Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.

• MeSH
• antioxidancia farmakologie   MeSH
• cisplatina * toxicita   MeSH
• ferroptóza * účinky léků   MeSH
• flavonoly * farmakologie   terapeutické užití   MeSH
• kosterní svaly účinky léků   patologie   metabolismus   MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• oxidační stres * účinky léků   MeSH
• protinádorové látky toxicita   MeSH
• svalová atrofie * chemicky indukované   patologie   metabolismus   prevence a kontrola   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antioxidancia MeSH
• cisplatina * MeSH
• dihydromyricetin MeSH Prohlížeč
• flavonoly * MeSH
• protinádorové látky MeSH

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.

• MeSH
• akutní poškození ledvin * chemicky indukované   patologie   metabolismus   prevence a kontrola   farmakoterapie   MeSH
• cisplatina * toxicita   MeSH
• diminazen * analogy a deriváty   farmakologie   terapeutické užití   MeSH
• inhibitory ACE farmakologie   MeSH
• krysa rodu Rattus MeSH
• ledviny účinky léků   patologie   metabolismus   MeSH
• lisinopril * farmakologie   MeSH
• potkani Wistar * MeSH
• protinádorové látky toxicita   MeSH
• valsartan * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• cisplatina * MeSH
• diminazen * MeSH
• inhibitory ACE MeSH
• lisinopril * MeSH
• protinádorové látky MeSH
• valsartan * MeSH

Although cisplatin is an effective chemotherapy drug for the treatment of various cancers, its clinical use is limited due to its side effects, especially nephrotoxicity. Unfortunately, acute kidney injury (AKI) caused by cisplatin remains one of the main challenges in effective cancer treatment. Evidence increasingly suggests that renal inflammation and pyroptotic inflammatory cell death of renal tubular epithelial cells (RTECs) mainly determine the progression and outcome of cisplatin-induced AKI. However, it is not clear how cisplatin regulates the pyroptosis of RTECs cells in AKI. The current study aimed to determine the regulation mechanism of AKI induced by cisplatin. We used cisplatin to induce AKI in vivo. We performed H&E staining of mouse kidney tissue sections and evaluated serological indicators of kidney injury (including blood urea nitrogen (BUN), serum creatinine, and tumor necrosis factor-alpha (TNF-alpha)). We used immunohistochemistry and western blot to detect the important substrate protein gasdermin D (GSDMD) and key target caspase-1 of pyroptosis, respectively. Cisplatin induced mouse AKI and RTECs pyroptosis. HK2 cell-derived exosomes treated with cisplatin influenced pyroptosis of the surrounding HK2 cells. Cisplatin-treated HK2 cells exosome-derived miR-122 regulated pyroptosis in the surrounding cells. Exosome-derived miR-122 affected cisplatin-induced AKI and HK2 cells pyroptosis by regulating the expression of embryonic lethal abnormal vision (ELAVL1). These results suggest that exosome miR-122 inhibited pyroptosis and AKI by targeting ELAVL1 under cisplatin treatment, and this offers a potential target for the treatment of AKI.

• MeSH
• akutní poškození ledvin * chemicky indukované   MeSH
• cisplatina toxicita   MeSH
• exozómy * metabolismus   patologie   MeSH
• mikro RNA * metabolismus   MeSH
• myši MeSH
• pyroptóza MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• mikro RNA * MeSH
• Mirn122 microRNA, mouse MeSH Prohlížeč

The main dose-limiting side effect of cisplatin is nephrotoxicity. The utilization of cisplatin is an issue of balancing tumour toxicity versus platinum-induced nephrotoxicity. In this study, we focused on intraorgan distribution of common essential trace elements zinc, copper, and iron in healthy mouse kidneys and distribution of platinum after cisplatin treatment. Renal distribution in 12 nontreated Nu-Nu mice (males) was assessed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). Furthermore, 9 Nu-Nu mice were treated with cisplatin. The order of elements concentration in kidneys was as follows: Fe > Zn > Cu. All three metals showed the higher concentrations at the cortex and medulla (28.60, 3.35, and 93.83 μg/g for Zn, Cu, and Fe, respectively) and lower concentration at the pelvis and the urinary tract (20.20, 1.93, and 62.48 μg/g for Zn, Cu, and Fe, respectively). No statistically significant difference between cortex and medulla was observed for these elements. After platinum treatment, the concentration of platinum in kidneys was enhanced more than 60-times, p < 0.001. Platinum significantly showed the highest accumulation in cortex (2.11 μg/g) with a gradient distribution. Platinum was less accumulated in medulla and pelvis than in cortex, and the lowest accumulation occurred in the urinary tract (1.13 μg/g). Image processing has been successfully utilized to colocalize metal distribution using LA-ICP-MS and histological samples images.

• MeSH
• buňky PC-3 MeSH
• cisplatina škodlivé účinky   farmakologie   toxicita   MeSH
• hmotnostní spektrometrie metody   MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• lidé MeSH
• měď analýza   MeSH
• myši nahé MeSH
• myši MeSH
• platina analýza   MeSH
• spektrální analýza metody   MeSH
• železo analýza   MeSH
• zinek analýza   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• měď MeSH
• platina MeSH
• železo MeSH
• zinek MeSH

The human proximal tubular HK-2 cell line is an immortalized cell line commonly used for studying proximal tubular toxicity. Even as their use is presently increasing, there unfortunately are no studies focused on functional changes in HK-2 cells associated with passaging. The aim of the present study, therefore, was to evaluate the functional stability of HK-2 cells during 13 weeks of continuous passaging after 6 and 24 h of treatment with model nephrotoxic compounds (i.e., acetaminophen, cisplatin, CdCl(2)). Short tandem repeat profile, the doubling time, cell diameter, glutathione concentration, and intracellular dehydrogenase activity were measured in HK-2 cells at each tested passage. The results showed that HK-2 cells exhibit stable morphology, cell size, and cell renewal during passaging. Mean doubling time was determined to be 54 h. On the other hand, we observed a significant effect of passaging on the susceptibility of HK-2 cells to toxic compounds. The largest difference in results was found in both cadmium and cisplatin treated cells across passages. We conclude that the outcomes of scientific studies on HK-2 cells can be affected by the number of passages even after medium-term cultivation and passaging for 13 weeks.

• MeSH
• buněčné kultury metody   MeSH
• buněčné linie MeSH
• cisplatina toxicita   MeSH
• kadmium toxicita   MeSH
• lidé MeSH
• neopioidní analgetika toxicita   MeSH
• paracetamol toxicita   MeSH
• protinádorové látky toxicita   MeSH
• proximální tubuly ledvin účinky léků   patologie   MeSH
• viabilita buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• kadmium MeSH
• neopioidní analgetika MeSH
• paracetamol MeSH
• protinádorové látky MeSH

PR domain containing 9 (Prdm9) is specifying hotspots of meiotic recombination but in hybrids between two mouse subspecies Prdm9 controls failure of meiotic chromosome synapsis and hybrid male sterility. We have previously reported that Prdm9-controlled asynapsis and meiotic arrest are conditioned by the inter-subspecific heterozygosity of the hybrid genome and we presumed that the insufficient number of properly repaired PRDM9-dependent DNA double-strand breaks (DSBs) causes asynapsis of chromosomes and meiotic arrest (Gregorova et al., 2018). We now extend the evidence for the lack of properly processed DSBs by improving meiotic chromosome synapsis with exogenous DSBs. A single injection of chemotherapeutic drug cisplatin increased frequency of RPA and DMC1 foci at the zygotene stage of sterile hybrids, enhanced homolog recognition and increased the proportion of spermatocytes with fully synapsed homologs at pachytene. The results bring a new evidence for a DSB-dependent mechanism of synapsis failure and infertility of intersubspecific hybrids.

• Klíčová slova
• DNA double-strand breaks, Prdm9, chromosomes, gene expression, genetics, genomics, hybrid sterility, meiosis, mouse,
• MeSH
• cisplatina toxicita   MeSH
• dvouřetězcové zlomy DNA účinky léků   MeSH
• histonlysin-N-methyltransferasa genetika   metabolismus   MeSH
• hybridizace genetická MeSH
• meióza účinky léků   genetika   MeSH
• mužská infertilita genetika   MeSH
• myši inbrední C57BL MeSH
• oprava DNA MeSH
• párování chromozomů účinky léků   genetika   MeSH
• protinádorové látky toxicita   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• histonlysin-N-methyltransferasa MeSH
• prdm9 protein, mouse MeSH Prohlížeč
• protinádorové látky MeSH

Our study demonstrates that four novel kinetically inert C,N-cyclometalated RuII complexes of the type [Ru(C^N)(N^N)2 ][PF6 ] containing a handle for functionalization on the C^N ligand are very potent cytotoxic agents against several different human cancer cell lines and are up to 400-fold more potent than clinically used cisplatin. In addition, the investigated ruthenium complexes are less cytotoxic in noncancerous cells, and exhibit higher selectivity for cancer cells than conventional platinum anticancer drugs. The high potency of the investigated ruthenium compounds can be attributed to several factors, including enhanced internalization and their capability to change mitochondrial transmembrane potential in cells. The new ruthenium complexes also interfere with protein synthesis with a markedly higher potency than conventional inhibitors of DNA translation. Notably, the latter mechanism has not been hitherto described for other cytotoxic Ru compounds and cisplatin.

• Klíčová slova
• anticancer agents, cell growth, mitochondrial disfunction, protein synthesis, ruthenium,
• MeSH
• apoptóza účinky léků   MeSH
• chemorezistence účinky léků   MeSH
• cisplatina toxicita   MeSH
• dusík chemie   MeSH
• komplexní sloučeniny chemie   metabolismus   toxicita   MeSH
• konfokální mikroskopie MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• ligandy MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemie   metabolismus   toxicita   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• uhlík chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• dusík MeSH
• komplexní sloučeniny MeSH
• ligandy MeSH
• protinádorové látky MeSH
• reaktivní formy kyslíku MeSH
• ruthenium MeSH
• uhlík MeSH

Fluorometric glutathione assays have been generally preferred for their high specificity and sensitivity. An additional advantage offered by fluorescent bimane dyes is their ability to penetrate inside the cell. Their ability to react with glutathione within intact cells is frequently useful in flow cytometry and microscopy. Hence, the aims of our study were to use monochlorobimane for optimizing a spectrofluorometric glutathione assay in cells and then to compare that assay with the frequently used ortho-phthalaldehyde assay. We used glutathione-depleting agents (e.g., cisplatin and diethylmalonate) to induce cell impairment. For glutathione assessment, monochlorobimane (40μM) was added to cells and fluorescence was detected at 394/490nm. In addition to the regularly used calculation of glutathione levels from fluorescence change after 60min, we used an optimized calculation from the linear part of the fluorescence curve after 10min of measurement. We found that 10min treatment of cells with monochlorobimane is sufficient for evaluating cellular glutathione concentration and provides results entirely comparable with those from the standard ortho-phthalaldehyde assay. In contrast, the results obtained by the standardly used evaluation after 60min of monochlorobimane treatment provided higher glutathione values. We conclude that measuring glutathione using monochlorobimane with the here-described optimized evaluation of fluorescence signal could be a simple and useful method for routine and rapid assessment of glutathione within intact cells in large numbers of samples.

• Klíčová slova
• Cell impairment, Fluorescence, Glutathione assay, Monochlorobimane, Ortho-phthalaldehyde,
• MeSH
• biotest ekonomika   metody   MeSH
• buněčné linie MeSH
• cisplatina toxicita   MeSH
• fluorescenční barviva chemie   MeSH
• fluorescenční spektrometrie ekonomika   metody   MeSH
• glutathion analýza   metabolismus   MeSH
• lidé MeSH
• malonáty toxicita   MeSH
• o-ftalaldehyd chemie   MeSH
• průtoková cytometrie MeSH
• pyrazoly chemie   MeSH
• senzitivita a specificita MeSH
• studie proveditelnosti MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• diethyl malonate MeSH Prohlížeč
• fluorescenční barviva MeSH
• glutathion MeSH
• malonáty MeSH
• monochlorobimane MeSH Prohlížeč
• o-ftalaldehyd MeSH
• pyrazoly MeSH

In this study, the pyrrolo[2,1-a]isoquinolines 4a-n were synthesized in good yields in a three steps synthesis from the corresponding α,β-unsaturated esters starting materials. These compounds were tested on six human cancer cells lines to measure the cytotoxic activity as a function of the electronic properties and aromaticity of the substituent at the C-2 position of the pyrroloisoquinoline. Our results reveal that the cytotoxic activity could be explained in terms of the distribution of electronic density across the ring joined to C-2. Also, this study identified 3-hydroxy (4d) and 3-chloro (4j) derivatives with powerful cytotoxic activities. The IC50 values of these compounds were found to be comparable to those of the commercially available Topotecan, Irinotecan, Etoposide, Tamoxifen, and Cisplatin.

• Klíčová slova
• cytotoxic activity, pyrrolo[2,1-a]isoquinoline, synthesis,
• MeSH
• cisplatina toxicita   MeSH
• isochinoliny chemie   farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• pyrroly chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cisplatina MeSH
• isochinoliny MeSH
• protinádorové látky MeSH
• pyrrolo(2,1-a)isoquinoline MeSH Prohlížeč
• pyrroly MeSH

Neutrophil gelatinase-associated lipocalin is an extracellular protein produced mostly in kidney. Recently, it has become a promising biomarker of renal damage in vivo. On the other hand, the validation of NGAL as a biomarker for nephrotoxicity estimation in vitro has not been characterized in detail yet. Since the HK-2 cells are frequently used human kidney cell line, we aimed to characterize the production of NGAL in these cells and to evaluate NGAL as a possible marker of cell impairment. We used heavy metals (mercury, cadmium), peroxide, drugs (acetaminophen, gentamicin) and cisplatin to mimic nephrotoxicity. HK-2 cells were incubated with selected compounds for 1-24h and cell viability was measured together with extracellular NGAL production. We proved that HK-2 cells possess a capacity to produce NGAL in amount of 2pg/ml/h. We found a change in cell viability after 24h incubation with all tested toxic compounds. The largest decrease of the viability was detected in mercury, acetaminophen, cisplatin and gentamicin. Unexpectedly, we found also a significant decrease in NGAL production in HK-2 cells treated with these toxins for 24h: to 11±5%, 54±5%, 57±6% and 76±9% respectively, compared with controls (=100%). Our results were followed with qPCR analysis when we found no significant increase in LCN2 gene expression after 24h incubation. We conclude that extracellular NGAL production negatively correlates with HK-2 cell impairment.

• Klíčová slova
• Cell viability, HK-2 cells, In vitro nephrotoxicity, NGAL, Nephrotoxicity markers,
• MeSH
• akutní poškození ledvin chemicky indukované   metabolismus   MeSH
• biologické markery metabolismus   MeSH
• buněčné linie MeSH
• cisplatina toxicita   MeSH
• gentamiciny toxicita   MeSH
• kadmium toxicita   MeSH
• lidé MeSH
• lipokalin-2 genetika   metabolismus   MeSH
• paracetamol toxicita   MeSH
• rtuť toxicita   MeSH
• terc-butylhydroperoxid toxicita   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• cisplatina MeSH
• gentamiciny MeSH
• kadmium MeSH
• LCN2 protein, human MeSH Prohlížeč
• lipokalin-2 MeSH
• paracetamol MeSH
• rtuť MeSH
• terc-butylhydroperoxid MeSH