Design, synthesis and anti-inflammatory assessment of certain substituted 1,2,4-triazoles bearing tetrahydroisoquinoline scaffold as COX 1/2-inhibitors.

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

Novel indolinone-tethered benzothiophenes as anti-tubercular agents against MDR/XDR M. tuberculosis: Design, synthesis, biological evaluation and in vivo pharmacokinetic study.

Joining the global effort to eradicate tuberculosis, one of the deadliest infectious killers in the world, we disclose in this paper the design and synthesis of new indolinone-tethered benzothiophene hybrids 6a-i and 7a-i as potential anti-tubercular agents. The MICs were determined in vitro for the synthesized compounds against the sensitive M. tuberculosis strain ATCC 25177. Potent compounds 6b, 6d, 6f, 6h, 7a, 7b, 7d, 7f, 7h and 7i were furtherly assessed versus resistant MDR-TB and XDR-TB. Structure activity relationship investigation of the synthesized compounds was illustrated, accordingly. Superlative potency was unveiled for compound 6h (MIC = 0.48, 1.95 and 7.81 µg/mL for ATCC 25177 sensitive TB strain, resistant MDR-TB and XDR-TB, respectively). Moreover, validated in vivo pharmacokinetic study was performed for the most potent derivative 6h revealing superior pharmacokinetic profile over the reference drug. For further exploration of the anti-tubercular mechanism of action, molecular docking was carried out for the former compound in DprE1 active site as one of the important biological targets of TB. The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency.

Design and synthesis of benzo[b]thiophene-based hybrids as novel antitubercular agents against MDR/XDR Mycobacterium tuberculosis.

In an effort to support the global fight against tuberculosis (TB), which is widely recognized as the most lethal infectious disease worldwide, we present the design and synthesis of new benzo[b]thiophene-based hybrids as promising candidates for the management of multidrug-resistant (MDR)/extensively drug-resistant (XDR) Mycobacterium tuberculosis. The isatin motif was incorporated into the target hybrids as it represents a privileged scaffold in antitubercular drug discovery. Since lipophilicity plays a pivotal role in the anti-TB agents' activity, the lipophilicity of the target hybrids was manipulated via the development of two series of N-1 methyl and N-1 benzyl substituted isatins (6a-h and 9a-h, respectively). Screening of the target hybrids was first performed against drug-sensitive M. tuberculosis (ATCC 25177). The structure-activity relationship outputs highlighted that incorporation of 3-unsubstituted benzo[b]thiophene and 5-methoxy isatin moieties was favorable for the antimycobacterial activity. Thereafter, the most potent molecules (6b-h, 9c-e, and 9h) were evaluated against the resistant strains MDR-TB (ATCC 35822) as well as against XDR-TB (RCMB 2674) where they displayed promising activity. To evaluate the safety of the target hybrids, an sulforhodamine B assay was conducted to determine their possible cytotoxic effects on VERO cells.

Novel 1,3-diaryl pyrazole derivatives bearing methylsulfonyl moiety: Design, synthesis, molecular docking and dynamics, with dual activities as anti-inflammatory and anticancer agents through selectively targeting COX-2.

Three series of novel 1-aryl-3-(4-methylsulfonylphenyl) pyrazole derivatives were synthesized, characterized by several spectroscopic techniques, and investigated as potential anti-inflammatory and anticancer agents. The biological evaluation showed that almost all the synthesized compounds have significant potency and selectivity for the COX-2 enzyme over COX-1 with noticeable anti-inflammatory activity compared to celecoxib and indomethacin. Accordingly, compounds 8a, 8b, 8e, 8j, 8l, 9a, 9b, 9c, and 10b showed the best COX-2 inhibition (IC50 ranged from 0.059 to 0.079 µM) with good anti-inflammatory activity (% of edema inhibition ranged from 87.9 to 67.5). Moreover, compound 8b possessed the highest selectivity index regarding COX-2 isozyme (SI = 211) in comparison to celecoxib (SI = 312) with good in vivo anti-inflammatory activity (% edema inhibition = 77.70 after 5 h). Also, compounds 8a, 8b, 8j, 8l, and 9a showed ulcerogenic liability and histopathological changes close to celecoxib. Molecular docking and dynamics simulations were also conducted to illustrate the binding modes inside the COX-2 active site. Furthermore, all compounds were screened against three cancer cell line panels to determine their antiproliferative properties by MTT assay. Compounds 8a, 8b, and 8e along with their cyclized forms 9a, 9b, and 9c exhibited a considerable antiproliferative effect on liver (IC50: 6.81-19.71 µM), colon (IC50: 7.64-15.34 µM), and breast (IC50: 6.77-18.41 µM) cancer cell lines. More importantly, compounds 8a, 8e, 9a, and 9b were found to be safe on normal HEK-293T kidney cells in comparison to cancer. cells, especially compound 8e with IC50 value of 66.45 µM. Mechanistic studies demonstrated the apoptotic activity of the most active compounds 8a, 8e, 9a, and 9b on MCF-7 cancer cells by inducing a strong S phase cell cycle arrest suggesting that the mechanism of its antiproliferative activity may be through COX-2 inhibition. Finally, the hit compounds 8a, 8b and 9a were discovered to have selective COX-2 inhibitory activity and good anti-inflammatory activity with minimal ulcerogenic effect as well as potent anticancer activity.

Measuring workplace violence for clinical dental hygienists.

OBJECTIVE: This study aimed to develop and assess a tool for measuring violence experienced by clinical dental hygienists in the workplace. METHODS: The basic questionnaire used in this study was created by referring to previous studies, the Negative Acts Questionnaire-Revised (NAQ-R) and the Workplace Bullying in Nursing-Type Inventory (WPBN-TI). The content feasibility was verified by ten experts in the field, and irrelevant questions were deleted, based on a content validity index value of 0.8. This study surveyed 205 clinical dental hygienists to test the tool's validity and reliability. Frequency analysis was conducted on items related to general characteristics and workplace violence. RESULTS: The questionnaire set was 31 questions, which, comprised five domains, were finalized through reliability verification. These domains were verbal attacks and alienation (9 questions), inappropriate work experiences (6 questions), physical threats (4 questions), workplace sexual harassment (6 questions) and verbal violence (6 questions) from patients and their family members. Among the study participants, 47.3% said they received rude signals from others, 17.9% said they were subjected to sexual evaluations regarding their appearance, and 29.4% said their abilities were ignored by patients and family members of patients. CONCLUSIONS: Clinical dental hygienists have been exposed to various types of violence in their workplaces, such as sexual and verbal harassment, by patients and their family members. This tool can be used in the dental setting to conduct surveys on workplace violence and establish a monitoring and support system.

Effect of treatment with direct acting antivirals on body mass index and hepatic steatosis in chronic hepatitis C.

Direct Acting Agents (DAAs) have high cure rate but still lack the knowledge of their effect on hepatic steatosis in chronic hepatitis C (CHC). Controlled Attenuation Parameter (CAP), evaluated with transient elastography, could help in assessment of steatosis grades. We aim to evaluate the effect of DAAs on BMI and steatosis in CHC using CAP. This cohort study included 155 CHC Egyptian patients divided into three groups according to the DAAs regimens. All patients were subjected to pre-treatment and 3-months post-treatment evaluation including BMI, laboratory workup and liver stiffness measurement with simultaneous CAP determination using the (FibroScan®) M probe. Patients mean age was 45.78 ± 11.6 years, 60.6% were females, mean BMI 26.63 ± 2.75 and 18.1% were cirrhotic. Baseline assessment revealed no steatosis in 43.9%, 32.9% had mild-moderate steatosis and 23.2% had severe steatosis. The overall sustained virological response 12 was 93.6%. Follow-up revealed stationary steatosis in 56.7% of patients and regression in 21.3%. Mean pre-treatment CAP were significantly lower in responders 244.9 ± 62.4 dB/m versus non-responders; 300 ±28.4 dB/m (P = 0.04). ROC curve delineated 273 dB/m as best cutoff for detection of responders with an AUC of 0.801, sensitivity 68.2%, and specificity 100%. BMI significantly increased after treatment (P = 0.004) particularly in patients with worsened steatosis (P = 0.001). Steatosis significantly correlated with BMI (r = 0.3, P value = < 0.001). DAAs causes a significant change in steatosis grade in a subset of treated patients. Pretreatment CAP was significantly lower in responders. BMI significantly increases following treatment particularly in patients with worsened steatosis.

Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides and their acetate esters.

A series of 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides IXa-l and their acetate esters Xa-l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057-0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED50 = 0.0012 mmol/kg), Xd (ED50 = 0.002 mmol/kg), Xf (ED50 = 0.004 mmol/kg), IXj (ED50 = 0.0047 mmol/kg), Xl (ED50 = 0.0076 mmol/kg), and Xi (ED50 = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study.

[On risk-oriented model of sanitary epidemiologic surveillance in occupational hygiene].

In 2015, Federal Service on surveillance in consumers rights protection and public well-being set a task to organize planned work of regional agencies on basis of risk-oriented model of control and supervision. Based on results of pilot project in Rospotrebnadzor Department of Perm area and St-Petersburg, the article covers methodic approaches to classification of objects liable to surveillance in occupational hygiene. The classification considers possibility of sanitary law violation, severity of this violation consequences and number of workers exposed to risk factors including hazardous work conditions. The authors specified recommendations on periodicity and forms of planned inspections considering evaluation of potential risk for human health, determined problems that require solution in implementation of risk-oriented model of surveillance.

[METHODS AND TECHNOLOGIES OF HEALTH RISK ANALYSIS IN THE SYSTEM OF THE STATE MANAGEMENT UNDER ASSURANCE OF THE SANITATION AND EPIDEMIOLOGICAL WELFARE OF POPULATION].

The methodology of the analysis of health risk at the present stage of development of Russian society is in-demand at all levels of government management. In conjunction with the methods of mathematical modeling, spatial-temporal analysis and economic tools the risk assessment in the analysis of the situation makes it possible to determine the level of safety of the population, workers and consumers, to select prior resources, and threat factors as a point for exertion efforts. At the planning stage risk assessment is a basis for the establishment of most effective measures for the minimization of hazard and dangers. At the realization stage the methodology allows to estimate the efficiency of measures; at the control and supervision phase it permits to select out priorities for the concentration of efforts on the objects of maximal health risk for population. Risk assessments, including the elements of evolutionary modeling, are incorporated in the system of state hygienic regulation, the formation of evidence base of harm to health, the organization of control and supervisory activities. This allows you to harmonize the domestic legal framework with ternational legal requirements and ultimately enhances the credibility of the Russian data on the safety of the environment products and services. There is seemed to be actual the further assignment of enforcement of methodology of health risk analysis in the field of assurance of sanitary and epidemiological well-being and health of employers; he development of informational and analytical base in the part of the establishment of models of dependencies "exposure-response" for different types and levels of exposure and risk contingents; the accuracy enhancement of estimations of exposure; improvement of the economic aspects of health risk analysis and forecasting of measures aimed at mitigation of the losses associated with the negative impact of manifold factors on the health of citizens.

Design, synthesis and biological evaluation of type-II VEGFR-2 inhibitors based on quinoxaline scaffold.

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a series of new quinoxaline-based derivatives was designed and synthesized. The target compounds were biologically evaluated for their inhibitory activity against VEGFR-2. The design of the target compounds was accomplished after a profound study of the structure activity relationship (SAR) of type-II VEGFR-2 inhibitors. Among the synthesized compounds, 1-(2-((4-methoxyphenyl)amino)-3-oxo-3,4 dihydroquinoxalin-6-yl)-3-phenylurea (VIIa) displayed the highest inhibitory activity against VEGFR-2. Molecular modeling study involving molecular docking and field alignment was implemented to interpret the variable inhibitory activity of the newly synthesized compounds.

[Evaluating exposure of population to dust, with consideration of components and dispersion contents of industrial discharges from enterprise extracting and processing mineral raw materials (discussion)].

The article covers results of study concerning disperse content of solid components of discharges from main dust- generating technologic operations in extraction and processing of mineral raw materials (pouring ore to conveyor, drying with combustion gas in fluid-bed, pouring of end product, sorting ore on riddle, drying on vibration dry and cool device, etc). Findings are that fractions under 10 and 2.5 micrometers approach 50% in general structure of dust discharges. Maximal share of low-disperse dust enters ambient air from vibraion dry and cool devices, riddles and pouring places. Exceeded reference values for acute and chronic exposure are registered on TSP and PM10 at a sanitary protection zone border and in the nearest living area points--that can forecast intolerable risks for health of population exposed and necessitate instrumental confirmation of the detected jeopardy level.

Knowledge, Attitude, and Risk Perception in Oral Isotretinoin Use: A Cross-Sectional Study from Jordan.

The most prevalent skin condition is acne vulgaris. Recent clinical practice guidelines recommend oral isotretinoin to treat moderate-to-severe acne. The aim of this study is to assess the knowledge, attitude, and risk perception of oral isotretinoin for acne treatment. This is a cross-sectional descriptive study conducted in the country of Jordan. The study sample includes people resident in Jordan aged ≥14 years who have been treated with oral isotretinoin for acne. The study involved 373 participants who previously used oral isotretinoin for skin disorders. Most were Jordanian (89.3%), aged 19-25 (37.3%), and from the central region (82.8%). Mostly, they used isotretinoin for severe or mild acne (25.2% and 24.1%, respectively), rosacea (4.1%), or to alleviate acne scars. Surprisingly, 58.1% did not consult their specialist for side effects, and 20% shared their treatment. The average proper use score was 9.98 out of 16. A link was found between higher risk knowledge scores and proper use scores. Side effects such as nausea, irregular heartbeat, and pancreatitis affected some users (11.5%, 10.5%, 7.0%, and 3.2%, respectively). Knowledge about isotretinoin's risks varied, with percentages recognizing teratogenicity (57.7%), liver damage (52.6%), and lipid profile effects (37.2%), while 25% believed that they had no side effects. The study revealed partial adherence to oral isotretinoin guidelines, with gaps in monitoring and consultation. A positive correlation emerged between risk knowledge and proper usage, emphasizing the need for comprehensive education and monitoring strategies in isotretinoin therapy for skin disorders.

Design, synthesis and biological evaluation of novel pyrazole-based compounds as potential chemotherapeutic agents.

Aim: Design and synthesis of pyrazole-based chemotherapeutic agents. Materials & methods: A series of novel diphenyl pyrazole-chalcone derivatives were synthesized and assessed for their cytotoxic activities against 14 cancer cell lines and their antimicrobial activities against MRSA and Escherichia coli along with their safety using HSF normal cell line. Results & conclusion: Majority of the compounds showed moderate-to-significant anticancer activity with selective high percentage inhibition (>80%) against HNO-97 while being nontoxic toward normal cells. Compounds 6b and 6d were the most potent congeners with IC50 of 10 and 10.56 µM respectively. The synthesized compounds exhibited moderate to potent antimicrobial activities. Interestingly, compound 6d exhibited a minimum inhibitory concentration of 15.7 µg/ml against MRSA; and a minimum inhibitory concentration of 7.8 µg/ml versus E. coli.

[Box: see text].

Targeting apoptosis; design, synthesis and biological evaluation of new benzoxazole and thiazole based derivatives.

Several novel approaches to target Bcl-2 proteins and apoptotic pathways have been identified in recent years for the treatment of different types of cancer including colorectal cancer. However, no effective treatments were yet developed for colorectal cancer. Twenty two novel benzoxazole and thiazole-based compounds were designed, synthesized, and evaluated as potential Bcl-2 inhibitors with anti-proliferative activity. Compounds 8g, 12e and 13d showed good to moderate anti-proliferative activity against most of the NCI 60 cell line panel with mean growth inhibition percent of 45.13, 42.29 and 29.25%, respectively. They showed the greatest cell growth inhibition percent to HCT-116 cell line with the values of 68.0, 59.11 and 43.44%, respectively. The aforementioned compounds were furtherly investigated for their effect on HCT-116 cell cycle, and they showed increase in the total apoptosis with 17, 22, and 5%, respectively. Also, the apoptotic effect of compounds 8g, 12e and 13d, were tested by their effect on altering caspase-3 expression level in HCT-116 human cell line. The three compounds showed an increase in the caspase-3 levels by 6, 8 and 3 folds, respectively in comparison with the same untreated ones. Moreover, they were evaluated for their in-vitro Bcl-2 inhibitory activity and they showed percent inhibition of 60.2, 69.2 and 50.0%, respectively. Finally, the most potent compounds 8g and 12e showed 3.864 and 2.834 folds increase in Bax level compared to the control respectively. On the other hand, Bcl-2 was down-regulated to 0.31 and 0.415 folds compared to the control. The induction of apoptosis through increase in caspase 3 expression and down-regulation of Bcl-2 is the suggested mechanism of action.

Association between COVID-19 vaccines and development of chronic morbidities: a cross-sectional study in the Jordanian population.

BACKGROUND: In Jordan, individuals recently diagnosed with chronic illnesses have expressed concerns with regard to COVID-19 vaccines. This study aims to investigate potential associations between COVID-19 vaccination and the likelihood of recipients developing chronic conditions such as autoimmune diseases, rheumatoid arthritis, diabetes, asthma, and hypertension. METHODOLOGY: Through a cross-sectional survey-based descriptive approach, this research was conducted to gather data within the Jordanian context. A web-based survey was utilized to collect demographic information, record vaccine-related side effects, and document the chronic disease status subsequent to COVID-19 vaccination. Statistical analysis was employed to reveal any potential associations between the vaccine, its side effects, and the emergence of chronic morbidities. RESULTS: The study involved 414 participants, among whom 10.4% exhibited pre-existing chronic diseases before vaccination. Remarkably, post-vaccination, 23.7% of participants were newly diagnosed with chronic illnesses. Statistical analysis indicated a significant correlation between COVID-19 vaccination and the subsequent development of chronic diseases (p-value ˂.01). the investigation found no significant association between vaccination and the emergence of diabetes, hypertension, or asthma (p-value ≥.01) However, an association was found between COVID-19 vaccination and the development of autoimmune diseases and rheumatoid arthritis (p-value ˂.01). CONCLUSIONS: This study highlights an association between the occurrence of autoimmune diseases and COVID-19 vaccination, while findings related to diabetes, asthma, and hypertension did not display significant associations. The results emphasize the necessity for further research to ascertain potential causal relationship.

COVID-19 vaccine was the rescue management offered during and after the pandemic times, however many patients complained from post-COVID vaccine side effects. Those side effects were either of short term or long term ones. People in Jordan are worried about the association of the COVID-19 vaccine and the occurrence of chronic morbidities just after vaccination. Therefore our study aimed to investigate any possible association of COVID-19 vaccines and increased tendency of chronic morbidities. In our research we chose the most common encountered post COVID-19 vaccine chronic diseases in clinical practice in Jordan; Diabetes, hypertension, asthma, rheumatoid arthritis and autoimmune diseases. The study participants (N = 414) were people in Jordan more than 18 years old and got vaccinated during the past three year 2020­2023.From our study we found that vaccinated participants suffered from many short term side effects, of which the most common were general fatigue and insomnia followed by headache and fever. As for the long term side effects of the COVID-19 vaccine we figured out an increase in the incidence of chronic morbidities in general post COVID-19 vaccine and an association between the occurrence of autoimmune diseases and rheumatoid arthritis and the COVID-19 vaccine. Therefore we concluded an important association between the COVID-19 vaccine and autoimmune diseases that should be taken into consideration in clinical practice or for future investigations.

1,2,4-Triazole-Tethered Indolinones as New Cancer-Fighting Small Molecules Targeting VEGFR-2: Synthesis, Biological Evaluations and Molecular Docking.

Targeting the VEGFR-2 signaling pathway is an inveterate approach toward combating pancreatic and hepatocellular cancers. Based on Sunitinib, the FDA-approved VEGFR-2 inhibitor, novel indolin-2-one-triazole hybrids were designed and synthesized as anti-hepatocellular and anti-pancreatic cancer agents with VEGFR-2 inhibitory activity. All the targeted compounds were assessed for their anti-cancer activity, revealing IC50 values extending from 0.17 to 4.29 µM for PANC1 and 0.58 to 4.49 µM for HepG2 cell lines. An extensive SAR study was conducted to explore the effect of different substituents along with N-alkylation. The potent anti-cancer analogs 11d, 11e, 11g, 11k and 14c were evaluated for their VEGFR-2 inhibitory actions, where their IC50 values ranged from 16.3 to 119.6 nM compared to Sorafenib, which revealed an IC50 of 29.7 nM, having compound 11d as the most active analog. An in silico ADME study was performed to confirm the drug-likeness of the synthesized compounds. Finally, molecular docking simulation was conducted for the most potent VEGFR-2 inhibitor (11d), demonstrating the strong binding with the vital amino acid residues of the VEGFR-2 ATP binding site.

Novel sulfonamide-indolinone hybrids targeting mitochondrial respiration of breast cancer cells.

Breast cancer (BC) still poses a threat worldwide which demands continuous efforts to present safer and efficacious treatment options via targeted therapy. Beside kinases' aberrations as Aurora B kinase which controls cell division, BC adopts distinct metabolic profiles to meet its high energy demands. Accordingly, targeting both aurora B kinase and/or metabolic vulnerability presents a promising approach to tackle BC. Based on a previously reported indolinone-based Aurora B kinase inhibitor (III), and guided by structural modification and SAR investigation, we initially synthesized 11 sulfonamide-indolinone hybrids (5a-k), which showed differential antiproliferative activities against the NCI-60 cell line panel with BC cells displaying preferential sensitivity. Nonetheless, modest activity against Aurora B kinase (18-49% inhibition) was noted at 100 nM. Screening of a representative derivative (5d) against 17 kinases, which are overexpressed in BC, failed to show significant activity at 1 µM concentration, suggesting that kinase inhibitory activity only played a partial role in targeting BC. Bioinformatic analyses of genome-wide transcriptomics (RNA-sequencing), metabolomics, and CRISPR loss-of-function screens datasets suggested that indolinone-completely responsive BC cell lines (MCF7, MDA-MB-468, and T-47D) were more dependent on mitochondrial oxidative phosphorylation (OXPHOS) compared to partially responsive BC cell lines (MDA-MB-231, BT-549, and HS 578 T). An optimized derivative, TC11, obtained by molecular hybridization of 5d with sunitinib polar tail, manifested superior antiproliferative activity and was used for further investigations. Indeed, TC11 significantly reduced/impaired the mitochondrial respiration, as well as mitochondria-dependent ROS production of MCF7 cells. Furthermore, TC11 induced G0/G1 cell cycle arrest and apoptosis of MCF7 BC cells. Notably, anticancer doses of TC11 did not elicit cytotoxic effects on normal cardiomyoblasts and hepatocytes. Altogether, these findings emphasize the therapeutic potential of targeting the metabolic vulnerability of OXPHOS-dependent BC cells using TC11 and its related sulfonamide-indolinone hybrids. Further investigation is warranted to identify their precise/exact molecular target.

[Scientific and methodologic basis of a program for occupational control of ambient air quality within a totally sanitary protective zone at an industrial center borderline (Permsky area experience)].

The authors suggested and tested an algorithm to select optimal placement of stationary and mobile points for controlling ambient air quality on borderline of united sanitary protective zone of industrial center. The method involves claster analysis to outline sites even in levels and lists of parameters, on borderline of united sanitary protective zone of industrial center. Informative value of the occupational control parameters is evaluated through conjugated analysis of general level of surface concentration of admixtures and enterprise's contribution into pollution. For each enterprise, separate control program is provided. Tests of the method demonstrated that it is effective and conclusive in formation of minimally sufficient programs for occupational control in complicated conditions of industrial centers with single-field enterprises, when industrial releases are close in composition and in created pollution level.

[Composition of the dust for the assessment of the exposure to the population in the areas of influence of industrial emissions of stationary sources].

The results of instrumental studies of the dispersion and component composition of the solid component of the dust gaseous emissions from industrial stationary sources of engineering and metallurgical enterprises are presented. Dust and gas mixtures were established to contain up to 80% fractions with a particle size less than 10 microns (PM10), and 40% of fractions with size smaller than 2.5 microns (PM2.5). In the composition of the dusts particles in the nano-sized range have been identified. The main chemical components of dusts are iron, silicon, aluminum and their oxides, but in the set of dusts manganese, chromium, vanadium, and other toxic metals account for 25% of the weight. Accounting disperse composition of dusts in the evaluation of pollution allows to establish the zone of influence of sources more accurately, correctly assess the exposure to the population with bearing in mind the such hygienic criteria as PM10 and PM2.5 sampling.

An ex vivo system for investigation of Plasmodium berghei invasion of the salivary gland of Anopheles stephensi mosquitoes.

Plasmodium sporozoites associated with the midgut and in the hemolymph of mosquitoes differ from sporozoites in the secretory cavities and ducts of the insects' salivary glands in their transcriptome, proteome, motility, and infectivity. Using an ex vivo Anopheles stephensi salivary gland culture system incorporating simple microfluidics and transgenic Plasmodium berghei with the fluorescent protein gene mCherry under the transcriptional control of the Pbuis4 promoter whose expression served as a proxy for parasite maturation, we observed rapid parasite maturation in the absence of salivary gland invasion. While in vivo Pbuis4::mCherry expression was only detectable in sporozoites within the salivary glands (mature parasites) as expected, the simple exposure of P. berghei sporozoites to dissected salivary glands led to rapid parasite maturation as indicated by mCherry expression. These results suggest that previous efforts to develop ex vivo and in vitro systems for investigating sporozoite interactions with mosquito salivary glands have likely been unsuccessful in part because the maturation of sporozoites leads to a loss in the ability to invade salivary glands.