxylin and eosin.&#x0D; Conclusion. As a result of the morphological study, there was no toxic effect of harmine hydrochloride at doses of 2.5 mg / kg, 5 mg / kg, 9 mg / kg and 10 mg / kg on the brain, at doses of 2.5 mg / kg and 5 mg / kg on the structure of the heart, spleen and adrenal glands. At doses of 9 mg / kg and 10 mg / kg, there is an initial toxic dose-dependent effect on the heart, spleen and adrenal glands.&#x0D; Bangladesh Journal of Medical Science Vol.18(3) 2019 p.598-606

Harmine Hydrochloride Triggers G2 Phase Arrest and Apoptosis in MGC-803 Cells and SMMC-7721 Cells by Upregulating p21, Activating Caspase-8/Bid, and Downregulating ERK/Bad Pathway.

This study aimed to investigate the effects of harmine hydrochloride (HMH) on digestive tumor cells in vitro and its molecular mechanism. MTT assays showed that HMH inhibited the proliferation of some human cancer cell lines and had no obvious inhibitory effects on human LO2 cells. Flow cytometry assays showed that HMH trigged G2 phase arrest in MGC-803 cells and SMMC-7721 cells, while the expression of cyclin A, cyclin B, p21, Myt1, and p-cdc2 (Tyr15) was upregulated. Flow cytometry assays also showed that the percentages of apoptotic cells were increased, the mitochondrial transmembrane potential (ΔΨm) decreased, and the cleavage of caspase-9, caspase-3, and poly (Adenosine diphosphate ribose) polymerase (PARP) were observed, the expression of Bad increased, phospho-Bad (S112) decreased, pro-caspase-8 was cleaved, and Bid (22 kDa) was cleaved. The expression of p-ERK decreased in both cells. In conclusion, these results demonstrated that HMH upregulates the expression of p21, activates Myt1 and inhibits cdc2 by phospho-cdc2 (Y15), and triggers G2 phase arrest in both MGC-803 cells and SMMC-7721 cells. It can also activate the mitochondria-related cell apoptosis pathway through the caspase-8/Bid pathway, inhibiting the ERK/Bad pathway and promoting apoptosis in both of these two cell types.

ANTIDEPRESSANT ACTION OF HARMINE HYDROCHLORIDE

The articles presents the results of antridepressant action of water-soluble form of harmine hydrochloride.

PERSPECTIVE DRUG DOSAGE OF NEUTROPIC REMEDY ON THE BASIS OF EXCIPIENT FROM ROOTS OF PEGANUM HARMALA L.

This article represents the results of technological researches on development of new neurotropic remedy based on water-soluble excipient of harmine hydrochloride. Peroral remedy in capsules at dose of 30 mg which correspond to pharmaceutical quality indices have been developed for the first time.