Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol

Mitochondria play a crucial role in the cell fate; in particular, reducing the accumulation of calcium in the mitochondrial matrix offers cardioprotection. This affect is achieved by a mild depolarization of the mitochondrial membrane potential, which prevents the assembly and opening of the mitochondrial permeability transition pore. For this reason, mitochondria are an attractive target for pharmacological interventions that prevent ischaemia/reperfusion injury. Isosteviol is a diterpenoid created from the acid hydrolysis of Steviarebaudiana Bertoni (fam. Asteraceae) glycosides that has shown protective effects against ischaemia/reperfusion injury, which are likely mediated through the activation of mitochondrial adenosine tri-phosphate (ATP)-sensitive potassium (mitoKATP) channels. Some triphenylphosphonium (triPP)-conjugated derivatives of isosteviol have been developed, and to evaluate the possible pharmacological benefits that result from these synthetic modifications, in this study, the mitochondriotropic properties of isosteviol and several triPP-conjugates were investigated in rat cardiac mitochondria and in the rat heart cell line H9c2. This study's main findings highlight the ability of isosteviol to depolarize the mitochondrial membrane potential and reduce calcium uptake by the mitochondria, which are typical functions of mitochondrial potassium channel openings. Moreover, triPP-conjugated derivatives showed a similar behavior to isosteviol but at lower concentrations, indicative of their improved uptake into the mitochondrial matrix. Finally, the cardioprotective property of a selected triPP-conjugated derivative was demonstrated in an in vivo model of acute myocardial infarct

КЛИНИЧЕСКИЙ СЛУЧАЙ ЭНДОВАСКУЛЯРНОГО ЛЕЧЕНИЯ ПОСТТРАВМАТИЧЕСКОЙ АНЕВРИЗМЫ ПОЧЕЧНОЙ АРТЕРИИ

Introduction. Aneurysm of renal artery is a rare and complex pathology of renal bloodstream. Large percentage of observations show that renal artery aneurysms are iatrogenic and happen due to urological interventions. Traumatic aneurysms are much less frequent. By the nature of the blood supply arterial aneurysms are subdiveded into those, which occur when the injured organ is only artery and arteriovenous aneurysms that occur while an artery is damaged along with the accompanying veins. Aneurysms may be treated only surgically, and the only exception is pregnancy. It is possible to use the open treatment option such as aneurysm resection with prosthetics, reanastomosing or its collateral plastics of the renal artery; exclusion of aneurysm with shunting of renal artery or its branches; resection of aneurysm with anastomosing of artery with azygos splanchnic arteries; complex reconstruction using autovein or internal iliac artery segment; including kidney resection at local infarction or nephrectomy in the case of evident nephrosclerosis.Materials and methods. This paper presents a clinical case of successful minimally invasive surgical treatment of traumatic aneurysm of renal artery. It was carried out through stenting of the right lowpolar renal artery: a coronary sheath was used to transfuse and implant the Explorer-Itgimedical Aneugraft 3.0 * 18.0 mm graft-system; the stent-graft was implanted into the right lowpolar renal artery so that it covers the aneurysm ostium. Results. The above case shows the possibility to successfully apply the endovascular method to treat posttraumatic aneurysms of renal arteries with derivative circulation.Conclusion. This technique can be safely and successfully used as an alternative to the traditional «open» surgery, as it is minimally invasive, and allows performing a complete blockade of the pathological blood flow and to avoid an additional operating trauma and compromenation of distal branches. Введение. Аневризма почечных артерий – редкая и сложная патология сосудистого русла почки. В большом проценте наблюдений аневризмы почечных артерий являются ятрогенными, возникающими в результате интервенционных урологических вмешательств. Травматические аневризмы встречаются значительно реже. По характеру кровоснабжения различают артериальные аневризмы, возникающие при ранении только артерии, и артериовенозные аневризмы, возникающие при одновременном повреждении артерии и сопутствующей вены. Лечение аневризм возможно только хирургическим способом, исключением является только беременность. Возможно применение открытых методов лечения, таких как резекция аневризмы с протезированием, реанастомозированием или ее боковой пластикой почечной артерии; выключение аневризмы с шунтированием почечной артерии или ее ветвей; резекция аневризмы с анастомозированием артерии с непарными висцеральными артериями; сложные реконструкции с использованием аутовены или сегмента внутренней подвздошной артерии; в том числе применение резекции почки при локальном инфаркте или нефрэктомии в случае выраженного нефросклероза. Материалы и методы. В данной работе представлен клинический случай успешного малоинвазивного хирургического лечения травматической аневризмы почечной артерии. Для этого выполнено стентирование правой нижнеполюсной почечной артерии: по коронарному проводнику проведена и имплантирована графт-система Itgimedical Aneugraft 3,0*18,0 мм – стент-графт имплантирован в нижнеполюсную правую почечную артерию с перекрытием шейки аневризмы.Результаты. Приведенный случай показывает возможность успешного применения эндоваскулярного метода для лечения посттравматических аневризм почечных артерий с артериовенозным сбросом.Заключение. Данная методика может безопасно и с успехом применяться в качестве альтернативы традиционного «открытого» хирургического вмешательства, поскольку она малоинвазивна, позволяет выполнять полную блокаду патологического кровотока, избегать дополнительной операционной травмы и компрометации дистальных ветвей.

Antiviral nucleoside analogs

[Figure not available: see fulltext.] The minireview surveys the modification of native nucleosides as a result of which huge libraries of nucleoside analogs of various structures were synthesized. Particular attention is paid to the synthesis of the so-called prodrug forms of nucleoside analogs which ensure their penetration into the cell and metabolism to active 5'-triphosphate derivatives. All the best known antiviral cyclic nucleoside analogs approved for the treatment of HIV infections, hepatitis B, C, and influenza since the 1960s, as well as those in various stages of clinical trials in recent years, are listed. Nucleoside analogs that have shown the ability to inhibit the replication of SARS-CoV and MERS-CoV are discussed, including remdesivir, approved by the FDA for emergency use in the fight against COVID-19

A CLINICAL CASE OF ENDOVASCULAR TREATMENT OF POST-TRAUMATIC ANEURYSMS OF RENAL ARTERIES

Introduction. Aneurysm of renal artery is a rare and complex pathology of renal bloodstream. Large percentage of observations show that renal artery aneurysms are iatrogenic and happen due to urological interventions. Traumatic aneurysms are much less frequent. By the nature of the blood supply arterial aneurysms are subdiveded into those, which occur when the injured organ is only artery and arteriovenous aneurysms that occur while an artery is damaged along with the accompanying veins. Aneurysms may be treated only surgically, and the only exception is pregnancy. It is possible to use the open treatment option such as aneurysm resection with prosthetics, reanastomosing or its collateral plastics of the renal artery; exclusion of aneurysm with shunting of renal artery or its branches; resection of aneurysm with anastomosing of artery with azygos splanchnic arteries; complex reconstruction using autovein or internal iliac artery segment; including kidney resection at local infarction or nephrectomy in the case of evident nephrosclerosis.Materials and methods. This paper presents a clinical case of successful minimally invasive surgical treatment of traumatic aneurysm of renal artery. It was carried out through stenting of the right lowpolar renal artery: a coronary sheath was used to transfuse and implant the Explorer-Itgimedical Aneugraft 3.0 * 18.0 mm graft-system; the stent-graft was implanted into the right lowpolar renal artery so that it covers the aneurysm ostium. Results. The above case shows the possibility to successfully apply the endovascular method to treat posttraumatic aneurysms of renal arteries with derivative circulation.Conclusion. This technique can be safely and successfully used as an alternative to the traditional «open» surgery, as it is minimally invasive, and allows performing a complete blockade of the pathological blood flow and to avoid an additional operating trauma and compromenation of distal branches

Macrophage Phenotype in Combination with Tumor Microbiome Composition Predicts RCC Patients’ Survival: A Pilot Study

The identification of new prognostic markers of renal cell carcinoma (RCC) is an urgent problem in oncourology. To investigate the potential prognostic significance of tumor microbiome and stromal inflammatory markers, we studied a cohort of 66 patients with RCC (23 clear cell RCC, 19 papillary RCC and 24 chromophobe RCC). The microbiome was analyzed in tumor and normal tissue by 16S rRNA amplicon sequencing. Characterization of the tumor stroma was performed using immunohistochemistry. A significant difference in alpha diversity was demonstrated between normal kidney tissue and all types of RCC. Further, we demonstrated that the bacterial burden was higher in adjacent normal tissue than in a tumor. For the first time, we demonstrated a significant correlation between bacterial burden and the content of PU.1+ macrophages and CD66b+ neutrophils in kidney tumors. Tumors with high content of PU.1+ cells and CD66b+ cells in the stroma were characterized by a lower bacterial burden. In the tumors with high bacterial burden, the number of PU.1+ cells and CD66b+ was associated with a poor prognosis. The identified associations indicate the great prognostic potential of a combined tumor microbiome and stromal cell analysis

Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model

A series of novel triphenylphosphonium (TPP) cations of the diterpenoid isosteviol (<b>1</b>, 16-oxo-<i>ent</i>-beyeran-19-oic acid) have been synthesized and evaluated in an in vivo phenotypic sea urchin embryo assay for antimitotic activity. The TPP moiety was applied as a carrier to provide selective accumulation of a connected compound into mitochondria. When applied to fertilized eggs, the targeted isosteviol TPP conjugates induced mitotic arrest with the formation of aberrant multipolar mitotic spindles, whereas both isosteviol and the methyltriphenylphosphonium cation were inactive. The structure–activity relationship study revealed the essential role of the TPP group for the realization of the isosteviol effect, while the chemical structure and the length of the linker only slightly influenced the antimitotic potency. The results obtained using the sea urchin embryo model suggested that TPP conjugates of isosteviol induced mitotic spindle defects and mitotic arrest presumably by affecting mitochondrial DNA. Since targeting mitochondria is considered as an encouraging strategy for cancer therapy, TPP-isosteviol conjugates may represent promising candidates for further design as anticancer agents