The roles of autophagy, ferroptosis and pyroptosis in the anti-ovarian cancer mechanism of harmine and their crosstalk.

This study aimed to investigate the role of autophagy, ferroptosis, and pyroptosis in the antitumour mechanism of harmine (Har) and its crosstalk in ovarian cancer. By transmission electron microscopy, we found that compared with those in the control group, the cytoplasm of human ovarian cancer cells (SKOV3) treated with Har showed increased numbers of autophagic vesicles, decreased intracellular mitochondrial volume, increased bilayer membrane density, and decreased cristae. Western blot, immunofluorescence, and monodasylcadaverine (MDC) staining all suggested that Har promoted autophagy in SKOV3 cells. LY294002 and siFOXO3 rescued the inhibition of the PI3K/AKT/mTOR/FOXO3 signalling pathway and the promotion of autophagy by Har. Additionally, the levels of ferroptosis- and pyroptosis-related proteins and the levels of Fe2+ , glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) suggested that Har promoted ferroptosis and pyroptosis in SKOV3 cells. Interestingly, pretreatment with chloroquine (CQ), erastin, rapamycin (Rap), or ferrostatin-1 (Fer-1) increased or reversed the ferroptosis and pyroptosis promoted by Har, respectively. In vivo, the volume of tumours in the Har group was decreased, and immunohistochemistry revealed decreased levels of Ki-67 and GPX4 and increased levels of ATG5 and NARL3. In conclusion, Har exerts its anti-ovarian cancer effect not only by promoting autophagy by regulating the PI3K/AKT/mTOR/FOXO3 signalling pathway but also by promoting ferroptosis and pyroptosis. Additionally, there is complex crosstalk between autophagy, ferroptosis, and pyroptosis in ovarian cancer.

Exploring potooxidative degradation pathways of harmol and harmalol alkaloids in water: effects of pH, excitation sources and atmospheric conditions.

This work explores the photochemical degradation of cationic species of 7-hydroxy-1-methyl-2H-pyrido[3,4-b]indole or harmol (1C) and the corresponding partially hydrogenated derivative 7-hydroxy-1-methyl-3,4-dihydro-2H-pyrido[3,4-b]indole or harmalol (2C) in aqueous solution. UV-visible absorption and fluorescence emission spectroscopy coupled with multivariate data analysis (MCR-ALS and PARAFAC), HPLC and HRESI-MS techniques were used for both quantitative and qualitative analysis. The formation of hydrogen peroxide reactive oxygen species (ROS) was quantified, and the influence of pH, oxygen partial pressure and photoexcitation source on the photochemical degradation of both compounds was assessed. The potential implications on the biosynthesis of ßCs and their biological role in living systems are discussed.

Harmine ameliorates CCl4-induced acute liver injury through suppression of autophagy and inflammation.

CCl4-induced acute liver injury (ALI) is characterized by heightened autophagy, inflammation, and oxidative damage. Accumulating evidence suggests that harmine exerts beneficial effects in countering CCl4-induced ALI by mitigating inflammation and oxidative stress. However, the impact of autophagy on CCl4-induced ALI and the protective role of harmine remain unclear. This study aimed to investigate the potential protective effects of harmine against CCl4-induced ALI in mice by suppressing autophagy and inflammation. Male Kunming mice were orally administered harmine or bifendate for seven days. Subsequently, one hour after the final administration, the model group and treatment groups were intraperitoneally injected with CCl4 to induce ALI. The findings revealed that harmine significantly reduced the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, and ameliorated the liver histopathological changes induced by CCl4. Furthermore, harmine diminished the levels of TNF-α and IL-6, restored the levels of glutathione (GSH) and superoxide dismutase (SOD), and suppressed the production of nitric oxide (NO) and malondialdehyde (MDA) in the liver. Mechanistically, harmine down-regulated LC3B II/I, p38 MAPK, TLR4, and NF-κB levels, while upregulating p62, Bcl-2, Beclin1, ULK1, and p-mTOR expression. In conclusion, harmine mitigated CCl4-induced ALI by inhibiting autophagy and inflammation through the p38 MAPK/mTOR autophagy pathway, the Bcl-2/Beclin1 pathway, and the TLR4/NF-κB pathway.

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a ß-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

Ayahuasca and its major component harmine promote antinociceptive effects in mouse models of acute and chronic pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayahuasca (AYA) is a psychedelic brew used in religious ceremonies. It is broadly used as a sacred medicine for treating several ailments, including pain of various origins. AIM OF THE STUDY: To investigate the antinociceptive effects of AYA and its mechanisms in preclinical models of acute and chronic pain in mice, in particular during experimental neuropathy. MATERIALS AND METHODS: The antinociceptive effects of AYA administered orally were assessed in the following models of pain: formalin test, Complete Freund's Adjuvant (CFA)-induced inflammation, tail flick test, and partial sciatic nerve ligation model of neuropathic pain. Antagonism assays and Fos immunohistochemistry in the brain were performed. AYA-induced toxicity was investigated. AYA was chemically characterized. The antinociceptive effect of harmine, the major component present in AYA, was investigated. RESULTS: AYA (24-3000 µL/kg) dose-dependently reduced formalin-induced pain-like behaviors and CFA-induced mechanical allodynia but did not affect CFA-induced paw edema or tail flick latency. During experimental neuropathy, single treatments with AYA (24-3000 µL/kg) reduced mechanical allodynia; daily treatments once or twice a day for 14 days promoted consistent and sustained antinociception. The antinociceptive effect of AYA (600 µL/kg) was reverted by bicuculline (1 mg/kg) and methysergide (5 mg/kg), but not by naloxone (5 mg/kg), phaclofen (2 mg/kg), and rimonabant (10 mg/kg), suggesting the roles of GABAA and serotonergic receptors. AYA increased Fos expression in the ventrolateral periaqueductal gray and nucleus raphe magnus after 1 h, but not after 6 h or 14 days of daily treatments. AYA (600 µL/kg) twice a day for 14 days did not alter mice's motor function, spontaneous locomotion, body weight, food and water intake, hematological, biochemical, and histopathological parameters. Harmine (3.5 mg/kg) promoted consistent antinociception during experimental neuropathy. CONCLUSIONS: AYA promotes consistent antinociceptive effects in different mouse models of pain without inducing detectable toxic effects. Harmine is at least partially accountable for the antinociceptive properties of AYA.

Discovery of novel harmine derivatives as GSK-3ß/DYRK1A dual inhibitors for Alzheimer's disease treatment.

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.

Design, synthesis, and biological evaluation of harmine derivatives as topoisomerase I inhibitors for cancer treatment.

A series of ß-carboline derivatives were designed and synthesized by introducing the chalcone moiety into the harmine. The synthesized derivatives were evaluated their anti-proliferative activities against six human cancer cell lines (MCF-7, MDA-MB-231, HepG2, HT29, A549, and PC-3) and one normal cell line (L02). Among them, compound G11 exhibited the potent anti-proliferative activity against MCF-7 cell line, with an IC50 value of 0.34 µM. Further biological studies revealed that compound G11 inhibited colony formation of MCF-7 cells, suppressed MCF-7 cell migration by downregulating migration-associated protein MMP-2. In addition, it could induce apoptosis of MCF-7 cells by downregulating Bcl-2 and upregulating Cleaved-PARP, Bax, and phosphorylated Bim proteins. Furthermore, compound G11 can act as a Topo I inhibitor, affecting DNA synthesis and transcription, thereby inhibiting cancer cell proliferation. Moreover, compound G11 inhibited tumor growth in 4T1 syngeneic transplant mice with an inhibition rate of 43.19 % at a dose of 10 mg/kg, and 63.87 % at 20 mg/kg, without causing significant toxicity to the mice or their organs, achieving the goal of reduced toxicity and increased efficacy. All these results indicate of G11 has enormous potential as an anti-tumor agent and merits further investigation.

Inhibition of DYRK1A attenuates vascular remodeling in pulmonary arterial hypertension via suppressing STAT3/Pim-1/NFAT pathway.

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling caused by the excessive proliferation and survival of pulmonary artery smooth muscle cells (PASMCs). Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in the regulation of multiple biological functions, including cell proliferation and survival. However, the role and underlying mechanisms of DYRK1A in PAH pathogenesis remain unclear. We found that DYRK1A was upregulated in PASMCs in response to hypoxia, both in vivo and in vitro. Inhibition of DYRK1A by harmine significantly attenuated hypoxia-induced pulmonary hypertension and pulmonary artery remodeling. Mechanistically, we found that DYRK1A promoted pulmonary arterial remodeling by enhancing the proliferation and survival of PASMCs through activating the STAT3/Pim-1/NFAT pathway, because STAT3 gain-of-function via adeno-associated virus serotype 2 (AAV2) carrying the constitutively active form of STAT3 (STAT3C) nearly abolished the protective effect of harmine on PAH. Collectively, our results reveal a significant role for DYRK1A in pulmonary arterial remodeling and suggest it as a drug target with translational potential for the treatment of PAH.

Anticancer Potential of ß-Carboline Alkaloids: An Updated Mechanistic Overview.

his comprehensive review is designed to evaluate the anticancer properties of ß-carbolines derived from medicinal plants, with the ultimate goal of assessing their suitability and potential in cancer treatment, management, and prevention. An exhaustive literature survey was conducted on a wide array of ß-carbolines including, but not limited to, harmaline, harmine, harmicine, harman, harmol, harmalol, pinoline, tetrahydroharmine, tryptoline, cordysinin C, cordysinin D, norharmane, and perlolyrine. Various analytical techniques were employed to identify and screen these compounds, followed by a detailed analysis of their anticancer mechanisms. Natural ß-carbolines such as harmaline and harmine have shown promising inhibitory effects on the growth of cancer cells, as evidenced by multiple in vitro and in vivo studies. Synthetically derived ß-carbolines also displayed noteworthy anticancer, neuroprotective, and cognitive-enhancing effects. The current body of research emphasizes the potential of ß-carbolines as a unique source of bioactive compounds for cancer treatment. The diverse range of ß-carbolines derived from medicinal plants can offer valuable insights into the development of new therapeutic strategies for cancer management and prevention.

1,3-Substituted ß-Carboline Derivatives as Potent Chemotherapy for the Treatment of Cystic Echinococcosis.

Echinococcosis is a global public health issue that generally occurs in areas with developed animal husbandry. In search of safe and effective therapeutic agents against echinococcosis, we designed and synthesized new 1,3-substituted ß-carboline derivatives based on harmine. Among them, compounds 1a, 1c, and 1e displayed potent inhibitory activity against Echinococcus granulosus in vitro, significantly better than albendazole and harmine. The morphological detection revealed that 1a, 1c, and 1e significantly changed the ultrastructure of Echinococcus granulosus protoscolices (PSCs). Furthermore, pharmacokinetic studies suggested that 1a possessed a better metabolic property. Encouragingly, 1a exhibited a highest cyst inhibition rate as 76.8% in vivo and did not display neurotoxicity in mice. Further mechanistic research illustrated that 1a has the potential to induce autophagy in PSCs, which may be responsible for the therapeutic effect of the drugs. Together, 1a could be a promising therapeutic agent against echinococcosis, warranting further study.

Innovative spectrofluorometric method for determination of harmaline and harmine in different matrices.

Harmaline and harmine are naturally occurring closely related ß-carboline alkaloids found in Peganum and Banisteriopsis plants. They have historical significance in traditional practices due to their potential psychoactive and therapeutic properties. Herein, a highly sensitive spectrofluorometric method was developed for the quantifying of harmaline and harmine in diverse matrices, including pure forms, seed samples, and spiked plasma. The procedures lie in addressing the challenge of overlapping fluorescence spectra exhibited by harmaline and harmine through the incorporation of hydroxypropyl-ß-cyclodextrin, altering their chemical properties and fluorescence characteristics. Synchronous fluorescence measurements coupled with first derivative mathematical technique make it possible to distinguish between the harmaline and harmine at 419 and 456 nm, respectively. The method effectiveness is demonstrated through spectral analysis, optimization of the measurement conditions, adopting validation parameters and application to the pure form, seed samples and spiked human plasma. This methodology facilitates accurate determination of these alkaloids over the concentration range of 10─200 ng/mL. Thus, the developed approach provides a robust mean for the precise determination of harmaline and harmine, contributing to analytical chemistry's ongoing efforts to address complex challenges in quantification across diverse matrices.

Novel harmine derivatives as potent acetylcholinesterase and amyloid beta aggregation dual inhibitors for management of Alzheimer's disease.

In this study, a series of potential ligands for the treatment of AD were synthesised and characterised as novel harmine derivatives modified at position 9 with benzyl piperazinyl. In vitro studies revealed that the majority of the derivatives exhibited moderate to potent inhibition against hAChE and Aß1 - 42 aggregation. Notably, compounds 13 and 17d displayed potent drug - likeness and ADMET properties, demonstrating remarkable inhibitory activities towards AChE (IC50 = 58.76 nM and 89.38 nM, respectively) as well as Aß aggregation (IC50 = 9.31 µM and 13.82 µM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aß1 - 42-induced SH - SY5Y damage, while maintaining low toxicity in SH - SY5Y cells. Further exploration of the mechanism through kinetic studies and molecular modelling confirmed that compound 13 could interact with both the CAS and the PAS of AChE. These findings suggested that harmine derivatives hold great potential as dual - targeted candidates for treating AD.

Harmine and Kaempferol treatment enhances NFATC1 and FOXP3 mediated regulatory T-cells' suppressive capacity in generalized vitiligo.

BACKGROUND: Generalized vitiligo (GV) is an autoimmune disease characterized by the progressive loss of melanocytes. OBJECTIVES: Current study was undertaken to assess in-vitro therapeutic potential of Harmine and Kaempferol for GV. METHODS: Calcium, calcineurin, NFATC1 levels, cell proliferation were assessed by various kits and ORAI1, PEIZO1, Calcineurin, GSK3B, DYRK1A transcripts and IFN-γ,IL-10,TGF-ß protein levels were assessed by qPCR and ELISA in blood and skin biopsy samples from Tregs of 52 patients and 50 controls. RESULTS: Harmine and Kaempferol treatment enhances Treg suppressive capacity, NFATs and FOXP3 expression in blood and skin Tregs of GV patients (p < 0.05). Furthermore, Harmine and Kaempferol treatment in Tregs increased calcineurin and NFATC1 activity and decreased DYRK1A transcripts in blood and skin Tregs of GV patients(p < 0.05). In-silico analysis revealed that Harmine and Kaempferol might boost Treg suppressive capacity by increasing calcineurin dephosphorylation activity leading to increase NFATs activation and also increase nuclear retention of NFATs by inhibiting DYRK1a phosphorylation activity. Moreover, calcineurin and NFATC1 activity in Tregs were positively correlated with Treg suppressive capacity, NFATC1 and FOXP3 expression (p < 0.05), whereas, DYRK1A transcripts were negatively correlated with Treg suppressive capacity, NFATC1 and FOXP3 expression (p < 0.05). These compounds significantly increased melanocytes' survival and proliferation in Treg:CD4+/CD8+:SK-Mel-28 cell line co-culture system from GV patients (p < 0.0001). CONCLUSIONS: For the first time the study suggests that Harmine and Kaempferol treated Tregs could control the CD8+ and CD4+T-cells' proliferation and IFN-γ production, leading to melanocytes' survival and proliferation. These compounds may serve as novel Treg-based therapeutics for GV; however, in vivo studies are warranted to assess the safety and efficacy of these compounds.

ß-Carbolines norharman and harman change neurobehavior causing neurological damage in Caenorhabditis elegans.

ß-Carbolines norharman and harman, belonging to the class of heterocyclic aromatic amines (HAAs), are typical hazardous substances produced during the thermal processing of food. Compared to other HAAs, there have been limited reports on the toxicity of ß-carbolines. Nevertheless, the current studies are concerned with the neurotoxic effects of norharman and harman at high doses. It is still unknown whether the relatively low dose of ß-carbolines in foods induces neurotoxicity and the mechanism of the toxicity. In this study, C. elegans was exposed to a series of gradients of norharman and harman (0, 0.05, 5, and 10 mg L-1). The survival rate and indicators of ethology (locomotor behaviors, foraging behavior, and chemotaxis ability) were assessed. The antioxidant system and the contents of neurotransmitters, as well as the activity of acetylcholinesterase (AChE), were evaluated. Additionally, the RNA-seq screening of differentially expressed genes (DEGs) revealed the potential molecular mechanisms of norharman- and harman-induced toxic effects. Our results indicated that the risk of long-term exposure to norharman and harman at low doses (food-related doses) should be emphasized. Moreover, ß-carbolines might induce neurotoxicity by causing oxidative damage, regulating the content of neurotransmitters, and interfering with cytochrome P450 metabolism. This study would provide a toxicological basis for the neurotoxicity of ß-carbolines and lay the foundation for the risk assessment of endogenous pollutants in food.

On a path toward a broad-spectrum anti-viral: inhibition of HIV-1 and coronavirus replication by SR kinase inhibitor harmine.

IMPORTANCE: This study highlights the crucial role RNA processing plays in regulating viral gene expression and replication. By targeting SR kinases, we identified harmine as a potent inhibitor of HIV-1 as well as coronavirus (HCoV-229E and multiple SARS-CoV-2 variants) replication. Harmine inhibits HIV-1 protein expression and reduces accumulation of HIV-1 RNAs in both cell lines and primary CD4+ T cells. Harmine also suppresses coronavirus replication post-viral entry by preferentially reducing coronavirus sub-genomic RNA accumulation. By focusing on host factors rather than viral targets, our study offers a novel approach to combating viral infections that is effective against a range of unrelated viruses. Moreover, at doses required to inhibit virus replication, harmine had limited toxicity and minimal effect on the host transcriptome. These findings support the viability of targeting host cellular processes as a means of developing broad-spectrum anti-virals.

In vitro and in vivo Efficacies of Novel Harmine Derivatives in the Treatment of Cystic Echinococcosis.

Introduction: Cystic echinococcosis (CE) is a chronic zoonotic parasitic disease caused by the larvae of the Echinococcus granulosus sensu lato (s.l.) cluster. The current existing drugs have limited therapeutic efficacy against cystic echinococcosis, and thus, there is an urgent need to develop new drugs. Methods: In this study, 7 harmine (HM) derivatives were screened and the effects of HM derivatives on E. granulosus sensu stricto (s.s.) were evaluated by in vitro and mouse experiments. The safety of the HM derivatives was assessed by cytotoxicity assays, acute toxicity study in animals and subacute toxicity study. Results: These results show that the HM derivatives H-2-168 and DH-004 exhibited more significant antiparasitic effects at an initial concentration of 40 µM. The results of further studies showed that H-2-168 and DH-004 had dose-dependent effects against protoscoleces and had satisfactory therapeutic outcomes in vivo. Electron microscopy observations demonstrated that H-2-168 and DH-004 caused severe disruption of the parasite ultrastructure. Notably, the results of the acute toxicity and subchronic toxicity studies showed that H-2-168 and DH-004 had significantly improved safety. In addition, we found that H-2-168 and DH-004 induced DNA damage in E. granulosus s.s., which may be the mechanism by which these drugs produce their therapeutic effects. Discussion: Overall, the data from this work demonstrate that H-2-168 and DH-004 are highly effective candidate compounds with low toxicity for the treatment of CE and will provide a new therapeutic strategy for CE pharmacological treatment.

ß-Carboline Alkaloids Resist the Aggregation and Cytotoxicity of Human Islet Amyloid Polypeptide.

ß-Carboline alkaloids have a variety of pharmacological activities, such as antitumor, antibiosis and antidiabetes. Harmine and harmol are two structurally similar ß-carbolines that occur in many medicinal plants. In this work, we chose harmine and harmol to impede the amyloid fibril formation of human islet amyloid polypeptide (hIAPP) associated with type 2 diabetes mellitus (T2DM), by a series of physicochemical and biochemical methods. The results indicate that harmine and harmol effectively prevent peptide fibril formation and alleviate toxic oligomer species. In addition, both small molecules exhibit strong binding affinities with hIAPP mainly through hydrophobic and hydrogen bonding interactions, thus reducing the cytotoxicity induced by hIAPP. Their distinct binding pattern with hIAPP is closely linked to the molecular configuration of the two small molecules, affecting their ability to impede peptide aggregation. The study is of great significance for the application and development of ß-carboline alkaloids against T2DM.

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo.

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.e. monoamine concentrations) were shown to affect MAO-A levels. We assessed the effect of MAOA (rs1137070, rs2064070, rs6323) and TPH2 (rs1386494, rs4570625) variants associated with risk for depression and related clinical phenomena on global MAO-A distribution volume (VT) using [11C]harmine PET in 51 participants (21 individuals with seasonal affective disorder (SAD) and 30 healthy individuals (HI)). Statistical analyses comprised general linear models with global MAO-A VT as dependent variable, genotype as independent variable and age, sex, group (individuals with SAD, HI) and season as covariates. rs1386494 genotype significantly affected global MAO-A VT after correction for age, group and sex (p < 0.05, corr.), with CC homozygotes showing 26% higher MAO-A levels. The role of rs1386494 on TPH2 function or expression is poorly understood. Our results suggest rs1386494 might have an effect on either, assuming that TPH2 and MAO-A levels are linked by their common product/substrate, 5-HT. Alternatively, rs1386494 might influence MAO-A levels via another mechanism, such as co-inheritance of other genetic variants. Our results provide insight into how genetic variants within serotonin turnover translate to the cerebral serotonin system. Clinicaltrials.gov Identifier: NCT02582398. EUDAMED Number: CIV-AT-13-01-009583.

Effect of Chemical Refining on the Reduction of ß-Carboline Content in Sesame Seed Oil.

ß-carbolines (harman and norharman) are potentially mutagenic and have been reported in some vegetable oils. Sesame seed oil is obtained from roasted sesame seeds. During sesame oil processing, roasting is the key procedure to aroma enhancement, in which ß-carbolines are produced. Pressed sesame seed oils cover most market share, while leaching solvents are used to extract oils from the pressed sesame cake to improve the utilization of the raw materials. ß-carbolines are nonpolar heterocyclic aromatic amines with good solubility in leaching solvents (n-hexane); therefore, the ß-carbolines in sesame cake migrated to the leaching sesame seed oil. The refining procedures are indispensable for leaching sesame seed oil, in which some small molecules can be reduced. Thus, the critical aim is to evaluate the changes in ß-carboline content during the refining of leaching sesame seed oil and the key process steps for the removal of ß-carbolines. In this work, the levels of ß-carbolines (harman and norharman) in sesame seed oil during chemical refining processes (degumming, deacidification, bleaching and deodorization) have been determined using solid phase extraction and high performance liquid chromatography-mass spectrometry (LC-MS). The results indicated that in the entire refining process, the levels of total ß-carbolines greatly decreased, and the adsorption decolorization was the most effective process in reducing ß-carbolines, which might be related to the adsorbent used in the decolorization process. In addition, the effects of adsorbent type, adsorbent dosage and blended adsorbent on ß-carbolines in sesame seed oil during the decolorization process were investigated. It was concluded that oil refining can not only improve the quality of sesame seed oil, but also reduce most of the harmful ß-carbolines.

Harmine exerts anxiolytic effects by regulating neuroinflammation and neuronal plasticity in the basolateral amygdala.

Increasing evidence indicates that an altered immune system is closely linked to the pathophysiology of anxiety disorders, and inhibition of neuroinflammation may represent an effective therapeutic strategy to treat anxiety disorders. Harmine, a beta-carboline alkaloid in various medicinal plants, has been widely reported to display anti-inflammatory and potentially anxiolytic effects. However, the exact underlying mechanisms are not fully understood. Our recent study has demonstrated that dysregulation of neuroplasticity in the basolateral amygdala (BLA) contributes to the pathological processes of inflammation-related anxiety. In this study, using a mouse model of anxiety challenged with Escherichia coli lipopolysaccharide (LPS), we found that harmine alleviated LPS-induced anxiety-like behaviors in mice. Mechanistically, harmine significantly prevented LPS-induced neuroinflammation by suppressing the expression of pro-inflammatory cytokines including IL-1ß and TNF-α. Meanwhile, ex vivo whole-cell slice electrophysiology combined with optogenetics showed that LPS-induced increase of medial prefrontal cortex (mPFC)-driven excitatory but not inhibitory synaptic transmission onto BLA projection neurons, thereby alleviating LPS-induced shift of excitatory/inhibitory balance towards excitation. In addition, harmine attenuated the increased intrinsic neuronal excitability of BLA PNs by reducing the medium after-hyperpolarization. In conclusion, our findings provide new evidence that harmine may exert its anxiolytic effect by downregulating LPS-induced neuroinflammation and restoring the changes in neuronal plasticity in BLA PNs.