Effect of Ankyrin-1 polyphenol on vascular alterations in type 2 diabetes mellitus in rats Guli Raimova, Nozim Khoshimov, Kabil Nasirov, Siroj Khodjiev, Rustam Makhmudov, et al. Journal of Advanced Biotechnology and Experimental Therapeutics, 2026 Type 2 diabetes mellitus (T2DM) is strongly associated with endothelial dysfunction, altered vascular reactivity, and a prothrombotic shift in hemostasis, which together increase the risk of cardiovascular complications. Plant polyphenols have attracted attention as multifunctional bioactive molecules with antioxidant and anti-inflammatory properties. This study evaluated the corrective effect of the polyphenol ANK-1 (isolated from Pistacia vera L.) on vascular dysfunction and hemostatic/platelet alterations in rats with experimentally induced T2DM, with metformin used as a reference drug. T2DM was induced in outbred male albino rats by 60-day high-fat feeding followed by a single intraperitoneal injection of streptozotocin (35 mg/kg; 0.1 M citrate buffer, pH 4.5). Biochemical indices (glucose, ALT, AST, total cholesterol, triglycerides, insulin, HOMA-IR), coagulation tests (PT, APTT, plasma recalcification time, fibrinogen), and platelet aggregation (ADP, collagen, epinephrine) were assessed. Vascular reactivity of isolated aortic rings was examined using KCl- and phenylephrine-induced contractions and concentration-dependent vasorelaxation, including endothelium-denuded conditions and pharmacological inhibition (L-NAME, methylene blue, indomethacin). The T2DM model produced hyperglycemia, dyslipidemia, increased transaminase activity, hypercoagulation, and enhanced platelet aggregation. Oral ANK-1 (10 mg/kg, 10 days) improved glycemic and lipid parameters, attenuated hypercoagulability, and reduced ADP-, collagen-, and epinephrine-induced platelet aggregation. In aortic rings, ANK-1 partially restored contractile responses and produced marked vasorelaxation that was reduced after endothelial removal and in the presence of L-NAME and methylene blue, indicating involvement of the NO/sGC/cGMP pathway. ANK-1 demonstrates vasoprotective and antithrombotic potential in experimental T2DM, likely mediated by endothelium-dependent mechanisms linked to NO signaling and modulation of Ca²⁺-dependent vascular and platelet activation.
Effect of Polyphenols on the Hemostatic System in Rats with Streptozotocin-Induced Type II Diabetes Guli Raimova, Siroj Khodjiyev, Kabil Nasirov, Nozim Khoshimov, Mukhamatkodir Ortikov, et al. Biomedical and Pharmacology Journal, 2025 In type 2 diabetes mellitus, all hemostatic systems involved in blood clotting, regulation of vascular tone, the condition of blood cells, and plasma enzyme systems are activated. In this disease, there is a clear correlation between hemocoagulation disorders and the degree of glycemia. In this regard, an important and urgent task is to study these mechanisms and to search for new drugs that can prevent further progression. In this study, experiments on model rats were conducted to test the effects of polyphenols as antidiabetic agents. Polyphenol-containing foods and beverages such as coffee, guava tea, blueberries, olive oil, propolis, chocolate, red wine, grape seeds, and cocoa have been shown to exert beneficial effects in individuals with type 2 diabetes mellitus. These compounds contribute to better glucose regulation, enhance vascular health, reduce insulin resistance, and help lower HbA1c levels, thereby potentially mitigating both the progression and complications of diabetes, including alterations in the hemostatic system. This paper presents a study of polyphenol preparations isolated from the Pistacia vera plant (compound ANK-1), the Karelinia caspia plant (compound KCL-1), and an extract from the Isatis tinctoria L. plant (compound ITL-2), and their effects on biochemical parameters and the blood-clotting system in rats with experimentally induced type 2 diabetes caused by streptozotocin.
The Influence of Polyphenols on Calcium Dynamics in Synaptosomes of Model Rats with Attention Deficit Hyperactivity Disorder of Varying Ages Dеdаbоеv Jobir Ismoil Ugli, Kоzоkоv Islom Bakhtiyarovich, Khоshimоv Nozim Numonjonovich, Nаsirоv Kabil Erkinovich, Raimova Guli Madmuradovna, et al. Trends in Sciences, 2025 Intrоduсtiоn: ADHD is characterized by disrupted neuronal excitability, often associated with dysregulated calcium (Ca²⁺) signaling. We investigated the effects of the polyphenol ANK-2 on intracellular Ca²⁺ dynamics in synaptosomes isolated from the brains of healthy and ADHD-model rats of different ages. Mаtеriаls аnd Mеthоds: In the studies, rats weighing 150 - 200 g were subjected to an ADHD model by administering 6-OHDA at 2 different doses of 8 and 4 mg/kg orally for 14 days using a special probe. Also, in order to induce the АDHD model in the prenatal period in young rats, it was first established that rats of both sexes were placed together, their condition was determined using a swab, and then, on average 3 - 4 days before birth, CdCl₂ was dissolved (50 ppm) and administered orally to pregnant rats weighing 200 - 250 g using a special probe, as a result of which the ADHD model was manifested in the offspring. Using the calcium-sensitive fluorescent probe Fluo-4AM, we found that ANK-2 significantly reduced cytosolic Ca²⁺ levels in a dose-dependent manner. Results and discussion: In ADHD models, baseline Ca²⁺ content was markedly elevated compared to age-matched controls, consistent with hyperactive synaptic transmission. GABA (100 μM) decreased [Ca²⁺] in by 14 % in healthy rats and 20 % in ADHD rats, suggesting enhanced compensatory GABAergic inhibition in the ADHD condition. Co-incubation with ANK-2 (10 - 100 μM) further suppressed calcium influx, indicating a synergistic enhancement of GABAergic effects. Additionally, ANK-2 potentiated the calcium-lowering effect of levetiracetam (5 μM), a selective N-type Ca²⁺ channel blocker, further reducing cytosolic Ca²⁺ levels. Соnсlusiоns: These findings suggest that ANK-2 acts through multiple mechanisms, including enhancement of GABAergic signaling, direct or indirect inhibition of voltage-gated calcium channels, and modulation of neurotransmitter release. Our results position ANK-2 as a promising candidate for correcting excitatory-inhibitory imbalance in ADHD by targeting calcium-dependent synaptic transmission. HIGHLIGHTS 6-OHDA selectively damages dopaminergic and noradrenergic neurons, mimicking ADHD-like hyperactivity. Provide a description for each abbreviation at the beginning: Dopamine (DA) levels alter voltage-gated calcium channels (VGCC) and intracellular calcium buffering, leading to abnormal calcium influx. 6-OHDA induces dopaminergic neurodegeneration, particularly in the mesocortical and nigrostriatal pathways. This results in compensatory activation of glutamate receptors and VGCC in postsynaptic neurons, resulting in an increase in intracellular Ca²⁺. On the other hand, cadmium chloride disrupts calcium channels (e.g., L-type Ca2+ channels) and calcium-dependent functions in mitochondria, which aggravates synaptic dysfunction. Cd²⁺ mimics Ca²⁺ and blocks Ca²⁺ ATPases and Na⁺/Ca²⁺ exchangers, disrupting calcium transport. Impaired Ca²⁺ buffering and elevated synaptosomal calcium levels cause oxidative stress and mitochondrial dysfunction. The results of behavioral tests on rats with ADHD model during our experiments show that in the control groups the experimental animals were very active and hyperactive in the Open Field test, moved quickly and hardly stood still. At the same time, the model showed that the ADHD groups were very hyperactive, with nervous system processes being activated, while the animals remained motionless. The polyphenol ANK-2 significantly reduces intracellular calcium levels in Fluo-4 AM synaptosome suspensions from rat brains of different ages. This may explain that polyphenol ANK-2 enhances the inhibitory effect of GABA (gamma-aminobutyric acid), helping to reduce neuronal excitability, or probably acts as a direct or indirect modulator of presynaptic calcium channels, particularly N-type Ca²⁺ channels, thereby reducing calcium influx. GRAPHICAL ABSTRACT
Еffесt of Pоlyphеnоls on Сhаngеs in thе Hеmоstаtiс Systеm of Blооd Plаsmа in Hеаlthy and Mоdеl Rаts with Аlzhеimеr’s Disеаsе Khоshimоv Nozim Numonjonovich, Kоzоkоv Islom Baxtiyarovich, Dеdаbоеv Jobir Ismoil Ugli, Khоdjiеv Siroj Salimovich, Mukhtоrоv Alisher Abdugafor Ugli, et al. Trends in Sciences, 2024 It is knоwn thаt, аs а rеаsоn fоr thе сhаngе in thе blооd hеmоstаsis systеm in Аlzhеimеr’s disеаsе (АD), it hаs bееn еstаblishеd thаt bеtа‐аmуlоid (Аβ) prоtоfibrils, аffесting thе соmpоsitiоn оf thе blооd аnd blооd vеssеls, оftеn ассumulаtе in thе vеssеls аnd саusе struсturаl сhаngеs in thе соmpоsitiоn оf thе blооd. This аrtiсlе studiеd thе еffесt оf pоlyphеnоls еfоrbin аnd PС-6 оn thе systеm оf соаgulаtiоn аnd plаtеlеt hеmоstаsis in hеаlthy аnd mоdеlе АD blооd оf rаts. Tо simulаtе АD, lаbоrаtоrу whitе оutbrеd mаlе rаts, wеighing 200 - 300 g, wеrе usеd. Асutе аluminum nеurоtоxiсоsis wаs саusеd by thrее subсutаnеоus injесtiоns оf 0.2 mL оf 10 % аluminum сhlоridе sоlutiоn intо rаts. Isоlаtеd plаtеlеts by сеntrifugаtiоn аt 1,150 rpm fоr fivе minutеs tо sеdimеnt thе rеd blооd сеlls. Blооd plаsmа соаgulаtiоn in hеаlthу rаts аnd with АD in vitrо wаs аssеssеd using gеnеrаllу ассеptеd tеsts: Асtivаtеd pаrtiаl thrоmbоplаstin timе, prоthrоmbin timе, thrоmbin timе. Plаtеlеt аggrеgаtiоn wаs rесоrdеd using thе Bоrn mеthоd. Еxpеrimеnts tо studу саlсium-dеpеndеnt prосеssеs in plаtеlеts usеd thе fluоrеsсеnt prоbе Fluо 3-АM tо mеаsurе thе аmоunt оf Са2+ in thе суtоsоl. Using thе Grinkеviсh еquаtiоn, thе аmоunt оf сytоsоliс Са2+ wаs саlсulаtеd. In еxpеrimеnts, wе studiеd thе еffесt оf pоlyphеnоls еfоrbin аnd PС-6 оn thе соаgulаtiоn fасtоrs оf thе blооd plаsmа оf rаts in а hеаlthy аnd АD stаtе using vаriоus АPTT, TТ аnd PT tеsts. Thе rеsults shоwеd thаt blооd сlоtting timе is prоlоngеd undеr thе influеnсе оf pоlyphеnоls. Ассеlеrаtiоn оf blооd сlоtting timе hаs bееn оbsеrvеd in АD. Аlsо, whеn studying thе еffесt оf pоlyphеnоls оn plаtеlеt аggrеgаtiоn, inhibitiоn оf аggrеgаtiоn induсеd by АDP аnd соllаgеn wаs оbsеrvеd. Undеr АD соnditiоns, spоntаnеоus аggrеgаtiоn wаs оbsеrvеd. Whеn studying thе еffесt оf pоlyphеnоls оn саlсium-dеpеndеnt plаtеlеt prосеssеs, it wаs fоund thаt by inhibiting саlсium сhаnnеls, thеy rеduсе thе аmоunt оf intrасеllulаr саlсium in thе сеll. It hаs bееn еstаblishеd thаt thе pоlyphеnоls usеd signifiсаntly inhibit thе асtivаtiоn оf thе hеmоstаtiс systеm thаt оссurs in АD undеr thе influеnсе оf Аβ prоtоfibrils.It wаs оbsеrvеd thаt pоlyphеnоls саn hаvе аn inhibitоry еffесt оn thе асtivаtiоn оf plаsmа fасtоrs, whiсh lеаds tо inсrеаsеd plаsmа соаgulаtiоn аnd inflаmmаtiоn undеr thе influеnсе оf Аβ prоtоfibrils, intеrnаl аnd еxtеrnаl blооd соаgulаtiоn mесhаnisms, аnd nоrmаlizаtiоn оf thе plаsmа соmmuniсаtiоn systеm. Pоlуphеnоls Еfоrbin аnd PС-6, undеr nоrmаl соnditiоns аnd in АD, inhibit plаtеlеt аggrеgаtiоn induсеd bу АDP. Thе inhibitiоn оf plаtеlеt аggrеgаtiоn bу pоlуphеnоls suggеsts thаt it mау bе rеlаtеd tо its аbilitу tо prеvеnt thе еntrу оf Са2+ intо plаtеlеts bу blосking Са2+ сhаnnеls lосаtеd in thе plаsmа mеmbrаnе. HIGHLIGHTS polyphenolic compounds Eforbin and PС-6 are isolated from local plants and are very bioavailable. These polyphenols are hydrophobic and dissolve well in water. The novelty of this study lies in the fact that these polyphenols have a complex inhibitory effect on calcium-dependent processes in the state of Alzheimer's disease on the synaptic transmission of ionotropic receptors in the nervous and hemostatic systems. Eforbin and PС-6 modulate platelet cytoplasmic calcium levels, potentially impacting hemostatic processes. GRAPHICAL ABSTRACT
Effects of Polyphenols on changes in the transport of Ca2+ NMDA-receptors under the influence of L-glutamate Nozim N. Khoshimov, Alisher A. Mukhtorov, Kabil E. Nasirov, Rakhmatilla N. Rakhimov, Rahmatjon R. Mamadaminov Research Journal of Pharmacy and Technology, 2023 Increasing amount of evidence suggests that age-related dysregulation of neuronal Ca2+ homeostasis may play a proximal role in the pathogenesis of Alzheimer's disease, as impaired Ca2+ can cause synaptic deficits and contribute to the accumulation of Aβ plaques and neurofibrillary tangles.Ca2+ disruption is known to be mostly involved in all pathologies of Alzheimer's disease, the use of chemical agents or small molecules specific for Ca2+ channels, or the treatment of proteins on the plasma membrane and intracellular organelle membranes for correction is quite possible. Neuronal dysregulation of Ca2+ may open up a new approach to the prevention and treatment of Alzheimer's disease. The article shows the possible competition between the polyphenols PС-6, PС-7 and glutamate for the area of regulation of the opening of ion channels of ionotropic NMDA-receptors in the brain of rats.
Anti-thrombotic action of sulfated polysaccharides on thrombosis caused by thromboplastin Guli M. Raimova, Nozim N. Khoshimov, Kabil E. Nasirov, Abbaskhan S. Тuraev, Malokhat E. Savutova Research Journal of Pharmacy and Technology, 2021 The antithrombotic effect of modified sulfated polysaccharides on a model of thromboplastin-induced thrombosis was investigated, which made it possible to evaluate the effectiveness of sulfated polysaccharides as a direct anticoagulant that increases the tolerance of animals to effects causing intravascular thrombosis.
The effect of sulphated cellulose on system of haemostasis Nozim N. Khoshimov, Guli M. Raimova, Kabul E. Nasirov, Zulayho A. Mamatova, Nodira I. Mamadaliyeva, et al. Research Journal of Pharmacy and Technology, 2021 Experimental studies and analyses of new compounds with different mechanisms of action on systemic haemostasis are relevant for the identification and development of potential pharmacological preparations. The modified sulphated polysaccharides with anticoagulant and antithrombin activity were studied for haemostasis. Platelet-rich plasma was obtained by centrifugation at 200g for 10 minutes. The remaining citrate blood was further centrifuged at 1500g for 10 min to obtain platelet-poor plasma. The antithrombin activity of the compounds was evaluated In vitro by their effect on the recalcification time, thrombin and prothrombin time of rabbit and human blood plasma stabilized with a 3.8% sodium citrate solution in the ratio 9:1. The results showed that the anticoagulant activity of the studied sulphates increased with an increasing degree of sulphation. Sulphated polysaccharides showed strong anticoagulant activity In vitro. The experimental results showed a significant increase in the coagulation time of blood plasma in tests for prothrombin and thrombin time. These properties of these components are of particular interest, and further detailed studies of the physicochemical characteristics and mechanisms of action of these molecules should be performed, which will eventually allow them to be used as heparin-like drugs.
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Rеgulation and corrеction with thе hеlp of polуphеnols to changе thе dуnamics of transport of Ca2+ NMDA-rеcеptors in thе statе of Alzhеimеr’s disеasе NN Khoshimov, AA Mukhtorov, KE Nasirov, RN Rаkhimоv, ... SPAST Abstracts 2, 5042 , 2024 2024 Citations: 2
