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Azacarbazoles have attracted significant interest due to their valuable properties, such as anti-pathogenic and antitumor activity. In this study, a series of structurally related tricyclic benzo[4,5]- and tertacyclic naphtho[2′,1′:4,5]imidazo[1,2-c]pyrimidinone derivatives with one or two positively charged tethers were synthesized and evaluated for anti-proliferative activity. Lead tetracyclic derivative 5b with two amino-bearing arms inhibited the metabolic activity of A549 lung adenocarcinoma cells with a CC50 value of 3.6 μM, with remarkable selectivity (SI = 17.3) over VA13 immortalized fibroblasts. Cell-cycle assays revealed that 5b triggers G2/M arrest without signs of apoptosis. A study of its interaction with various DNA G4s and duplexes followed by dual luciferase and intercalator displacement assays suggests that intercalation, rather than the modulation of G4-regulated oncogene expression, might contribute to the observed activity. Finally, a water-soluble salt of 5b was shown to cause no acute toxic effects, changes in mice behavior, or any decrease in body weight after a 72 h treatment at concentrations up to 20 mg/kg. Thus, 5b is a promising candidate for studies in vivo; however, further investigations are needed to elucidate its molecular target(s). [ABSTRACT FROM AUTHOR]

Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC50 down to 1–4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (N-(4-methoxyphenyl)-N,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca2+ or Mg2+ cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation. [ABSTRACT FROM AUTHOR]

Purpose: There is still controversy over the criteria for acute ACL tear. In this paper, knee joint function and walking were considered possible ones. Method: The study included 21 subjects with acute ACL tear and 20 healthy volunteers as a control group. Biomechanical gait analysis was performed using the inertial sensor system including EMG recording. All subjects (but for controls) were divided into two groups: Group 1—"up to 4 weeks" and Group 2—"from 4 weeks to 3 months". Results: Temporal gait parameters in subjects from Group 1 demonstrate the asymmetry of 4% and more in terms of the gait cycle with a decrease in the affected limb, and are within normal range in Group 2. The amplitudes at the hip and knee joints in the affected limb are reduced which is especially pronounced in Group 1 (2–4 and 6–10 degrees, respectively). The affected knee joint shows a decrease in the range of motion by up to 5 degrees in the first half of the stance phase and flexion by less than 40 degrees in the swing phase. The tibialis anterior and quadriceps femoris muscle function is decreased in the affected limb only in Group 1 (72% and 78% from normal, respectively). Conclusions: The severity of the condition after an ACL tear is largely determined by functional changes. The time factor is of secondary importance. [ABSTRACT FROM AUTHOR]

The treatment of many bacterial diseases remains a significant problem due to the increasing antibiotic resistance of their infectious agents. Among others, this is related to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA) and Mycobacterium tuberculosis. In the present article, we report on antibacterial compounds with activity against both S. aureus and MRSA. A straightforward approach to 2-(1H-indol-3-yl)quinazolin-4(3H)-one and their analogues was developed. Their structural and functional relationships were also considered. The antimicrobial activity of the synthesized compounds against Mycobacterium tuberculosis H37Rv, S. aureus ATCC 25923, MRSA ATCC 43300, Candida albicans ATCC 10231, and their role in the inhibition of the biofilm formation of S. aureus were reported. 2-(5-Iodo-1H-indol-3-yl)quinazolin-4(3H)-one (3k) showed a low minimum inhibitory concentration (MIC) of 0.98 μg/mL against MRSA. The synthesized compounds were assessed via molecular docking for their ability to bind long RSH (RelA/SpoT homolog) proteins using mycobacterial and streptococcal (p)ppGpp synthetase structures as models. The cytotoxic activity of some synthesized compounds was studied. Compounds 3c, f, g, k, r, and 3z displayed significant antiproliferative activities against all the cancer cell lines tested. Indolylquinazolinones 3b, 3e, and 3g showed a preferential suppression of the growth of rapidly dividing A549 cells compared to slower growing fibroblasts of non-tumor etiology. [ABSTRACT FROM AUTHOR]

Prostate cancer is the second most common cancer among men. We designed and synthesized new ligands targeting prostate-specific membrane antigen and suitable for bimodal conjugates with diagnostic and therapeutic agents. In vitro studies of the affinity of the synthesized compounds to the protein target have been carried out. Based on these ligands, a series of bimodal conjugates with a combination of different mitosis inhibitors and antiandrogenic drugs were synthesized. The cytotoxicity of the compounds obtained in vitro was investigated on three different cell lines. The efficacy of the two obtained conjugates was evaluated in vivo in xenograft models of prostate cancer. These compounds have been shown to be highly effective in inhibiting the growth of PSMA-expressing tumors. [ABSTRACT FROM AUTHOR]

Currently, inertial sensors are often used to study balance in an upright stance. There are various options for recording balance data with different locations and numbers of sensors used. Methods of data processing and presentation also differ significantly in published studies. We propose a certain technical implementation of the method and a previously tested method for processing primary data. In addition, the data were processed along three mutually perpendicular planes. The study was conducted on 109 healthy adults. A specially developed inertial sensor, commercially available for medical purposes, was used. Thus, this work can outline the limits of normative values for the calculated stabilometric measures. Normative data were obtained for three oscillation planes with the sensor located on the sacrum. The obtained parameters for the vertical component of the oscillations are of the same order as for the frontal and sagittal components. Normative parameters are required in any clinical study, as the basis from which we start in the evaluation of clinical data. In this study, such normative parameters are given for one of the most commonly used Romberg's tests. The obtained normative data can be used for scientific and clinical research. [ABSTRACT FROM AUTHOR]

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI2 is an effective catalyst in the Diels–Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc2O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2. [ABSTRACT FROM AUTHOR]

Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCTwt, and HCT(−/−). Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC50 = 1.2–3.5 µM) and a reasonable selectivity index (SI = 3–10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index—estimated as LD50/ED50—for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action. [ABSTRACT FROM AUTHOR]

In order to obtain antimicrobial compounds with improved properties, new conjugates comprising two different biologically active agents within a single chimeric molecule based on chloramphenicol (CHL) and a hydrophobic cation were synthesized and studied. Chloramphenicol amine (CAM), derived from the ribosome-targeting antibiotic CHL, and the plant isoquinoline alkaloid berberine (BER) are connected by alkyl linkers of different lengths in structures of these conjugates. Using competition binding, double reporter system, and toeprinting assays, we showed that synthesized CAM-Cn-BER compounds bound to the bacterial ribosome and inhibited protein synthesis like the parent CHL. The mechanism of action of CAM-C5-BER and CAM-C8-BER on the process of bacterial translations was similar to CHL. Experiments with bacteria demonstrated that CAM-Cn-BERs suppressed the growth of laboratory strains of CHL and macrolides-resistant bacteria. CAM-C8-BER acted against mycobacteria and more selectively inhibited the growth of Gram-positive bacteria than the parent CHL and the berberine derivative lacking the CAM moiety (CH3-C8-BER). Using a potential-sensitive fluorescent probe, we found that CAM-C8-BER significantly reduced the membrane potential in B. subtilis cells. Crystal violet assays were used to demonstrate the absence of induction of biofilm formation under the action of CAM-C8-BER on E. coli bacteria. Thus, we showed that CAM-C8-BER could act both on the ribosome and on the cell membrane of bacteria, with the alkylated berberine fragment of the compound making a significant contribution to the inhibitory effect on bacterial growth. Moreover, we showed that CAM-Cn-BERs did not inhibit eukaryotic translation in vitro and were non-toxic for eukaryotic cells. [ABSTRACT FROM AUTHOR]

In this work, we present the first synthesis of dispirooxindole-β-lactams employing optimized methodology of one-pot Staudinger ketene-imine cycloaddition with N-aryl-2-oxo-pyrrolidine-3-carboxylic acids as the ketene source. Spiroconjugation of indoline-2-one with β-lactams ring is considered to be able to provide stabilization and wide scope of functionalization to resulting scaffolds. The dispipooxindoles obtained demonstrated medium cytotoxicity in the MTT test on A549, MCF7, HEK293, and VA13 cell lines, and one of the compounds demonstrated antibacterial activity against E. coli strain LPTD. [ABSTRACT FROM AUTHOR]

Featured Application: The results of this study can be useful for further research into features related to the development of military crawl locomotion in groups of different ages, and for understanding the development of this type of locomotion in ontogenesis. In rehabilitation clinics, it is possible to compare patients' indicators with the norm registered in this study (which could be further expanded), to assess the degree of violations in the motor control system. The biomechanics of military crawl locomotion is poorly covered in scientific literature so far. Crawl locomotion may be used as a testing procedure which allows for the detection of not only obvious, but also hidden locomotor dysfunctions. The aim of the study was to investigate the biomechanics of crawling among healthy adult participants. Eight healthy adults aged 15–31 (four women and four men) were examined by means of a 3D kinematic analysis with Optitrack optical motion-capture system which consists of 12 Flex 13 cameras. The movements of the shoulder, elbow, knee, and hip joints were recorded. A person was asked to crawl 4 m on his/her belly. The obtained results including space-time data let us characterize military crawling in terms of pelvic and lower limb motions as a movement similar to walking but at a more primitive level. Progressive and propulsive motions are characterized as normal; additional right–left side motions—with high degree of reciprocity. It was found that variability of the left-side motions is significantly lower than that of the right side (Z = 4.49, p < 0.0001). The given normative data may be used as a standard to estimate the test results for patients with various pathologies of motor control (ataxia, abasia, etc.). [ABSTRACT FROM AUTHOR]

Featured Application: Authors are encouraged to provide a concise description of the specific application or a potential application of the work. This section is not mandatory. The objective of the study was to evaluate the clinical, functional, and biomechanical symptoms in patients with anterior cruciate ligament (ACL) rupture before and after ACL reconstruction. The study enrolled 20 patients and 20 healthy subjects as controls. Walking biomechanics was assessed at three time points: before surgery and three months and a year or more after surgical reconstruction. Impact loads on both sides differed significantly from the respective values before surgery (p<0.05). Walking cycle duration decreased with time after surgery. On both sides (affected and unaffected), hip movement amplitudes were significantly smaller than in control (p<0.05). They remained so in the follow-up periods after the reconstruction. Before ACL reconstruction, the amplitude of the main flexion of the knee was significantly reduced both on the affected and unaffected sides. The amplitude gradually increased after the reconstruction, and a year post-surgery, it reached, on the operated side, the same values as in the control group. Complete functional recovery of the knee joint was not achieved within a year after the ACL surgical reconstruction. The remaining changes, however, were not clinically pronounced and could only be detected by instrumental gait analysis. The compensatory processes developed bilaterally, in both the hip and knee joints. [ABSTRACT FROM AUTHOR]

A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range. [ABSTRACT FROM AUTHOR]

Walking function disorders are typical for patients after cerebral stroke. Biofeedback technology (BFB) is currently considered effective and promising for training walking function, including in patients after cerebral stroke. Most studies recognize that BFB training is a promising tool for improving walking function; however, the data on the use of highly selective walking parameters for BFB training are very limited. The aim of our study was to investigate the feasibility of using BFB training targeting one of the basic parameters of gait symmetry—stance phase duration—in cerebral stroke patients in the early recovery period. The study included 20 hemiparetic patients in the early recovery period after the first hemispheric ischemic stroke. The control group included 20 healthy subjects. The BFB training and biomechanical analysis of walking (before and after all BFB sessions) were done using an inertial system. The mean number of BFB sessions was nine (from 8 to 11) during the three weeks in clinic. There was not a single negative response to BFB training among the study patients, either during the sessions or later. The spatiotemporal parameters of walking showed the whole syndrome complex of slow walking and typical asymmetry of temporal walking parameters, and did not change significantly as a result of the study therapy. The changes were more significant for the functioning of hip and knee joints. The contralateral hip amplitude returned to the normal range. For the knee joint, the amplitude of the first flexion increased and the value of the amplitude of hyperextension decreased in the middle of the stance phase. Concerning muscle function, the observed significant decrease in the function of m. Gastrocnemius and the hamstring muscles on the paretic side remained without change at the end of the treatment course. We obtained positive dynamics of the biomechanical parameters of walking in patients after the BFB training course. The feasibility and efficacy of their use for targeted correction need further research. [ABSTRACT FROM AUTHOR]

Deforming osteoarthritis (OA) of the knee is a progressive disease associated with pain and compromised function of the joint. Typical biomechanical modifications in the gait of subjects with medial knee OA are characterized by decreased gait speed and overload on the affected limb. The borderline stage for conservative versus surgical management is Grade II OA. The aim of this research was to study preoperatively the specific features of gait, knee, and hip function in patients with Grade II medial OA. We examined 26 patients with Grade II unilateral gonarthritis with varus deformity and 20 healthy adults. Biomechanical parameters of gait were recorded using an inertial sensor system. The gait cycle (GC) slightly increased both for the affected and for the intact limb. The hip joint movements showed significant symmetrical reduction in the first flexion amplitude, as well as a symmetrical delay in full hip extension at the end of the stance phase. In the knee, the first flexion amplitude was significantly reduced on the affected side compared to healthy control. The extension amplitude in the single support phase was significantly increased in both the affected and the intact lower limbs. The swing amplitude was significantly reduced on the affected side. On the affected side, the changes were more pronounced, both in incidence and in severity. The affected knee showed a syndrome of three reduced amplitudes. In patients, walking is characterized by several groups of symptoms: those of unloading of the affected limb, those of limiting the load on the affected joint and the musculoskeletal system as a whole, and those of gait harmonization. The symptoms of unloading the affected side and those of harmonization are the common symptoms of adaptation, typical for several pathological conditions with a relatively preserved function. The intensity of the observed symptoms can help assess changes in the subject's functional condition over time and during the treatment. [ABSTRACT FROM AUTHOR]

In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds. [ABSTRACT FROM AUTHOR]

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action. [ABSTRACT FROM AUTHOR]

The effects of different factors—such as age, sex, performance level, and athletic shoe features—on postural balance in athletes remain unclear. The main objective of our study is to identify the features of postural stability in athletes of different age, sex, performance level, and using different types of athletic shoes. This study assessed postural stability in athletes (n = 936, 6–47 years) in a normal bipedal stance with eyes open (EO) and eyes closed (EC). Postural stability was evaluated based on the center of pressure (COP), sway area (AS), and velocity (VCP) while standing on a stabiloplatform. Children (6–12 years) and teen athletes (13–17 years) showed reduced AS-EO (p < 0.01) and VCP-EO (p < 0.01) compared to control (n = 225, 7–30 years). In male and female athletes aged 18+, only VCP-EC was lower versus control. In females (13–17 and 18+), VCP-EO and EC were lower than in males (p < 0.05). Only in the Shooting group, the athletes' performance levels had an effect on VCP-EO (p = 0.020). Long use of rigid athletic shoes with stiff ankle support was associated with reduced posture stability. Postural stability in athletes was mostly influenced by the athlete's age, and, to a lesser extent, by their sex, performance level, and athlete shoe features. [ABSTRACT FROM AUTHOR]