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Background: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Pathological cardiac hypertrophy, a common feature in various cardiovascular diseases, can be more effectively managed through combination therapies using natural compounds. Harmine, a β‐carboline alkaloid found in plants, possesses numerous pharmacological functions, including alleviating cardiac hypertrophy. Similarly, Selenomethionine (SE), a primary organic selenium source, has been shown to mitigate cardiac autophagy and alleviate injury. To explores the therapeutic potential of combining Harmine with SE to treat cardiac hypertrophy. The synergistic effects of SE and harmine against cardiac hypertrophy were assessed in vitro with angiotensin II (AngII)‐induced hypertrophy and in vivo using a Myh6R404Q mouse model. Co‐administration of SE and harmine significantly reduced hypertrophy‐related markers, outperforming monotherapies. Transcriptomic and metabolic profiling revealed substantial alterations in key metabolic and signalling pathways, particularly those involved in energy metabolism. Notably, the combination therapy led to a marked reduction in the activity of key glycolytic enzymes. Importantly, the addition of the glycolysis inhibitor 2‐deoxy‐D‐glucose (2‐DG) did not further potentiate these effects, suggesting that the antihypertrophic action is predominantly mediated through glycolytic inhibition. These findings highlight the potential of SE and harmine as a promising combination therapy for the treatment of cardiac hypertrophy. [ABSTRACT FROM AUTHOR]

Survival motor neuron protein (SMN), which is linked to spinal muscular atrophy, is a key component of the Gemin complex, which is essential for the assembly of small nuclear RNA-protein complexes (snRNPs). After initial snRNP assembly in the cytoplasm, both snRNPs and SMN migrate to the nucleus and associate with Cajal bodies, where final snRNP maturation occurs. It is assumed that SMN must be free from the Cajal bodies for continuous snRNP biogenesis. Previous observation of the SMN granules docked in the Cajal bodies suggests the existence of a separation mechanism. However, the precise processes that regulate the spatial separation of SMN complexes from Cajal bodies remain unclear. Here, we have employed a super-resolution microscope alongside the β-carboline alkaloid harmine, which disrupts the Cajal body in a reversible manner. Upon removal of harmine, SMN and Coilin first appear as small interconnected condensates. The SMN condensates mature into spheroidal structures encircled by Coilin, eventually segregating into distinct condensates. Expression of a multimerization-deficient SMN mutant leads to enlarged, atypical Cajal bodies in which SMN is unable to segregate into separate condensates. These findings underscore the importance of multimerization in facilitating the segregation of SMN from Coilin within Cajal bodies. [ABSTRACT FROM AUTHOR]

Indole alkaloids, a class of plant-derived nitrogen-containing compounds, have emerged as promising candidates for osteoporosis treatment. Their favorable biocompatibility profile demonstrated efficacy in preclinical models, and low reported toxicity make them attractive alternatives to existing therapies. This review focuses on the therapeutic potential of specific indole alkaloids, including vindoline, rutaecarpine, harmine, and its derivatives, in promoting bone health and managing osteoporosis. [ABSTRACT FROM AUTHOR]

The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several β-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with β-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, β-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential. [ABSTRACT FROM AUTHOR]

Introduction: A significant global public health issue is diabetes. By repairing, maintaining, or increasing the original tissue function, regenerative medicine aims to lessen the patients' suffering. Due to their ability to multitask, herbal medicines are gaining attractiveness in traditional medicine. Aim to the Work: To study the possible regenerative capacity of Harmine on diabetic pancreas experimentally induced by streptozotocin in adult male rats. Material and Methods: Thirty adult albino rats divided equally into three groups. Control group (group I). Diabetic group (group II): rats were nurtured a fat excessive diet pro three weeks prior to a single intraperitoneal dose of freshly supplied STZ (40 mg/kg). Diabetic+ harmine group (group III): rats treated as group II and on day eight after the onset of diabetes, harmine was given in a dose 6.5 mg/kg over the course 28 daylights in a gavage approach. Paraffin sections were practiced for H&E and Immunohistochemical study. Results: The pancreatic islets histology of the diabetic group concealed marked distortion alongside cellular vacoulations and nuclear pyknosis. Consequently confirmed immunohistochemically by significant increase (p>0.01) in caspase-3 and significant decrease (p>0.01) in insulin, Ki67 and HSP70 immunoexpression. The pancreatic islets of diabetic rats given harmine for four weeks displayed reduced degenerative structure, greater islets mass, and fewer vacuolated cells. Immunohistochemical beta cell indicators, such as a statistically significant decrease (p>0.01) in caspase-3 immunoexpression and a significant increase (p>0.01) in insulin, Ki67, and HSP70 immunoexpression compared to group II, served as proof of this. Conclusion: Harmine is proficient pro beta cell projiferation, expansion of islet build and recover glycemic check. These findings implying harmine analogs possibly will partake unique therapeutic potential for the medication of human diabetes. [ABSTRACT FROM AUTHOR]

The primary objective of this review is to provide a comprehensive overview of the challenges involved in detecting ancient ayahuasca, a traditional hallucinogenic drink from the Amazon region, which is prepared using Banisteriopsis caapi liana and other plants, by utilizing advanced analytical techniques. The presence of harmine and harmaline in Andean archaeological findings has led certain authors to speculate that the Banisteriopsis liana may have been the source plant responsible for their occurrence. Consequently, the utilization of this liana can be traced back to at least 500 CE. However, a combination of archaeological, ethnobotanical, biochemical and analytical chemistry considerations has rendered uncertain the true origins of the presence of harmine and harmaline in ancient mummies and artifacts. Thus, the archaeological evidence does not convincingly prove the ancient usage of ayahuasca. [ABSTRACT FROM AUTHOR]

Abstract Background As antimicrobial resistance (AMR) has become a global health crisis, new strategies against AMR infection are urgently needed. Quorum sensing (QS), responsible for bacterial communication and pathogenicity, is among the targets for anti-virulence drugs that thrive as one of the promising treatments against AMR infection. Methods We identified a natural compound, Harmine, through virtual screening based on three QS receptors of Pseudomonas aeruginosa (P. aeruginosa) and explored the effect of Harmine on QS-controlled and pathogenicity-related phenotypes including pyocyanin production, exocellular protease excretion, biofilm formation, and twitching motility of P. aeruginosa PA14. The protective effect of Harmine on Caenorhabditis elegans (C. elegans) and mice infection models was determined and the synergistic effect of Harmine combined with common antibiotics was explored. The underlaying mechanism of Harmine’s QS inhibitory effect was illustrated by molecular docking analysis, transcriptomic analysis, and target verification assay. Results In vitro results suggested that Harmine possessed QS inhibitory effects on pyocyanin production, exocellular protease excretion, biofilm formation, and twitching motility of P. aeruginosa PA14, and in vivo results displayed Harmine’s protective effect on C. elegans and mice infection models. Intriguingly, Harmine increased susceptibility of both PA14 and clinical isolates of P. aeruginosa to polymyxin B and kanamycin when used in combination. Moreover, Harmine down-regulated a series of QS controlled genes associated with pathogenicity and the underlying mechanism may have involved competitively antagonizing autoinducers’ receptors LasR, RhlR, and PqsR. Conclusions This study shed light on the anti-virulence potential of Harmine against QS targets, suggesting the possible use of Harmine and its derivates as anti-virulence compounds.

Background: As antimicrobial resistance (AMR) has become a global health crisis, new strategies against AMR infection are urgently needed. Quorum sensing (QS), responsible for bacterial communication and pathogenicity, is among the targets for anti-virulence drugs that thrive as one of the promising treatments against AMR infection. Methods: We identified a natural compound, Harmine, through virtual screening based on three QS receptors of Pseudomonas aeruginosa (P. aeruginosa) and explored the effect of Harmine on QS-controlled and pathogenicity-related phenotypes including pyocyanin production, exocellular protease excretion, biofilm formation, and twitching motility of P. aeruginosa PA14. The protective effect of Harmine on Caenorhabditis elegans (C. elegans) and mice infection models was determined and the synergistic effect of Harmine combined with common antibiotics was explored. The underlaying mechanism of Harmine's QS inhibitory effect was illustrated by molecular docking analysis, transcriptomic analysis, and target verification assay. Results: In vitro results suggested that Harmine possessed QS inhibitory effects on pyocyanin production, exocellular protease excretion, biofilm formation, and twitching motility of P. aeruginosa PA14, and in vivo results displayed Harmine's protective effect on C. elegans and mice infection models. Intriguingly, Harmine increased susceptibility of both PA14 and clinical isolates of P. aeruginosa to polymyxin B and kanamycin when used in combination. Moreover, Harmine down-regulated a series of QS controlled genes associated with pathogenicity and the underlying mechanism may have involved competitively antagonizing autoinducers' receptors LasR, RhlR, and PqsR. Conclusions: This study shed light on the anti-virulence potential of Harmine against QS targets, suggesting the possible use of Harmine and its derivates as anti-virulence compounds. [ABSTRACT FROM AUTHOR]

Harmine is a naturally occurring p-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy. [ABSTRACT FROM AUTHOR]

Small molecules as ligands target multifunctional ribonucleic acids (RNA) for therapeutic engagement. This study explores how the anticancer DNA intercalator harmine interacts various motifs of RNAs, including the single-stranded A-form poly (rA), the clover leaf tRNAphe, and the double-stranded A-form poly (rC)-poly (rG). Harmine showed the affinity to the polynucleotides in the order, poly (rA) > tRNAphe > poly (rC)·poly (rG). While no induced circular dichroism change was detected with poly (rC)poly (rG), significant structural alterations of poly (rA) followed by tRNAphe and occurrence of concurrent initiation of optical activity in the attached achiral molecule of alkaloid was reported. At 25 °C, the affinity further showed exothermic and entropy-driven binding. The interaction also highlighted heat capacity (ΔCop) and Gibbs energy contribution from the hydrophobic transfer (ΔGhyd) of binding with harmine. Molecular docking calculations indicated that harmine exhibits higher affinity for poly (rA) compared to tRNAphe and poly (rC)·poly (rG). Subsequent molecular dynamics simulations were conducted to investigate the binding mode and stability of harmine with poly(A), tRNAphe, and poly (rC)·poly (rG). The results revealed that harmine adopts a partial intercalative binding with poly (rA) and tRNAphe, characterized by pronounced stacking forces and stronger binding free energy observed with poly (rA), while a comparatively weaker binding free energy was observed with tRNAphe. In contrast, the stacking forces with poly (rC)·poly (rG) were comparatively less pronounced and adopts a groove binding mode. It was also supported by ferrocyanide quenching analysis. All these findings univocally provide detailed insight into the binding specificity of harmine, to single stranded poly (rA) over other RNA motifs, probably suggesting a self-structure formation in poly (rA) with harmine and its potential as a lead compound for RNA based drug targeting.

Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and β-carboline alkaloid harmine against cancer cell lines and Plasmodium falciparum. The hybrids were prepared from the corresponding amines by 1,1′-carbonyldiimidazole (CDI)-mediated synthesis. In vitro evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine 16 as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 (IC50 = 5.48 ± 3.35 μmol L−1). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the Plasmodium life cycle identified CQ-based UT harmiquine 12 as a novel antiplasmodial hit because it displayed low IC50 values in the submicromolar range against CQ-sensitive and resistant strains (IC50 0.06 ± 0.01, and 0.19 ± 0.02 μmol L−1, respectively), and exhibited high selectivity against Plasmodium, compared to mammalian cells (SI = 92).

Indole alkaloids, a class of plant-derived nitrogen-containing compounds, have emerged as promising candidates for osteoporosis treatment. Their favorable biocompatibility profile demonstrated efficacy in preclinical models, and low reported toxicity make them attractive alternatives to existing therapies. This review focuses on the therapeutic potential of specific indole alkaloids, including vindoline, rutaecarpine, harmine, and its derivatives, in promoting bone health and managing osteoporosis.

This study focuses on the effects of harmine (H), an alkaloid derived from the Peganum harmala plant known to have harmful effects on rats' liver, kidneys, and oxidative stress. The study examines the preventive benefits of using ethanolic extract of Matricaria chamomilla (EEC). Six groups (n = 8) of rats were created. Group 1 (control); Group 2 received a single injection of H (40 mg/kg); Group 3 received EEC (200 mg/kg); Group 4 received EEC (500 mg/kg); Groups 5 and 6 received H (40 mg/kg) and EEC (200 mg/kg) or (500 mg/kg) for 21 days; all groups were subjected to stress via the forced swim test. According to the findings, H caused a rise in the weight of the body, liver, and kidneys, whereas EEC therapy showed a strong protective impact on organ weights. Furthermore, H treatment resulted in a marked rise in serum total cholesterol and malondialdehyde (MDA) levels, along with a marked fall in the liver and kidney's total antioxidant capacity and reduced glutathione (GSH) content. Furthermore, EEC treatment mitigated all the negative effects of H treatment. Microscopic examination of the liver and renal tissues along with these parameters was conducted. Nevertheless, the data did not demonstrate any appreciable alterations in organ morphology or structure following H and EEC therapy. Considering its potent anti-free radical activity against H-induced oxidative effects in the liver and kidney, it may be inferred that MC has a potential antioxidant effect. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma is an aggressive type of skin cancer with a complex genetic landscape caused by the malignant transformation of melanocytes. This study aimed at providing an in silico network model based on the systematic profiling of the melanoma-associated genes considering germline mutations, somatic mutations, and genome-wide association study signals accounting for a total of 232 unique melanoma risk genes. A protein–protein interaction network was constructed using the melanoma risk genes as seeds and evaluated to describe the functional landscape in which the melanoma genes operate within the cellular milieu. Not only were the majority of the melanoma risk genes able to interact with each other at the protein level within the core of the network, but this showed significant enrichment for genes whose expression is altered in human melanoma specimens. Functional annotation showed the melanoma risk network to be significantly associated with processes related to DNA metabolism and telomeres, DNA damage and repair, cellular ageing, and response to radiation. We further explored whether the melanoma risk network could be used as an in silico tool to predict the efficacy of anti-melanoma phytochemicals, that are considered active molecules with potentially less systemic toxicity than classical cytotoxic drugs. A significant portion of the melanoma risk network showed differential expression when SK-MEL-28 human melanoma cells were exposed to the phytochemicals harmine and berberine chloride. This reinforced our hypothesis that the network modeling approach not only provides an alternative way to identify molecular pathways relevant to disease but it may also represent an alternative screening approach to prioritize potentially active compounds. [ABSTRACT FROM AUTHOR]

Modifications at the harmine (HAM) 9‐N position demonstrated effective antitumor activity in previous studies. However, the difficult preparation, low yield and poor stability of derivatives limited their applications. A partial activity priming was carried out by converting the 9‐position substituted propargyl group of HAM to propynyl group. Molecular docking simulations of compound 9i with DYRK1A kinase showed that it was able to embed itself into the active pocket of the DYRK1A protein and formed hydrogen bonds with multiple active amino acid residues at a low binding energy. The results of molecular dynamics simulations showed that the RMSD (root mean square deviation) fluctuations of the complex were more gentle, and the trends of the changes in Rg (radius of gyration) and SASA (solvent accessible surface area) were lower, indicating that the DYRK1A protein was less disturbed and the structure of the complex was more compact and stable. The cytotoxicity assay indicated that compound 9i displayed good antiproliferative activity against human cancer cells MGC‐803, HepG2, and PANC‐1. In addition, 9i was able to reduce the ratio of polynomials induced by the Ras overexpression model of Caenorhabditis elegans, which showed anti‐Ras activity, and the RT‐qPCR results suggested that its anti‐Ras ability was not achieved by directly inhibiting the expression of the let‐60/Ras genes, and that 9i was able to upregulate the expression of SOD‐3 activation of oxidative stress, which means that it may be useful as a pro‐oxidant for the treatment of cancers caused by Ras over‐activation. [ABSTRACT FROM AUTHOR]

Background: There is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic "ayahuasca" for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy. Methods: We investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects. Results: DMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p < 0.001] and acute experience sampling items over time, characterized by psychological insights [PIQ, F(2,58.5) = 28.514, p < 0.001], emotional breakthroughs [EBI, F(2,60) = 26.509, p < 0.001], and low scores on the challenging experience questionnaire [CEQ, F(2,60) = 12.84, p < 0.001]. Participants attributed personal and spiritual significance to the experience (GSR) with mainly positive persisting effects (PEQ) at 1- and 4-months follow-up. Acute drug effects correlated positively with persisting effects. We found no changes in trait measures of personality, psychological flexibility, or general well-being, and no increases in psychopathology (SCL-90-R) were reported. Discussion and Conclusion: Our results suggest that the experience induced by the standardized DMT + harmine formulation induces a phenomenologically rich psychedelic experience, demonstrates good psychological safety and tolerability, is well tolerated, and induces beneficial psychological processes that could possibly support psychotherapy. Further studies are required to investigate the psychotherapeutic potential in patients. [ABSTRACT FROM AUTHOR]

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 β-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. [ABSTRACT FROM AUTHOR]

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 Aβ1 − 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 Aβ aggregation (IC50 = 9.31 μM and 13.82 μM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aβ1 − 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. [ABSTRACT FROM AUTHOR]

Harmaline and harmine, are the major ß-carbolines present in the seeds of the Peganum harmala L. These compounds are known as herbal active principals with potential use in pharmaceutical and medicine. To assess the growth inhibitory effect of phyto-alkaloids, harmaline and harmine, on cancer cell lines. The P. harmala L.'s alkaloids were extracted by acidic/basic extraction method and identified by two methods, Fourier Transform Infra-Red Spectroscopy (FTIR) and High-Performance Liquid Chromatography (HPLC). breast cancer cell lines, MDA_MB_231, were subjected to different concentration (1-100 µg/mL) of the P. harmala extract at different time courses (24h, 48h). Methylthiazol Tetrazolium (MTT) test, the half maximal inhibitory concentration (IC50) and the morphological changes through optical microscopy were evaluated cell lines, the P. harmala extract decreased cell viability in longer time exposure in a dose dependent manner. The more concentrated extract led to higher motility of MDA-MB-231 at 24h. It was observed that 30 µg/mL is the minimum lethal dose that kills approximately 50% of cells at 24 hours in MDA-MB-231 cell line (IC50). The morphological observation ensured the apoptosis nature of P. harmala on cells as their membrane kept intact and no membrane permeabilization was observed. The results revealed that the P. harmala extracts decreased significantly growth rate and cell survival of cancer cell lines. higher growth inhibition of MDA-MB-231 cell line by the P. harmala extract was confirmed. [ABSTRACT FROM AUTHOR]

BackgroundThere is growing scientific evidence for the therapeutic benefits of the Amazonian plant-based psychedelic “ayahuasca” for neuropsychiatric disorders such as depression and anxiety. However, there are certain challenges when incorporating botanical ayahuasca into biomedical research and clinical therapy environments. Formulations inspired by ayahuasca, which contain specific and standardized active components, are a potential remedy.MethodsWe investigated subjective acute and persisting effects of a novel formulation containing the reversible monoamine oxidase inhibitor harmine (orodispersible tablet containing 100 mg MAO-I) and N,N-dimethyltryptamine (incremental intranasal dosing of up to 100 mg DMT), compared with two other conditions, namely harmine alone and placebo, in a crossover RCT in 31 healthy male subjects.ResultsDMT + harmine, but not harmine alone, induced a psychedelic experience assessed with the 5D-ASC rating scale [global score: F(2,60) = 80.21, p

Peganum harmala L. (P. harmala), also known as Espand, Harmel, or Syrian rue, and Hypericum perforatum L. (H. perforatum), commonly known as St. John's wort, are two of the widely cultivated industrial crops and used worldwide in antihepatoma-related products. However, their main functional substances are still not clear, thus impeding the efficacy evaluations and quality controls of relative products around the world. In this work, the anti-hepatoma biomarkers of P. harmala and H. perforatum were clarified through the development of principal components analysis (PCA)-HPLC secondary metabolite mapping models. The chemical fingerprints of plant extracts were profiled by HPLC and then mapped to produce the secondary metabolite models using PCA. The models correlated the chemical information with the anti-hepatoma activities of plant extracts, thus indicating the functional inhibitors of P. harmala and H. perforatum against hepatoma cells. The activities of the identified compounds were validated by cytotoxic and apoptotic assays. The major inhibitors of P. harmala and H. perforatum against human hepatoma were determined to be harmine and quercetin, respectively. The IC50 values and the induced apoptotic rate of harmine on HepG2 cells were 20.7 ± 2.8 μM and 46.7 ± 3.5 %, respectively. The IC50 values and the induced apoptotic rate of quercetin on HepG2 cells were 49.5 ± 6.6 μM and 38.7 ± 2.6 %, respectively. In conclusion, the results significantly expanded the understanding of the biochemical foundations of P. harmala and H. perforatum, thus evidently supporting their current applications around the world. Moreover, harmine and quercetin could be used as biomarkers to evaluate the efficacy and quality of related products of industrial crops in therapeutic and health-improving applications.

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 Aβ1 − 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 Aβ aggregation (IC50 = 9.31 μM and 13.82 μM, respectively). More importantly, compounds 13 and 17d showed exceptional neuroprotective effects against Aβ1 − 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.

Rationale: The psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are often attributed to agonism at brain serotonin 5-HT2A receptors by N,N-dimethyltryptamine (DMT). To reduce first pass metabolism of oral DMT, ayahuasca preparations additionally contain reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation of DMT in brain via systemic MAOA inhibition. Objectives: We measured the pharmacokinetic profile of harmine and/or DMT in rat brain, and tested for pharmacodynamic effects on brain glucose metabolism and DMT occupancy at brain serotonin 5-HT2A receptors. Methods: We first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low sub-cutaneous doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored effects of DMT and/or harmine (1 mg/kg each) on brain glucose metabolism with [18F]FDG-PET. Results: Results confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in brain, while correspondingly increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 μM. We did not observe significant effects of low dose DMT and/or harmine on cerebral [18F]FDG-PET uptake. Conclusion: These preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on serotonin receptor occupancy and cerebral metabolism. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the contractile responses of vascular smooth muscle cells (VSMCs) to spasmogens after incubation with harmaline, harmine, and harmalol, which are alkaloids obtained from Peganum harmala L., a member of the Zygophyllaceae family. Methods: Contractile responses of VSMCs to norepinephrine (NE; 1 µmol/L) and potassium chloride (KCl; 60 mmol/L) were recorded in rat aortic ring preparations pre-incubated with 0.5, 1, 5 and 10 µmol/L of each alkaloid for 15 min. Responses were expressed as mean values of contractions in incubated preparations, relative to the recorded tension prior to treatment with alkaloids. Results: Pre-incubation with harmaline at concentration of 10 µmol/L significantly reduced contractile responses to NE by 69.0 ± 3.0 % (p < 0.00002), and decreased KCl-induced contraction by 34.0 ± 9.0 % (p < 0.05). Harmalol was the most effective in inhibiting contractions to KCl (48.0 ± 9.0 %, p < 0.01). However, harmalol produced relatively moderate inhibitory effects on NE-induced contractions (46.0 ± 4.0 %, p < 0.005), followed by harmine (52.0 ± 8.0 %, p < 0.02), but it did not significantly affect contractile responses to KCl. Conclusion: These results highlight the differential effects of pre-incubation with alkaloids from P. harmala and their potential effects on the prevention of VSMC spasms induced by either chemicals or stimuli that change the membrane potential. [ABSTRACT FROM AUTHOR]

The worldwide overall 5‐year survival rate of esophageal squamous cell carcinoma (ESCC) patients is less than 20%, and novel therapeutic strategies for these patients are urgently needed. Harmine is a natural β‐carboline alkaloid, which received great interest in cancer research because of its biological and anti‐tumor activities. The aim of this study is to examine the effects of harmine on ESCC and its mechanism. We investigated the effects of harmine on proliferation, cell cycle, apoptosis, and tumor growth in vivo. RNA sequencing (RNA‐seq), real‐time PCR, and western blotting were used to detect the mechanism. Harmine inhibited ESCC cell growth in vitro and tumor growth in vivo. Differentially expressed genes in harmine‐treated ESCC cells were mainly involved in protein processing in the endoplasmic reticulum (ER). Real‐time PCR and western blotting confirmed harmine‐induced cellular ER stress. CRISPR‐Cas9 knockout of C/EBP homologous protein (CHOP) abolished harmine‐induced expression of death receptor 5 and apoptosis. Harmine also induced the expression of CHOP‐mediated sestrin‐2, which in turn contributes to autophagosome formation via suppressing the AMP‐activated protein kinase‐protein kinase B‐mammalian target of rapamycin signaling pathway. In conclusion, our results demonstrate that harmine inhibits the growth of ESCC through its regulation of ER stress, suggesting that it is a promising candidate for ESCC treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recently, the Amazonian plant medicine “ayahuasca”—containing the psychedelic compound N,N-dimethyltryptamine (DMT) and numerous β-carboline alkaloids, such as harmine—has been suggested to exhibit beneficial effects in patients with affective and other mental health disorders. Although ayahuasca ingestion is considered safe, its pharmacokinetics/pharmacodynamics and tolerability profile pose some challenges and may limit the clinical applicability in vulnerable patient populations. While overdosing and the admixture of intolerable plant constituents may explain some of the common adverse reactions, the peroral route of administration may represent another relevant source of gastro-intestinal intolerabilities and unpredictable pharmacokinetics across users. To overcome these challenges, the present work aimed at creating ayahuasca-analogue formulations with improved pharmacokinetics and tolerability profiles. To this end, we developed peroral formulas and compared them with parenteral formulas specifically designed to circumvent the gastro-intestinal tract. In more detail, peroral administration of a capsule (containing purified DMT and harmine) was tested against a combined administration of an oromucosal harmine tablet and an intranasal DMT spray at two dose levels in an open-label within-subject study in 10 healthy male subjects. Pharmacokinetic and pharmacodynamic profiles were assessed by means of continuous blood sampling, vital sign monitoring, and psychometric assessments. Common side effects induced by traditional herbal ayahuasca such as nausea, vomiting, and diarrhea were significantly attenuated by our DMT/harmine formulations. While all preparations were well tolerated, the combined buccal/intranasal administration of harmine and DMT yielded substantially improved pharmacokinetic profiles, indicated by significantly reduced variations in systemic exposure. In conclusion, the combined buccal/intranasal administration of harmine and DMT is an innovative approach that may pave the way towards a safe, rapid-acting, and patient-oriented administration of DMT/harmine for the treatment of affective disorders.Clinical Trial Registration:clinicaltrials.gov, identifier NCT04716335

Rationale: The psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are often attributed to agonism at brain serotonin 5-HT2A receptors by N,N-dimethyltryptamine (DMT). To reduce first pass metabolism of oral DMT, ayahuasca preparations additionally contain reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation of DMT in brain via systemic MAO-A inhibition.Objectives: We measured the pharmacokinetic profile of harmine and/or DMT in rat brain, and tested for pharmacodynamic effects on brain glucose metabolism and DMT occupancy at brain serotonin 5-HT2A receptors.Methods: We first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low sub-cutaneous doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored effects of DMT and/or harmine (1 mg/kg each) on brain glucose metabolism with [18F]FDG-PET.Results: Results confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in brain, while correspondingly increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 µM. We did not observe significant effects of low dose DMT and/or harmine on cerebral [18F]FDG-PET uptake.Conclusion: These preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on serotonin receptor occupancy and cerebral metabolism.

One of the most important health issues facing the world today is obesity. It is an important independent risk factor for developing type 2 diabetes. Harmine offers various pharmacological effects, such as anti-inflammatory and anti-tumor effects. The current study aims to investigate Harmine's anti-diabetic and anti-adipogenic properties in albino mice after inducing low-grade inflammation with a high-fat diet (HFD). About forty-eight male albino mice were divided into four groups. Group 1: control mice were injected with daily saline and fed a normal chow diet of 21% protein for 5 months. Group 2: mice were treated daily with IP-injected Harmine (30 mg/kg body weight) and were fed a normal chow diet for 5 months. Group 3: mice were fed HFD to induce type 2 Diabetes Mellitus (T2DM) for 5 months. Group 4: mice were fed HFD for 14 weeks and treated with Harmine for the last 6 weeks. A figh-fat diet caused a significant increase in body and organ weight, lipid profiles, and destructive changes within the pancreas, kidney, and liver tissue. The administration of Harmine led to a remarkable improvement in the histological and ultrastructural changes induced by HFD. The findings indicate that mice cured using Harmine had lower oxidative stress, a higher total antioxidant capacity, and a reduced lipid profile compared to HFD mice. Harmine led to the hepatocytes partly restoring their ordinary configuration. Furthermore, it was noticed that the pathological incidence of damage in the structure of both the kidney and pancreas sections reduced in comparison with the diabetic group. Additional research will be required to fully understand Harmine and its preventive effects on the two forms of diabetes. [ABSTRACT FROM AUTHOR]

In order to explore the antifungal activity of 6-(piperazin-1-yl)-harmine amide derivative, based on previous derivative studies, 15 novel 6-(piperazin-1-yl)-harmine derivatives were designed and synthesized. The antifungal activity was evaluated and the structure-activity relationship was analyzed. The in vitro bioassay results demonstrated that the target compounds showed antifungal activities against Botrytis cinerea, Fusarium graminearum, Valsa pyri and Fusarium oxysporum, especially compound 5j displayed excellent activity against F. oxysporum with inhibition rate of 61.7% at 50 μg/mL, which was better than the positive control boscalid. [ABSTRACT FROM AUTHOR]

Objective: The aim of this research was to explore the effects on echinococcosis of harmine, an active ingredient of Peganum harmala. Methods: The gene targets were screened out by use of an online database. STRING was exploited to build a protein interaction network model, DAVID to carry out gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and AutoDockTools for molecular docking. All mice were randomly divided into 3 groups: a model group, a normal group, and a harmine group. Blood indicators were detected and histological analysis was carried out. NCTC-1469 was treated with either harmine or control. Gene expression was evaluated by Western blot. Results: Network pharmacological analysis concluded that 6 gene targets (HLA-B, HLA-DQB1, IL-6, tumor necrosis factor [TNF], HLA-A, and F3) might act as the major targets in the treatment of echinococcosis with harmine. GO function and KEGG pathway enrichment analyses showed that harmine might treat echinococcosis mainly by regulating the immune response. Molecular docking confirmed that harmine docked well to the targets and that the interactions were reliable. Harmine could regulate the content of inflammatory factors to modulate the immune response of mice, but caused liver damage. Pathological histology analysis confirmed that harmine had great suppressive efficacy against echinococcosis infection. However, the use of harmine would have a certain negative effect on the spleen of mice. The contents of HLA-B, HLA-DQB1, TNF, HLA-A, and F3 were observably enhanced, while Interleukin-6 was reduced in mouse liver tissue and cells after harmine treatment. As forecast by network pharmacology, harmine exerted antiechinococcosis effects by multiple targets and pathways. Finally, harmine treatment might regulate the Th17/Treg balance in mice with echinococcosis infection. Conclusions: Harmine displayed great suppressive efficacy against echinococcosis infection by regulating the immune response. These findings suggest that harmine could be a potential therapeutic agent for echinococcosis management by targeting specific gene targets. [ABSTRACT FROM AUTHOR]

Objective: Pancreatic cancer is one of the deadliest cancers related to the digestive system in the world. Due to the increasing resistance of cancer cells to chemotherapy and its side effects, there is a need for drugs with fewer side effects and natural origin. In this study, the effect of harmine combined with fluorouracil on apoptosis induction in pancreatic cancer cells (AsPC-1) and the expression of apoptotic genes was investigated. Methods: In this experimental study, MTT assay was used to study the cytotoxic effects. Annexin V/propidium iodide test and DAPI staining method were used to determine the type of cell death. The expression of apoptotic genes (P53, Bax, Caspase-3, and Caspase-9) was measured by real-time PCR. The data were analyzed using one-way ANOVA in SPSS software, version 16. The significance level was set at 0.05. Results: The results of MTT assay showed that the use of harmine at 20 μg/mL concentration combined with 10 μg/mL fluorouracil significantly reduced the growth (IC50) of AsPC-1 cells. The results of DAPI staining and annexin V/propidium iodide test showed the induction of apoptosis in treated samples. In addition, the results of real-time PCR showed that the expression of BAX, P53, Caspase-3 and Caspase-9 genes increased in the treated groups compared to the control group. Conclusion: The combined use of harmine and fluorouracil can induce apoptosis in pancreatic cancer cells due to high cytotoxicity and reduce the concentration of chemotherapy drugs. Therefore, this method can be used along with other treatment methods for pancreatic cancer.

Harmaline (1) and harmalol (2) represent two 3,4-dihydro-β-carboline (DHβCs) most frequently reported in a vast number of living systems. Fundamental aspects including the photosensitizing properties, cellular uptake, as well as the cyto- and phototoxicity of 1 and 2 were investigated herein. The molecular basis underlying the investigated processes are elucidated. Data reveal that both alkaloids show a distinctive pattern of extracellular DNA photodamage. Compound 1 induces a DNA photodamage profile dominated by oxidised purines and sites of base loss (AP sites), whereas 2 mostly induces single-strand breaks (SSBs) in addition to a small extent of purine oxidative damage. In both cases, DNA oxidative damage would occur through type I mechanism. In addition, a concerted hydrolytic attack is suggested as an extra mechanism accounting for the SSBs formation photoinduced by 2. Subcellular internalisation, cyto- and phototoxicity of 1 and 2 and the corresponding full-aromatic derivatives harmine (3) and harmol (4) also showed quite distinctive patterns in a structure-dependent manner. These results are discussed in the framework of the potential biological, biomedical and/or pharmacological roles reported for these alkaloids. The subtle structural difference (i.e., the exchange of a methoxy group for a hydroxyl substituent at C(7)) between harmaline and harmalol, gives rise to distinctive photosensitizing and subcellular localisation patterns. [ABSTRACT FROM AUTHOR]

Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B). [ABSTRACT FROM AUTHOR]

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 β-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.

Type 1 diabetes (T1D) presents with two therapeutic challenges: the need to correct underlying autoimmunity and restore β‐cell mass. We harnessed the unique capacity of regulatory T cells (Tregs) and the T cell receptor (TCR) to direct tolerance induction along with tissue‐localized delivery of therapeutic agents to restore endogenous β‐cell function. Specifically, we designed a combinatorial therapy involving biomaterials‐based poly(lactic‐co‐glycolic acid) nanoparticles co‐loaded with the Treg growth factor, IL‐2, and the β‐cell regenerative agent, harmine (a tyrosine‐regulated kinase 1A [DYRK1A] inhibitor), conjugated to the surface of Tregs. We observed continuous elution of IL‐2 and harmine from nanoparticles for at least 7 days in vitro. When conjugated to primary human Tregs, IL‐2 nanoparticles provided sufficient IL‐2 receptor signaling to support STAT5 phosphorylation for sustained phenotypic stability and viability in culture. Inclusion of poly‐L‐lysine (PLL) during nanoparticle‐cell coupling dramatically increased conjugation efficiency, providing sufficient IL‐2 to support in vitro proliferation of IL‐2‐dependent CTLL‐2 cells and primary murine Tregs. In 12‐week‐old female non‐obese diabetic mice, adoptive transfer of IL‐2/harmine nanoparticle‐conjugated NOD.BDC2.5 Tregs, which express an islet antigen‐specific TCR, significantly prevented diabetes demonstrating preserved in vivo viability. These data provide the preclinical basis to develop a biomaterials‐optimized cellular therapy to restore immune tolerance and promote β‐cell proliferation in T1D through receptor‐targeted drug delivery within pancreatic islets. [ABSTRACT FROM AUTHOR]

Harmine is a beta-carboline alkaloid present in various plants, including in the seeds of Peganum harmala L. This study aimed to investigate the anti-inflammatory activity and mechanism of harmine using macrophages stimulated with various toll-like receptor (TLR) agonists and a model of endotoxemia. The expression of inflammatory mediators induced by ligands of TLRs 2, 3, 4, and 9 were examined in thioglycollate-elicited peritoneal macrophages isolated from BALB/c and C57BL/6 mouse strains. Further, the activation of NF-κB, MAPK, AP-1, and STAT1 was explored using lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly(I:C)). Finally, the liver inflammatory response during endotoxemia was examined. Harmine inhibited inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-12, and other markers induced by various TLR agonists. The inhibition of NF-κB activity by harmine occurred via the modulation of p65 phosphorylation, independent of IκBα degradation. The inhibition of AP-1 activity by harmine was associated with the modulation of JNK. Harmine inhibited the LPS-induced serine and tyrosine phosphorylation of STAT1, but only affected serine phosphorylation by poly(I:C) treatment. In vivo, harmine inhibited iNOS and COX-2 expression during endotoxemia. Collectively, the results show that harmine can be effective against infectious inflammation through modulation of NF-κB, JNK, and STAT1. [ABSTRACT FROM AUTHOR]

• Harmine had an excellent inhibitory effect on pulmonary fibrosis. • In the process of anti-pulmonary fibrosis, the action of harmine is closely related to DNA damage repair and TP53-Gadd45α pathway. • Our findings imply that harmine is a promising candidate for anti-fibrosis therapy, which is expected to provide more effective treatments for patients with pulmonary fibrosis. Harmine has many pharmacological activities and has been found to significantly inhibit the fibrosis of keloid fibroblasts. DNA damage repair (DDR) is essential to prevent fibrosis. This study aimed to investigate the effects of harmine on pulmonary fibrosis and its underlying mechanisms. Bleomycin and TGF-β1 were used to construct pulmonary fibrosis models in vivo and in vitro, then treated with harmine to explore harmine's effects in treating experimental pulmonary fibrosis and its related mechanisms. Then, RNA sequencing was applied to investigate further the crucial DDR-related genes and drug targets of harmine against pulmonary fibrosis. Finally, the expression levels of DDR-related genes were verified by real-time quantitative PCR (RT-qPCR) and western blot. Our in vivo experiments showed that harmine treatment could improve weight loss and lung function and reduce tissue fibrosis in mice with pulmonary fibrosis. The results confirmed that harmine could inhibit the viability and migration of TGF-β1-induced MRC-5 cells, induce their apoptosis, and suppress the F-actin expression, suggesting that harmine could suppress the phenotypic transition from lung fibroblasts to lung myoblasts. In addition, RNA sequencing identified 1692 differential expressed genes (DEGs), and 10 DDR-related genes were screened as critical DDR-related genes. RT-qPCR and western blotting showed that harmine could down-regulate the expression of CHEK1, ERCC1, ERCC4, POLD1, RAD51, RPA1, TOP1, and TP53, while up-regulate FEN1, H2AX and GADD45α expression. Harmine may inhibit pulmonary fibrosis by regulating DDR-related genes and activating the TP53-Gadd45α pathway. [ABSTRACT FROM AUTHOR]

Background and purpose: Cisplatin is a chemotherapeutic drug used to treat cancer, however, causes kidney toxicity. Harmine is a plant-derived alkaloid with a wide range of therapeutic applications. The effects of harmine on the renal side effects of cisplatin in mice were studied in this study. Experimental approach: Forty-eight male BALB/c mice were randomly divided into eight groups (n = 6). They were treated with saline, cisplatin (5.5 mg/kg), harmine (5, 10, and 15 mg/kg/day), cisplatin + harmine (5, 10, and 15 mg/kg/day), respectively. All administrations were done daily and intraperitoneally for 4 days. The criteria related to histology, oxidation, anti-oxidation, inflammation, and apoptosis of renal tissue were evaluated. Findings / Results: There was a significant decrease in total antioxidant capacity of renal tissue, renal corpuscles diameter, and IL-10 expression level in the cisplatin group than in the control group, while the values of these parameters were significantly similar to the control group in the moderate or high doses of harmine + cisplatin groups. There were significant increases in serum urea and creatinine levels, bowman space, the amounts of malondialdehyde, apoptosis rate, and TNF-α, NF-κB, IL-1β, and caspase-3 gene expressions in kidney tissue of the cisplatin group compared to the control group, while these criteria did not differ in the moderate or high doses of harmine + cisplatin groups. Conclusion and implications: Harmine protected the kidneys against cisplatin-induced damage. Antioxidant, anti-inflammatory, and anti-apoptotic harmine properties were involved in this healing effect.