Flavonoids exhibit a wide range of biological activities, including antioxidant, anti-inflammatory, antidiabetic, antitumor, antiproliferative, and hemorheological effects. This review discusses the hemorheological activity of flavonoids and the underlying mechanisms. The hemorheological activity of flavonoids and flavonoid complexes has been studied in both in vitro and in vivo models of myocardial infarction, arterial hypertension, atherosclerosis, cerebrovascular insufficiency, pancreatitis, hepatitis, and rheumatoid arthritis, as well as in aging animals. Flavonoids are known to decrease whole blood viscosity, reduce red blood cell (RBC) aggregation, improve RBC deformability, and even, in some cases, decrease fibrinogen levels and plasma viscosity. The key mechanisms underlying the hemorheological effects of flavonoids are the following: (1) antioxidant protection from oxidative stress and (2) stabilization of membrane fluidity. The antioxidant effect is mediated through neutralization of reactive oxygen species outside RBCs, within the RBC membrane, and in the cytoplasm, thereby protecting RBC membranes (both lipid and protein constituents) from oxidative damage. Flavonoids also contribute to the maintenance and enhancement of endogenous antioxidant defense systems in RBCs. Clinical trials of flavonoid-based agents have demonstrated both hemorheological activity and therapeutic efficacy in patients with diabetes mellitus, coronary heart disease, venous insufficiency, dyscirculatory encephalopathy, arterial hypertension, and other conditions. The introduction of effective and low-toxicity flavonoid preparations with hemorheological activity into treatment regimens for conditions associated with hyperviscosity syndrome may enable the development of new therapeutic strategies for many diseases and improve patient outcomes.

Nitrogen-containing fused tetracyclic systems, exemplified by the synthetic 11H-indeno[1,2-b]quinoxalin-11-one core and the natural alkaloid tryptanthrin (indolo[2,1-b]quinazolin-6,12-dione), constitute structural scaffolds whose rigid, planar architecture enables high-affinity interaction with nucleic acids and kinase active sites. Converting the exocyclic carbonyls at C-11 and C-6, respectively, into oximes has become a productive strategy in medicinal chemistry. This transformation modulates frontier orbital energies, installs N,O- and N,N-chelating pharmacophores, and enables nitric oxide (NO) release. Here, we summarize current knowledge of the synthesis, stereochemical characterization, and diverse biological activities of these tetracyclic ketoximes and related derivatives. Microwave, sonochemical, visible-light photocatalytic, and multicomponent methods now afford efficient, economical routes to the parent ketones and their oximes. X-ray crystallography, spectroscopy, and density functional theory have firmly established the thermodynamic preference for the E-oxime configuration and clarified how this geometry, along with potential target-induced isomerization, shapes binding. The oximes bind c-Jun N-terminal kinases (JNK1–3) with high affinity, a property that accounts for their neuroprotective effects in models of cerebral ischemia and Alzheimer-like pathology, their dual JNK inhibition and NO-mediated cardioprotection in hypertension and myocardial infarction, and their anti-inflammatory activity via suppression of NF-κB/AP-1 signaling. Broader studies also document anticancer, antimicrobial, antiviral, and antidiabetic activities arising from DNA intercalation, topoisomerase inhibition, metal-ion coordination, and kinase blockade. Compelling preclinical profiles notwithstanding, low oral bioavailability and rapid hepatic clearance remain major pharmacokinetic obstacles. Ongoing work on new formulations, prodrug strategies, and structure–activity optimization seeks to slow systemic elimination. Precise stereochemical definition combined with pleiotropic pharmacology positions tetracyclic ketoximes as attractive candidates for next-generation agents against complex multifactorial diseases.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. AMD development is associated with inflammation, oxidative stress, and a progressive proteostasis imbalance, in whose regulation, c-Jun N-terminal kinases (JNKs) play a crucial role. JNK inhibition is being discussed as a new way to prevent and treat AMD, but there are no data on JNK signaling in the retina and its changes with age and with AMD development. Here, for the first time, we assessed JNK-signaling activity in the retina and did not detect its age-related changes in healthy Wistar rats. By contrast, manifestation and progression of the AMD-like pathology in OXYS rats occurred simultaneously with JNK pathway activation. We also confirmed that selective JNK3 inhibitor 11H-indeno[1,2-b] quinoxalin-11-one oxime sodium salt (IQ-1S) can suppress neurodegenerative changes in the OXYS rat retina. Its effects were prevention of the destructive changes in retinal synapses and the suppression of the JNK signaling pathway activity during active progression of AMD signs in OXYS rats.

Disruption of the blood–brain barrier (BBB) accompanies many brain diseases, including stroke, neurodegenerative diseases, and brain tumors, leading to swelling, increased neuroinflammation, and neuronal death. In recent years, it has become clear that the c-Jun N-terminal kinase (JNK) signaling pathway is involved in disruption of the structural integrity of the BBB. Activation of the JNK signaling pathway has a negative effect on the functioning of the cellular elements of the neurovascular unit that form the BBB. The aim of this review is to assess the role of the JNK signaling pathway in the disruption of the structural integrity of the BBB in animal models of stroke (MCAO/R, middle cerebral artery occlusion with reperfusion), Alzheimer’s disease, and brain tumors and to analyze the effects of compounds of various natures that directly or indirectly affect the activity of the JNK signaling pathway. These compounds can reduce damage to the BBB and brain edema, reduce neuroinflammation and oxidative stress, reduce the expression of proapoptotic factors, and increase the expression of tight junction proteins. Certain compounds mitigate BBB dysfunction, being promising candidates for neuroprotective therapies. These agents exert their effects, in part, through inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway, a mechanism linked to reduced neuronal damage and improved BBB integrity.

Taxifolin (TAX) (5,7,3',4'-tetrahydroxyflavanol, dihydroquercetin) belongs to the flavonoid family. TAX elicits a wide range of pharmacological effects, and for this reason, it is of high commercial interest as a flavonoid. The widespread use of TAX in medical practice is limited by the physicochemical properties of the compound and, in part, the related features of its pharmacokinetics: absorption, distribution, metabolism, and excretion. The purpose of this review is to provide an overview of technological methods that can be utilized to enhance the solubility of TAX, potentially increasing its bioavailability. The review describes various technological approaches: micronization, crystal engineering, self-microemulsifying systems, liposomes and their modifications, microemulsifying systems, phospholipid nanoparticles, inclusion complexes (clathrate generation), and chemical modification. Most of the approaches described in the review for improving the solubility and bioavailability of TAX have proven to be successful. Nanotechnologies are the most efficient means for improving the solubility and bioavailability of TAX. Developing new TAX substances with improved solubility and bioavailability holds promise as a basis for the development of innovative drugs.

We investigated the effect of a decrease in blood viscosity on the mean BP during isovolumic hemodilution and vasodilating activity of the endothelium in normotensive Wistar rats and spontaneously hypertensive rats (SHR). Blood viscosity was reduced by isovolumic hemodilution (replacement of 10% of circulating blood with an equal volume of plasma). Hemodilution caused the same reduction in blood viscosity by 16% in both groups of rats. In Wistar rats, a decrease in blood viscosity did not significantly change in the mean BP; no significant correlations between blood viscosity and mean BP were observed before and after hemodilution. In SHR, a decrease in blood viscosity led to a significant decrease in the mean BP by 18%. Correlations were found between the mean BP and blood viscosity in SHR before (r=0.63; p=0.028) and after (r=0.71; p=0.009) isovolumic hemodilution. In SHR, a decrease in the index of vasodilating activity of the endothelium due to a decrease in the vasodilatory response to intravenous administration of the endothelium-dependent vasodilator acetylcholine was revealed. In SHR, BP passively follows the change, in this case, the decrease in blood viscosity, which attests to impaired BP regulation in response to changes in shear stress on the vascular endothelium caused by the development of endothelial dysfunction in hypertensive animals.

The neuroprotective activity of tryptanthrin and its oxime was compared in male Wistar rats with a model of intraluminal occlusion of the middle cerebral artery. Neurobehavioral tests were performed 4, 24, and 48 h after focal cerebral infarction (FCI) using a modified neurological severity score (mNSS); additionally, the horizontal stability test, the plantar sensitivity test of the fore and hind limbs, holding on the tilted cage top test, and negative geotaxis test were performed. The size of FCI and the severity of brain tissue swelling were examined on day 2 after occlusion. Tryptanthrin and its oxime were administered at a dose of 10 mg/kg intraperitoneally during FCI, then daily for 2 days. In the control group, the mean score of neurological deficit remained at a high level for 2 days. FCI size was 43.8±3.4

In experiments on Wistar rats, the effect of a new selective JNK inhibitor tryptanthrin oxime (TR-Ox) on parameters of systemic hemodynamics, cardiohemodynamics, and post-infarction fibrosis was studied 4 months after acute myocardial ischemia (1 h) followed by reperfusion. TR-Ox was administered intraperitoneally at a dose of 12 mg/kg 20 min before reperfusion, and then once a day for the next 4 days. Administration of TR-Ox to animals in the acute phase of myocardial infarction contributed to more complete preservation of myocardial viability in the delayed period: a relative increase of muscle elements proportion in the scar, a decrease in the formation of connective tissue areas with complete and >50% replacement of the myocardium, and deceleration of fibrotic scarring in myocardium areas distant from the focus of injury, resulting in improved systolic and diastolic myocardial function. Four months after myocardial infarction, significant improvement in systemic hemodynamics and cardiohemodynamics parameters was observed in the group treated with TR-Ox: stroke volume, cardiac output, left ventricular systolic pressure, maximum rates of left ventricle pressure rise and fall significantly increased and the left ventricle end-diastolic pressure decreased in comparison with the corresponding parameters in the control group.

The effect of a new JNK inhibitor IQ-1 (11 H -indeno[1,2- b ]quinoxalin-11-one oxime) was studied in male Wistar rats in a model of acute myocardial ischemia/reperfusion. Area at risk and myocardial infarct zones were studied in two series of experiments: 16 h after a single dose of IQ-1 (25 mg/kg intraperitoneally during cardiac ischemia) and on day 5 after its course administration (25 mg/kg intraperitoneally during cardiac ischemia and daily over 4 days). On day 5 after ischemia/reperfusion, cardiodynamic indicators were also studied: systolic, end-diastolic, and minimum pressure in the left ventricle, stress—time index, as well as the maximum rates of pressure rise and fall in the left ventricle (+dP/dt max and -dP/dt max ). In 16 h after ischemia/reperfusion, the infarct area in the control was 24±2% of the total area of the sections, while after administration of IQ-1 this parameter was 14±1% ( p <0.05). On day 5, the infarct area in the control group was 25±1% of the total area of myocardial sections. A course of IQ-1 administration led to a significant reduction in the infarct area to 10±2% of the total area of myocardial slices. Course administration of IQ-1 led to improvement in contractile function and weakening of the diastolic dysfunction of the left ventricle: systolic pressure in the left ventricle increased by 20%, +dP/dt max by 23%, voltage—time index by 12%, -dP/dt max by 43%, and the minimum pressure in the left ventricle decreased by 3.4 times.

We studied the radical-binding and antioxidant activities of the alkaloid tryptanthrin (TR) and its new synthetic derivative tryptanthrin oxime (TR-Ox), as well as the cytoprotective activity of TR-Ox under conditions of oxidative stress. The antiradical activity of TR-Ox was revealed in the test of binding with stable chromogen radical 2,2-diphenyl-1-picrylhydrazyl and in the superoxide radical generation test (riboflavin photoreduction reaction with detection by NBT reduction). TR-Ox was inferior to ionol and dihydroquercetin by the antiradical activity. In these tests, TR did not exhibit antiradical activity. TR-Ox did not show iron-chelating activity (in the test with the formation of the o-phenanthroline-Fe2+ complex and its destruction in the presence of chelating agents). In brain homogenate, TR-Ox significantly reduced the increase in spontaneous chemiluminescence. Under conditions of oxidative stress induced by 15 mM H2O2 in the SH-SY5Y neuroblastoma cell culture, TR-Ox exhibited cytoprotective activity and increased the number of viable cells.

Introduction. Oxidative stress is a non-specific pathogenetic link in inflammatory diseases of the oral mucosa, which has a destructive effect on its structure and function. In this regard, natural antioxidants such as (p-tyrosol) are of great interest to researchers. The purpose of this paper was to study the effect of p-tyrosol on the morphofunctional changes in the microcirculatory during experimental stomatitis. Materials and methods. The experiment was carried out on 72 Wistar rats with experimental stomatitis. The animals were divided into four groups, each including 18 subjects: the control (intact rats; group 1 with the burn and no treatment (group 2), with the burn and subsequent administration of p-tyrosol (group 3), and with the burn and subsequent administration of Lidocaine + Chamomile flower extract (group 4). Results. The animals of group 3 had the smallest values of the altered vessels, the precapillary diffusion index and the Kernogan index on days 3, 7, and 12. On the contrary, the numerical density of the unchanged arterioles, venules, and capillaries was the greatest. VEGF expression was detected in group 3 on days 7 and 12, and in group 4, on day 12, thus indicating a more intense angiogenesis. Conclusion. On the background of p-tyrosol administration, there is an increased blood supply in the treated area due to the following factors: a growing density of unchanged microvessels, the germination of the ves-sels in the treated area, and induced angiogenesis.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment worldwide. The development of AMD is associated with inflammation, oxidative stress, and progressive proteostasis imbalance, in the regulation of which c-Jun N-terminal kinases (JNK) play a crucial role. JNK inhibition is discussed as an alternative way for prevention and treatment of AMD and other neurodegenerative diseases. Here we assess the retinoprotective potential of the recently synthesized JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S) using senescence-accelerated OXYS rats as a model of AMD. The treatment with IQ-1S (50 mg/kg body weight intragastric) during the period of active disease development (from 4.5 to 6 months of age) improved some (but not all) histological abnormalities associated with retinopathy. IQ-1S improved blood circulation, increased the functional activity of the retinal pigment epithelium, reduced the VEGF expression in the endothelial cells, and increased the expression of PEDF in the neuroretina. The result was a decrease in the degeneration of photoreceptors and neurons of the inner layers. IQ-1S significantly improved the retinal ultrastructure and increased the number of mitochondria, which were significantly reduced in the neuroretina of OXYS rats compared to Wistar rats. It seems probable that using IQ-1S can be a good prophylactic strategy to treat AMD.

Activation of c-Jun N-terminal kinases (JNKs) is involved in myocardial injury, left ventricular remodeling (LV), and heart failure (HF) after myocardial infarction (MI). The aim of this research was to evaluate the effects of a selective JNK inhibitor, 11H-indeno [1,2-b]quinoxalin-11-one oxime (IQ-1), on myocardial injury and acute myocardial ischemia/reperfusion (I/R) in adult male Wistar rats. Intraperitoneal administration of IQ-1 (25 mg/kg daily for 5 days) resulted in a significant decrease in myocardial infarct size on day 5 after MI. On day 60 after MI, a significant (2.6-fold) decrease in LV scar size, a 2.2-fold decrease in the size of the LV cavity, a 2.9-fold decrease in the area of mature connective tissue, and a 1.7-fold decrease in connective tissue in the interventricular septum were observed compared with the control group. The improved contractile function of the heart resulted in a significant (33%) increase in stroke size, a 40% increase in cardiac output, a 12% increase in LV systolic pressure, a 28% increase in the LV maximum rate of pressure rise, a 45% increase in the LV maximum rate of pressure drop, a 29% increase in the contractility index, a 14% increase in aortic pressure, a 2.7-fold decrease in LV end-diastolic pressure, and a 4.2-fold decrease in LV minimum pressure. We conclude that IQ-1 has cardioprotective activity and reduces the severity of HF after MI.

— According to the Alzheimer’s Disease International (ADI) international organization about 50 million people in the world suffer from Alzheimer’s disease (AD). However, there are no effective methods for preventing or slowing the progression of AD. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway is discussed below as an alternative way to prevent the development of AD and other neurodegenerative diseases. In the present study, we evaluated the ability of a recently synthesized selective JNK3 inhibitor, 11 H -indeno[1,2- b ]quinoxalin-11-one oxime sodium salt (IQ-1S), to suppress neurodegenerative processes in OXYS rats at an early stage of development of AD at the ages of 4.5 to 6 months. Treatment with IQ-1S (50 mg/kg intragastrically) led to the suppression of the development of neurodegenerative processes in the cerebral cortex of OXYS rats: an increase in the proportion of unchanged neurons, a decrease in the proportion of neurons with signs of destruction and irreversible damage, and a normalization of the glioneuronal index, which was facilitated by a decrease in the severity of hyperviscosity syndrome blood in OXYS rats. The use of the IQ-1S JNK3 inhibitor may be a promising strategy for the prevention of early neurodegenerative disorders and, possibly, the treatment of AD.

The activation of c-Jun N-terminal kinase (JNK) plays an important role in stroke outcomes. Tryptanthrin-6-oxime (TRYP-Ox) is reported to have high affinity for JNK and anti-inflammatory activity and may be of interest as a promising neuroprotective agent. The aim of this study was to investigate the neuroprotective effects of TRYP-Ox in a rat model of transient focal cerebral ischemia (FCI), which involved intraluminal occlusion of the left middle cerebral artery (MCA) for 1 h. Animals in the experimental group were administered intraperitoneal injections of TRYP-Ox 30 min before reperfusion and 23 and 47 h after FCI. Neurological status was assessed 4, 24, and 48 h following FCI onset. Treatment with 5 and 10 mg/kg of TRYP-Ox decreased mean scores of neurological deficits by 35–49 and 46–67% at 24 and 48 h, respectively. At these doses, TRYP-Ox decreased the infarction size by 28–31% at 48 h after FCI. TRYP-Ox (10 mg/kg) reduced the content of interleukin (IL) 1β and tumor necrosis factor (TNF) in the ischemic core area of the MCA region by 33% and 38%, respectively, and attenuated cerebral edema by 11% in the left hemisphere, which was affected by infarction, and by 6% in the right, contralateral hemisphere 24 h after FCI. TRYP-Ox reduced c-Jun phosphorylation in the MCA pool at 1 h after reperfusion. TRYP-Ox was predicted to have high blood–brain barrier permeability using various calculated descriptors and binary classification trees. Indeed, reactive oxidant production was significantly lower in the brain homogenates from rats treated with TRYP-Ox versus that in control animals. Our data suggest that the neuroprotective activity of TRYP-Ox may be due to the ability of this compound to inhibit JNK and exhibit anti-inflammatory and antioxidant activity. Thus, TRYP-Ox may be considered a promising neuroprotective agent that potentially could be used for the development of new treatment strategies in cerebral ischemia.

The effect of p-tyrosol on the main hemodynamic parameters and contractile function of the heart was studied and a morphometric assessment of left-ventricular remodeling was performed in Wistar rats 2 months after acute 1-h myocardial ischemia followed by reperfusion. p-Tyrosol in a dose of 20 mg/kg was injected intraperitoneally 5 times: 20 min before the start of reperfusion, 4 h after the start of reperfusion, and then once a day over the next 3 days. Administration of p-tyrosol to animals in the acute period of myocardial infarction slowed down the formation of systolic and diastolic myocardial dysfunction, improved the pumping function of the heart, maintained the hemodynamic parameters at a significantly higher level, and reduced left-ventricular remodeling in the late period of myocardial infarction. In 2 months after acute myocardial ischemia modeling, the dimensions of the left-ventricular cavity, the area of the postinfarction focus, and the area of connective tissue in rats treated with p-tyrosol were significantly lower than in the control group. In the group treated with p-tyrosol, no anterior left-ventricular wall aneurysms were found.

The c-Jun N-terminal kinases (JNKs) regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival, and cell death. Therefore, JNKs represent attractive targets for therapeutic intervention. In an effort to develop improved JNK inhibitors, we synthesized the lithium salt of 11H-indeno[1,2-b]quinoxaline-11-one oxime (IQ-1L) and evaluated its affinity for JNK and biological activity in vitro and in vivo. According to density functional theory (DFT) modeling, the Li+ ion stabilizes the six-membered ring with the 11H-indeno[1,2-b]quinoxaline-11-one (IQ-1) oximate better than Na+. Molecular docking showed that the Z isomer of the IQ-1 oximate should bind JNK1 and JNK3 better than (E)-IQ-1. Indeed, experimental analysis showed that IQ-1L exhibited higher JNK1-3 binding affinity in comparison with IQ-1S. IQ-1L also was a more effective inhibitor of lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue monocytes and was a potent inhibitor of proinflammatory cytokine production by MonoMac-6 monocytic cells. In addition, IQ-1L inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. In a rat model of focal cerebral ischemia (FCI), intraperitoneal injections of 12 mg/kg IQ-1L led to significant neuroprotective effects, decreasing total neurological deficit scores by 28, 29, and 32% at 4, 24, and 48 h after FCI, respectively, and reducing infarct size by 52% at 48 h after FCI. The therapeutic efficacy of 12 mg/kg IQ-1L was comparable to that observed with 25 mg/kg of IQ-1S, indicating that complexation with Li+ improved efficacy of this compound. We conclude that IQ-1L is more effective than IQ-1S in treating cerebral ischemia injury and thus represents a promising anti-inflammatory compound.

We developed a model of blood hyperviscosity avoiding extreme impact on the blood. The model shows reproducibility in rat blood under common storage conditions (4±1°C; stabilization with citrate-phosphate-glucose additive solution). Storage of rat blood under these condition leads to impairment of its rheological properties, which manifested in an increase in blood viscosity in a wide range of shear rates (3-300 sec —1 ). An increase in blood viscosity appeared the first day of storage and reached a maximum on the third day. During further 11-day storage, the blood viscosity did not change significantly. A hybrid macromolecular compound O-(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoyl)-(1→6)-α-D-glucan improved the hemorheological properties during storage. The most pronounced effect was observed on the third day of storage and manifested in a decrease in blood viscosity in the range of shear rates of 50-300 sec —1 . Thus, storage of rat blood with citrate-phosphate-glucose additive solution for 3 days at 4±1°C reproduces the phenomenon of blood hyperviscosity; this model can be used to screen agents with hemorheological activity.

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.