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In this paper the effects on the interaction of highly positively charged substitution-inert platinum polynuclear complexes (SI-PPCs) with negatively charged DNA and heparin are examined and compared by theoretical chemistry methods. Electrostatic and hydrogen bonding interactions contribute to the overall effects on the biomolecule. Root Mean Square (RMS) deviation, Solvent Accessible Surface, RMS fluctuation, and interaction analysis all confirm similar effects on both biomolecules, dictated predominantly by the total positive charge and total number of hydrogen bonds formed. Especially, changes in structural parameters suggesting condensation and reduction of available surface area will reduce or prevent normal protein recognition and may thus potentially inhibit biological mechanisms related to apoptosis (DNA) or reduced vascularization viability (HEP). Thermodynamic analyses supported these findings with favourable interaction energies. The comparison of DNA and heparin confirms the general intersectionality between the two biomolecules and confirms the intrinsic dual-nature function of this chemotype. The distinction between the two-limiting mode of actions (HS or DNA-centred) could reflect an intriguing balance between extracellular (GAG) and intracellular (DNA) binding and affinities. The results underline the need to fully understand GAG-small molecule interactions and their contribution to drug pharmacology and related therapeutic modalities. This report contributes to that understanding.

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AIMS: To identify the cardiac biogenic amine profile of obese rats and associate these compounds with parameters of cardiovascular disease. MAIN METHODS: Wistar rats (n = 20) were randomly distributed into two groups: control and obese. Obesity was induced by a high-sugar fat diet. Biochemical parameters were evaluated. Doppler Echocardiography and systolic blood pressure; interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), protein carbonylation, ferric reducing antioxidant power (FRAP), and catalase activity were measured in cardiac tissue. HPLC evaluated the cardiac biogenic profile. Data were compared using the Student's T or Mann-Whitney tests and Spearman's correlation at 5% significance. The principal component analysis (PCA) was performed. KEY FINDINGS: Obesity generated hypertension, cardiac remodeling and dysfunction, and imbalanced all biochemical, inflammatory, and oxidative markers (p < 0.001). Eight biogenic amines were found in cardiac tissue. Obesity increased serotonin and decreased agmatine, putrescine, cadaverine, and spermidine. Serotonin (r = 0.534 to 0.808) was strong and positively correlated with obesity, biochemical parameters, cardiac inflammation, oxidative stress, hypertension, cardiac remodeling, and dysfunction (p < 0.001). Spermidine (r = -0.560 to -0.680), putrescine (r = -0.532 to -0.805), cadaverine (r = -0.534 to -0.860), and agmatine (r = -0.579 to -0.884) were inversely correlated with the same parameters (p < 0.001). PCA allowed for distinguishing the control and obese groups. SIGNIFICANCE: There are strong correlations between cardiac biogenic amine levels, cardiac remodeling, and dysfunction resulting from obesity. CONCLUSION: There is an association between cardiac biogenic amines and cardiovascular disease in obesity. In addition, agmatine, putrescine, cadaverine, and, mainly, serotonin may be new biomarkers for cardiovascular health in obesity and help to improve the diagnosis and treatment of CVD resulting or not from obesity. However, more research is needed to support this conclusion.

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Polyamines (PAs) are polycationic biogenic amines ubiquitously present in all life forms and are involved in molecular signaling and interaction, determining cell fate (e.g., cell proliferation, dif-ferentiation, and apoptosis). The intricate balance in the PAs' levels in the tissues will determine whether beneficial or detrimental effects will affect homeostasis. It's crucial to note that endoge-nous polyamines, like spermine and spermidine, play a pivotal role in our understanding of neu-rological disorders as they interact with membrane receptors and ion channels, modulating neuro-transmission. In spiders and wasps, monoamines (histamine, dopamine, serotonin, tryptamine) and polyamines (spermine, spermidine, acyl polyamines) comprise, with peptides and other sub-stances, the low molecular weight fraction of the venom. Acylpolyamines are venom components exclusively from spiders and a species of solitary wasp, which cause inhibition chiefly of iono-tropic glutamate receptors (AMPA, NMDA, and KA iGluRs) and nicotinic acetylcholine receptors (nAChRs). The first venom acylpolyamines ever discovered (argiopines, Joro and Nephila toxins, and philanthotoxins) have provided templates for the design and synthesis of numerous analogs. Thus far, analogs with high potency exert their effect at nanomolar concentrations, with high se-lectivity toward their ionotropic and ligand receptors. These potent and selective acylpolyamine analogs can serve biomedical purposes and pest control management. The structural modification of acylpolyamine with photolabile and fluorescent groups converted these venom toxins into use-ful molecular probes to discriminate iGluRs and nAchRs in cell populations. In various cases, the linear polyamines, like spermine and spermidine, constituting venom acyl polyamine backbones, have served as cargoes to deliver active molecules via a polyamine uptake system on diseased cells for targeted therapy. In this review, we examined examples of biogenic amines that play an essential role in neural homeostasis and cell signaling, contributing to human health and disease outcomes, which can be present in the venom of arachnids and hymenopterans. With an empha-sis on the spider and wasp venom acylpolyamines, we focused on the origin, structure, derivatiza-tion, and biomedical and biotechnological application of these pharmacologically attractive, chemically modular venom components.

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Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging.

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BACKGROUND: The implications of SARS-CoV-2 infection on male fertility remain largely unknown. Besides their well-known pro- and anti-inflammatory actions, prostaglandins and polyamines are present in semen, where they play key roles in sperm quality. OBJECTIVES: To analyze semen parameters, oxidative profile and the seminal fluid prostaglandin and polyamine systems in samples collected from individuals without coronavirus disease 2019 diagnosis and men who recovered from coronavirus disease 2019. MATERIALS AND METHODS: This study compared semen collected from men without positive coronavirus disease 2019 diagnosis with samples obtained from individuals 1-6 months and 7-30 months post SARS-CoV-2 infection. Semen parameters, thiobarbituric acid reactive substances, cyclooxygenase 2 expression by fluorescence immunocytochemistry and immunoblotting, prostaglandin levels by enzyme immunoassay, ornithine decarboxylase activity by a radioactive assay, and polyamine and acetylated polyamine levels by thin-layer chromatography were assessed. RESULTS: In both groups of semen samples from coronavirus disease 2019 recovered men, sperm vitality, total and progressive sperm motility, and putrescine levels were significantly decreased when compared with samples from the uninfected group. In contrast, lipid peroxidation, leukocyte-associated cyclooxygenase 2 expression, and prostaglandin D2 levels were higher in semen from coronavirus disease 2019 recovered men than in samples from uninfected individuals. While sperm concentration and morphology, ornithine decarboxylase activity, and N-acetylputrescine levels were statistically diminished in semen obtained up to 6 months after coronavirus disease 2019 recovery, these parameters remained unchanged when samples were collected 7-30 months after coronavirus disease 2019 recovery. Coronavirus disease 2019 vaccination did not show negative effects on any of the parameters evaluated. DISCUSSION AND CONCLUSION: Our work provides insights into the detrimental impact of coronavirus disease 2019 on several sperm parameters, in some cases, even more than a year after SARS-CoV-2 infection, which would be accompanied by alterations in the seminal fluid prostaglandin and polyamine profiles. Therefore, future treatments targeting the prostaglandin and polyamine pathways in coronavirus disease 2019 recovered men could lead to a successful reinstatement of semen parameters.

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Rhizosphere soil of aromatic rice inhabits different fungal species that produce many bioactive metabolites including 2-acetyl-1-pyrroline (2AP). The mechanism for the biosynthesis of 2AP in the fungal system is still elusive. Hence, the present study investigates the role of possible nitrogen (N) precursors such as some amino acids and polyamines as well as the enzymes involved in 2AP synthesis in the fungal species isolated from the rhizosphere of aromatic rice varieties. Three fungal isolates were found to synthesize 2AP (0.32-1.07 ppm) and maximum 2AP was synthesized by Aspergillus niger (1.07 ppm) isolated from rhizosphere of Dehradun Basmati (DB). To determine the N source for 2AP synthesis, various N sources such as proline, glutamate, ornithine putrescine, spermine, and spermidine were used in place of putrescine in the synthetic medium (Syn18). The results showed that maximum 2AP synthesis was found with putrescine (1.07 ppm) followed by spermidine (0.89 ppm) and spermine (0.84 ppm). Further, LC-QTOF-MS analysis revealed the mobilization of spermine and spermidine into the putrescine, indicating that putrescine is the key N source for 2AP synthesis. Moreover, higher enzyme activity of DAO, PAO, and ODC as well as higher content of methylglyoxal metabolite in the A. niger NFCCI 5060 as compared to A. niger NFCCI 4064 (control) suggests the prominent role of these enzymes in the synthesis of 2AP. In conclusion, this study showed evidence of the polyamines mediated 2AP biosynthesis in A. niger NFCCI 5060.

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Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin's primary action mechanism, COX-independent ways are associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) is related to the increase in spermidine/spermine-N1-acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells; however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-γ on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-γ with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.

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Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. A centenary approach to antimonial-based drugs was first initiated with the synthesis of urea stibamine by Upendranath Brahmachari in 1922. The need for new drug development led to resistance toward antimoniates. New drug development to treat leishmaniasis is urgently needed. In this way, searching for new substances with antileishmanial activity, we synthesized ten anthranyl phenylhydrazide and three quinazolinone derivatives and evaluated them against promastigotes and the intracellular amastigotes of Leishmania amazonensis. Three compounds showed good activity against promastigotes 1b, 1d, and 1g, with IC50 between 1 and 5 µM. These new phenylhydrazides were tested against Leishmania arginase, but they all failed to inhibit this parasite enzyme, as we have shown in a previous study. To explain the possible mechanism of action, we proposed the enzyme PTR1 as a new target for these compounds based on in silico analysis. In conclusion, the new anthranyl hydrazide derivatives can be a promising scaffold for developing new substances against the protozoa parasite.

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Plant growth-promoting rhizobacteria (PGPR) are members of the plant rhizomicrobiome that enhance plant growth and stress resistance by increasing nutrient availability to the plant, producing phytohormones or other secondary metabolites, stimulating plant defense responses against abiotic stresses and pathogens, or fixing nitrogen. The use of PGPR to increase crop yield with minimal environmental impact is a sustainable and readily applicable replacement for a portion of chemical fertilizer and pesticides required for the growth of high-yielding varieties. Increased plant health and productivity have long been gained by applying PGPR as commercial inoculants to crops, although with uneven results. The establishment of plant-PGPR relationships requires the exchange of chemical signals and nutrients between the partners, and polyamines (PAs) are an important class of compounds that act as physiological effectors and signal molecules in plant-microbe interactions. In this review, we focus on the role of PAs in interactions between PGPR and plants. We describe the basic ecology of PGPR and the production and function of PAs in them and the plants with which they interact. We examine the metabolism and the roles of PAs in PGPR and plants individually and during their interaction with one another. Lastly, we describe some directions for future research.

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Venom-derived proteins and peptides have prevented neuronal cell loss, damage, and death in the study of neurodegenerative disorders. The cytoprotective effects of the peptide fraction (PF) from Bothrops jararaca snake venom were evaluated against oxidative stress changes in neuronal PC12 cells and astrocyte-like C6 cells. PC12 and C6 cells were pre-treated for 4 h with different concentrations of PF, and then H2O2 was added (0.5 mM in PC12 cells; 0.4 mM in C6 cells) and incubated for 20 h more. In PC12 cells, PF at 0.78 µg mL-1 increased viability (113.6 ± 6.3%) and metabolism (96.3 ± 10.3%) cell against H2O2-induced neurotoxicity (75.6 ± 5.8%; 66.5 ± 3.3%, respectively), reducing oxidative stress markers such as ROS generation, NO production, and arginase indirect activity through urea synthesis. Despite that, PF showed no cytoprotective effects in C6 cells, but potentiated the H2O2-induced damage at a concentration lower than 0.07 µg mL-1. Furthermore, the role of metabolites derived from L-arginine metabolism was verified in PF-mediated neuroprotection in PC12 cells, using specific inhibitors of two of the key enzymes in the L-arginine metabolic pathway: the α-Methyl-DL-aspartic acid (MDLA) to argininosuccinate synthetase (AsS), responsible for the recycling of L-citrulline to L-arginine; and, L-NΩ-Nitroarginine methyl ester (L-Name) to nitric oxide synthase (NOS), which catalyzes the synthesis of NO from L-arginine. The inhibition of AsS and NOS suppressed PF-mediated cytoprotection against oxidative stress, indicating that its mechanism is dependent on the production pathway of L-arginine metabolites such as NO and, more importantly, polyamines from ornithine metabolism, which are involved in the neuroprotection mechanism described in the literature. Overall, this work provides novel opportunities for evaluating whether the neuroprotective properties of PF shown in particular neuronal cells are sustained and for exploring potential drug development pathways for the treatment of neurodegenerative diseases.

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