The use of 4-Hexylresorcinol as antibiotic adjuvant.

Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two generally accepted major approaches to this problem are the search for new antibiotics and the development of antibiotic adjuvants to enhance the antimicrobial activity of known compounds. It was therefore the aim of the present study to test whether alkylresorcinols, a class of phenolic lipids, can be used as adjuvants to potentiate the effect of various classes of antibiotics. Alkylresorcinols were combined with 12 clinically used antibiotics. Growth-inhibiting activity against a broad range of pro- and eukaryotic microorganisms was determined. Test organisms did comprise 10 bacterial and 2 fungal collection strains, including E. coli and S. aureus, and clinical isolates of K. pneumoniae. The highest adjuvant activity was observed in the case of 4-hexylresorcinol (4-HR), a natural compound found in plants with antimicrobial activity. 50% of the minimal inhibitory concentration (MIC) of 4-HR caused an up to 50-fold decrease in the MIC of antibiotics of various classes. Application of 4-HR as an adjuvant revealed its efficiency against germination of bacterial dormant forms (spores) and prevented formation of antibiotic-tolerant persister cells. Using an in vivo mouse model of K. pneumoniae-induced sepsis, we could demonstrate that the combination of 4-HR and polymyxin was highly effective. 75% of animals were free of infection after treatment as compared to none of the animals receiving the antibiotic alone. We conclude that alkylresorcinols such as 4-HR can be used as an adjuvant to increase the efficiency of several known antibiotics. We suggest that by this approach the risk for development of genetically determined antibiotic resistance can be minimized due to the multimodal mode of action of 4-HR.

[Combined rehabilitation in the patients presenting with dorsopathies of the lumbar spine and concomitant irritable bowel syndrome based at a therapeutic clinic].

BACKGROUND: Comorbidity constitutes a serious challenge for rehabilitative medicine. The comorbidity of the dorsopathy of the lumbar spine and irritable bowel syndrome mutually complicates the clinical course of both conditions, significantly reduces the patients' quality of life. and increases the costs of diagnostic procedures and restoration of the working capacity. The approaches to the non-pharmacological management of the patients presenting with these diseases remain to be developed. AIMS: The objective of the present study was to evaluate the effectiveness of the proposed combined non-medicinal rehabilitation modality which included a course of therapy with the application of modulated sinusoidal currents, total wrappings with the use of a Rapan saline solution, and sedative inhalations additionally introduced into the basic medicinal therapy of the patients presenting with dorsopathy of the lumbar spine combined with irritable bowel syndrome in the stationary phase. MATERIALS AND METHODS: A total of 59 patients at the age from 20 to 65 years suffering from dorsopathy of the lumbar spine and concomitant irritable bowel syndrome were examined and treated. All the patients were randomized into two groups, the main (n=21) and control (n=38) one, matched for the sex and age. The patients in the control group received the conventional medical treatment in accordance with the adopted medical and economic standards during 2 weeks. The patients of the main group received, in addition to the basal medicinal therapy, the proposed combined rehabilitative physiotherapeutic treatment that included a course of therapy with modulated sinusoidal currents, total wrapping with the use of a Rapan saline solution, and sedative inhalations of the of peony root extract. The effectiveness of these rehabilitation modalities was monitored before and after the course of therapy based on the estimation of bowel function dynamics, the severity of pain syndrome, and the patient's quality of life in terms of the health status with the use of the SF-36 questionnaire. RESULTS: The therapeutic and rehabilitative procedures resulted in a well apparent improvement of the genera condition in the patients of the main group associated with a greater degree of reduction of the incidence of specific clinical symptoms, more rapid relief of the pain syndrome, and a more pronounced improvement of the quality of life indices in comparison with the same variables in the patients comprising the control group. After the course of the treatment and rehabilitation, the incidence of spinal pain in the patients of the main group was significantly reduced by 87% (p=0.001) compared with those of the control group (32%; p=0.005). The frequency of abdominal pain decreased in the main group by 47% (p=0.021) versus the control group (by 27%; p=0.007). The quality of life indices increased 1.2 times in the main group but remained unaltered in the control group. DISCUSSION: The patients of the main group exhibited a more pronounced than in the control group positive dynamics of health conditions characterized by a well apparent reduction in the incidence of the major clinical symptoms of the disease, faster alleviation of the pain syndrome, and the marked improvement of the quality of life indices. CONCLUSIONS: The results of the study with the inclusion of therapy with modulated sinusoidal currents together with total wrapping using the Rapan saline solution and sedative inhalations into the program of the combined treatment of the patients presenting with dorsopathy of the lumbar spine and concomitant irritable bowel syndrome provide a basis for recommending this physiotherapeutic modality for personalized rehabilitation of this group of patients under conditions of a therapeutic clinic.

Adding dimension to cellular mechanotransduction: Advances in biomedical engineering of multiaxial cell-stretch systems and their application to cardiovascular biomechanics and mechano-signaling.

Hollow organs (e.g. heart) experience pressure-induced mechanical wall stress sensed by molecular mechano-biosensors, including mechanosensitive ion channels, to translate into intracellular signaling. For direct mechanistic studies, stretch devices to apply defined extensions to cells adhered to elastomeric membranes have stimulated mechanotransduction research. However, most engineered systems only exploit unilateral cellular stretch. In addition, it is often taken for granted that stretch applied by hardware translates 1:1 to the cell membrane. However, the latter crucially depends on the tightness of the cell-substrate junction by focal adhesion complexes and is often not calibrated for. In the heart, (increased) hemodynamic volume/pressure load is associated with (increased) multiaxial wall tension, stretching individual cardiomyocytes in multiple directions. To adequately study cellular models of chronic organ distension on a cellular level, biomedical engineering faces challenges to implement multiaxial cell stretch systems that allow observing cell reactions to stretch during live-cell imaging, and to calibrate for hardware-to-cell membrane stretch translation. Here, we review mechanotransduction, cell stretch technologies from uni-to multiaxial designs in cardio-vascular research, and the importance of the stretch substrate-cell membrane junction. We also present new results using our IsoStretcher to demonstrate mechanosensitivity of Piezo1 in HEK293 cells and stretch-induced Ca2+ entry in 3D-hydrogel-embedded cardiomyocytes.

Lipid-protein interactions: Lessons learned from stress.

Biological membranes are essential for normal function and regulation of cells, forming a physical barrier between extracellular and intracellular space and cellular compartments. These physical barriers are subject to mechanical stresses. As a consequence, nature has developed proteins that are able to transpose mechanical stimuli into meaningful intracellular signals. These proteins, termed Mechanosensitive (MS) proteins provide a variety of roles in response to these stimuli. In prokaryotes these proteins form transmembrane spanning channels that function as osmotically activated nanovalves to prevent cell lysis by hypoosmotic shock. In eukaryotes, the function of MS proteins is more diverse and includes physiological processes such as touch, pain and hearing. The transmembrane portion of these channels is influenced by the physical properties such as charge, shape, thickness and stiffness of the lipid bilayer surrounding it, as well as the bilayer pressure profile. In this review we provide an overview of the progress to date on advances in our understanding of the intimate biophysical and chemical interactions between the lipid bilayer and mechanosensitive membrane channels, focusing on current progress in both eukaryotic and prokaryotic systems. These advances are of importance due to the increasing evidence of the role the MS channels play in disease, such as xerocytosis, muscular dystrophy and cardiac hypertrophy. Moreover, insights gained from lipid-protein interactions of MS channels are likely relevant not only to this class of membrane proteins, but other bilayer embedded proteins as well. This article is part of a Special Issue entitled: Lipid-protein interactions.

Aerobic biological treatment of thermophilically digested sludge.

Aerobic biological treatment of digested sludge was studied in a continuously operated laboratory set-up. An aerated reactor was filled with thermophilically digested sludge from the Moscow wastewater treatment plant and inoculated with special activated sludge. It was then operated at the chemostat mode at different flow rates. Processes of nitrification and denitrification, as well as dephosphatation, occurred simultaneously during biological aerobic treatment of thermophilically digested sludge. Under optimal conditions, organic matter degradation was 9.6%, the concentrations of ammonium nitrogen and phosphate decreased by 89 and 83%, respectively, while COD decreased by 12%. Dewaterability of digested sludge improved significantly. The processes were found to depend on hydraulic retention time, oxygen regime, and temperature. The optimal conditions were as follows: hydraulic retention time 3-4 days, temperature 30-35 degrees C, dissolved oxygen levels 0.2-0.5 mg/L at continuous aeration or 0.7-1 mg/L at intermittent aeration. Based on these findings, we propose a new combined technology of wastewater sludge treatment. The technology combines two stages: anaerobic digestion followed by aerobic biological treatment of digested sludge. The proposed technology makes it possible to degrade the sludge with conversion of approximately 45% volatile suspended solids to biogas, to improve nitrogen and phosphorus removal in reject water from sludge treatment units, and to achieve removal of malodorous substances after 8-9 days of anaerobic-aerobic sludge treatment.