Natural products-based antiangiogenic agents: new frontiers in cancer therapy

Angiogenesis, vital for tumor growth and metastasis, is a promising target in cancer therapy. Natural compounds offer potential as antiangiogenic agents with reduced toxicity. This review provides a comprehensive overview of natural product-based antiangiogenic therapies, focusing on molecular mechanisms and therapeutic potential. A systematic search identified relevant articles from 2019 to 2023. Various natural compounds, including polyphenols, terpenes, alkaloids, cannabinoids, omega-3 fatty acids, polysaccharides, proteins, and carotenoids, were investigated for their antiangiogenic properties. Challenges such as dose standardization, routes of administration, and potential side effects remain. Further studies, including in-depth animal models and human epidemiological studies, must elucidate clinical efficacy and safety. Synergistic effects with current antiangiogenic therapies, such as bevacizumab and tyrosine kinase inhibitors, should be explored. Additionally, the potential hormone-dependent effects of compounds like genistein highlight the need for safety evaluation. In conclusion, natural products hold promise as adjunctive therapies to conventional antineoplastic drugs in modulating angiogenesis in cancer. However, robust clinical trials are needed to validate preclinical findings and ensure safety and efficacy

A combined blockade of glycine and calcium-dependent potassium channels abolishes the respiratory rhythm

In order to test whether glycinergic inhibition is essential for the in vivo respiratory rhythm, we analysed the discharge properties of neurones in the medullary respiratory network after blockade of glycine receptors in the in situ perfused brainstem preparation of mature wild type and oscillator mice with a deficient glycine receptor. In wild type mice, selective blockade of glycine receptors with low concentrations of strychnine (0.03-0.3 muM) provoked considerable changes in neuronal discharge characteristics: The cycle phase relationship of inspiratory, postinspiratory and expiratory specific patterns of membrane potential changes was altered profoundly. Inspiratory, postinspiratory and expiratory neurones developed a propensity for fast voltage oscillations that were accompanied by multiple burst discharges. These burst discharges were followed by "after-burst" hyperpolarisations that were capable of triggering secondary burst discharges. Blockade of glycine receptors and the "big" Ca2+-dependent K+-conductance by charybdotoxin (3.3 nM) resulted in loss of the respiratory rhythm, whilst only tonic discharge activity remained. In contrast, rhythmic activity was only weakened, but preserved after the "small" Ca2+-dependent activated K+ conductance was blocked with apamin (8 nM). Also low concentrations of pentobarbital sodium (6 mg/kg) abolished rhythmic respiratory activity after blockade of glycine receptors in the wild type mice and in glycine receptor deficient oscillator mice. The data imply that failure of glycine receptors provokes enhanced bursting behaviour of respiratory neurones, whilst the additional blockade of BKCa channels by charybdotoxin or with pentobarbital abolishes the respiratory rhythm. (C) 2003 IBRO. Published by Elsevier Ltd. All rights reserved

Reorganisation of respiratory network activity after loss of glycinergic inhibition

gamma -Aminobutyric acid (GABA)-ergic and glycinergic inhibition is believed to play a major role in the respiratory network. In the present study we tested whether specific blockade of glycinergic inhibition resulted in changes in respiratory network interaction and function. Using the working heart-brainstem preparation from adult mice, we recorded phrenic nerve activity and the activity of different types of respiratory neurones located in the ventrolateral medulla. Strychnine (0.03-0.3 muM) was given systemically to block glycine receptors (Gly-R). During exposure to strychnine, post-inspiratory (PI) neurones shifted their onset of discharge into the inspiratory phase. As a consequence, the post-inspiratory phase failed and the rhythm changed from a three-phase cycle (inspiration, post-inspiration, expiration, with a frequency of about. 0.24 Hz) to a faster, two-phased cycle (inspiration expiration, frequency about 0.41 Hz). Inspiratory and expiratory neurones altered their augmenting membrane potential pattern to a rapidly peaking pattern. Smaller voltage oscillations at approximately 10 Hz and consisting of excitatory and inhibitory postsynaptic potential sequences occurred during the expiratory interval. Due to their high frequency and low amplitude, such oscillations would be inadequate for lung ventilation. We conclude that, under physiological conditions, glycinergic inhibition does indeed play a major role in the generation of a normal respiratory rhythm in adult mice. After failure of glycinergic inhibition a faster respiratory rhythm seems to operate through reciprocal GABAergic inhibition between inspiratory and expiratory neurones, while phase switching is organised by activation of intrinsic membrane properties

Histaminergic modulation of the intact respiratory network of adult mice

Histaminergic modulation of neuronal activity in the respiratory network was investigated under normoxic and hypoxic conditions in the working heart-brainstem preparation of adult mice. Systemic application of histamine, as well as the H-1 and H-3 receptor agonists 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT) and imetit, 0.5-10 muM, significantly increased the frequency of respiratory burst discharges. Dimaprit, an H-2 receptor agonist, had no effect on respiratory activity. To test for ongoing histaminergic modulation we applied the histamine receptor antagonists pyrilamine (H-1); cimetidine (H-2) and thioperamide (H-3), each 0.5-10 muM. Only the H-1 receptor antagonist had significant effects, viz. reduction of respiratory frequency and depression of burst amplitude. Underlying effects of histamine receptor activation were identified at the cellular level. Intracellular recordings showed that histamine mediated an increase in synaptic drive potentials in inspiratory neurones while augmentation of inhibitory and excitatory synaptic activity was observed in expiratory neurones. The augmented synaptic depolarisation of inspiratory neurones was blocked by the H-1 receptor antagonist. Histaminergic modulation is also involved in the hypoxic response of the respiratory network. Blockade of H-1 receptors significantly attenuated secondary depression of the biphasic hypoxic responses, while hypoxic augmentation was not affected. We conclude that histamine is a functional neuromodulator, which is tonically active in the respiratory network and is activated further during hypoxia. The data indicate that histaminergic neuromodulation acts predominantly via H-1 receptors

The respiratory rhythm in mutant oscillator mice

Since glycinergic inhibition is important for respiratory rhythm generation in mature mammals, we tested the hypothesis that the loss of glycine receptors during postnatal development (P17-P23) of homozygous mutant oscillator mice (spd(ot)/spd(ot)) may result in serious impairment of respiratory rhythm. We measured breathing in a plethysmographic recording chamber on conscious oscillator mice and used an in situ perfused brainstem preparation to record phrenic nerve activity, as well as membrane properties of respiratory neurones. The deletion of glycinergic inhibition did not result in failure of respiratory rhythm: homozygous mutant oscillator mice continue to generate a disturbed respiratory rhythm until death. Postsynaptic activity and membrane potential trajectories of respiratory neurones revealed a persistence of GABAergic inhibition and changes in respiratory rhythm and pattern generation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved

Respiratory rhythm generation: Plasticity of a neuronal network

The exchange of gases between the external environment and the organism is controlled by a neural network of medullary neurons that produces rhythmic activity that ultimately leads to periodic contractions of thoracic, abdominal, and diaphragm muscles. This occurs in three neural phases: inspiration, postinspiration, and expiration. The present article deals with the mechanisms underlying respiratory rhythm generation and the processes of dynamic adjustment of respiratory activity by neuromodulation as it occurs during normoxia and hypoxia. The respiratory rhythm originates from the "pre-Botzinger complex" which is a morphologically defined region within the lower brainstem. There is a primary oscillating network consisting of reciprocally connected early-inspiratory and postinspiratory neurons, whereas various other subgroups of respiratory neurons shape the activity pattern. Rhythm generation and pattern formation result from neuronal interactions within the network, that is, from cooperative adjustments of intrinsic membrane properties and synaptic processes in the respiratory neurons. There is evidence that in neonatal mammals, as well as under certain pathological situations in adult mammals, the respiratory rhythm derives from early-inspiratory burster neurons that drive inspiratory output neurons. The respiratory network is influenced by a variety of neuromodulators. Stimulation of appropriate receptors mostly activates signal pathways that converge on cAMP-dependent protein kinase and protein kinase C. Both pathways exert modulatory effects on voltage- and ligand-controlled ion channels. Many neuromodulators are continuously released within the respiratory region or accumulated under pathological conditions such as hypoxia. The functional significance of such ongoing neuromodulation is seen in variations of network excitability. In this review, the authors concentrate on the modulators serotonin, adenosine, and opioids

Respiratory rhythm generation: Plasticity of a neuronal network

The exchange of gases between the external environment and the organism is controlled by a neural network of medullary neurons that produces rhythmic activity that ultimately leads to periodic contractions of thoracic, abdominal, and diaphragm muscles. This occurs in three neural phases: inspiration, postinspiration, and expiration. The present article deals with the mechanisms underlying respiratory rhythm generation and the processes of dynamic adjustment of respiratory activity by neuromodulation as it occurs during normoxia and hypoxia. The respiratory rhythm originates from the "pre-Botzinger complex" which is a morphologically defined region within the lower brainstem. There is a primary oscillating network consisting of reciprocally connected early-inspiratory and postinspiratory neurons, whereas various other subgroups of respiratory neurons shape the activity pattern. Rhythm generation and pattern formation result from neuronal interactions within the network, that is, from cooperative adjustments of intrinsic membrane properties and synaptic processes in the respiratory neurons. There is evidence that in neonatal mammals, as well as under certain pathological situations in adult mammals, the respiratory rhythm derives from early-inspiratory burster neurons that drive inspiratory output neurons. The respiratory network is influenced by a variety of neuromodulators. Stimulation of appropriate receptors mostly activates signal pathways that converge on cAMP-dependent protein kinase and protein kinase C. Both pathways exert modulatory effects on voltage- and ligand-controlled ion channels. Many neuromodulators are continuously released within the respiratory region or accumulated under pathological conditions such as hypoxia. The functional significance of such ongoing neuromodulation is seen in variations of network excitability. In this review, the authors concentrate on the modulators serotonin, adenosine, and opioids