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Altered Mitochondrial Function in MASLD: Key Features and Promising Therapeutic Approaches
Get PDFMetabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), encompasses a range of liver conditions from steatosis to nonalcoholic steatohepatitis (NASH). Its prevalence, especially among patients with metabolic syndrome, highlights its growing global impact. The pathogenesis of MASLD involves metabolic dysregulation, inflammation, oxidative stress, genetic factors and, notably, mitochondrial dysfunction. Recent studies underscore the critical role of mitochondrial dysfunction in MASLD’s progression. Therapeutically, enhancing mitochondrial function has gained interest, along with lifestyle changes and pharmacological interventions targeting mitochondrial processes. The FDA’s approval of resmetirom for metabolic-associated steatohepatitis (MASH) with fibrosis marks a significant step. While resmetirom represents progress, further research is essential to understand MASLD-related mitochondrial dysfunction fully. Innovative strategies like gene editing and small-molecule modulators, alongside lifestyle interventions, can potentially improve MASLD treatment. Drug repurposing and new targets will advance MASLD therapy, addressing its increasing global burden. Therefore, this review aims to provide a better understanding of the role of mitochondrial dysfunction in MASLD and identify more effective preventive and treatment strategies
Синтеза и in vitro студија редокс особина халогенованих и нехалогенованих деривата пирола
Get PDFThe redox balance plays a crucial role in maintaining biological processes under normal conditions. Antioxidants inhibit and reduce harmful oxidation processes, while pro-oxidants can act as anti-cancer agents by promoting ROS-mediated cell death. The aim of this study is to compare the redox properties of seven newly synthesised tribromopyrrole derivatives with three novel and four previously synthesized non-halogenated analogues in an in vitro model (in human serum) and with exogenously induced oxidative stress. The obtained values of their oxy scores (OS) were compared and the result showed that four non-halogenated pyrrole derivatives with secondary amide group M2, M10, M11 and M12 have lower OS values than Trolox, a water-soluble analogue of vitamin E with proven antioxidant properties. All four compounds show strong resistance to oxidative stress, which is reflected in the maintenance of negative OS values when exposed to exogenous oxidative stress using TBH in the reaction mixture. This capability to resist invading ROS should be expected also in an endogenous environment, where constant prooxidant production takes place at a low, homeostatic level, but even more so in pathological conditions. The tribrominated derivative M15 showed prooxidant activity with a significantly higher OS value than all other compounds tested. The comparison of the dose-response of Trolox and the five compounds with the lowest OS also shows that compounds M2, M7 and M10 have better antioxidant activity than Trolox.Редоксравнотежа игра кључну улогу у одржавању биолошких процеса у нормалним условима. Антиоксиданси инхибирају и смањују штетне процесе оксидације, док прооксиданси могу деловати као антиканцерски агенси промовишући ћелијску смрт посредовану реактивним кисеоничним врстама. Циљ овог рада је да се упореде редокс својства седам новосинтетисаних деривата трибромопирола и нехалогенованих аналога(три новосинтетисанаи четири претходно синтетисана) у in vitroмоделу (у хуманом серуму) и са егзогеноиндукованим оксидативним стресом. Упоређене су добијене вредности њихових окси скорова (ОС) и резултат је показао да четири нехалогенована деривата пирола са секундарном амидном групом М2, М10, М11и М12имају ниже вредности ОС од Тролокса, аналога витамина Е растворљивог у води са доказаним антиоксидативним својствима. Сва четири једињења показују јаку отпорност на оксидативни стрес, што се огледа у одржавању негативних вредности ОС када су изложене егзогеном оксидативном стресу коришћењем ТБХ у реакционој смеши. Ову способност да се одупируРОС треба очекивати и у ендогеном окружењу, где се константна производња прооксиданата одвија на ниском, хомеостатском нивоу, али још више у патолошким стањима.Трибромовани дериват М15је показао прооксидативну активност са значајно вишом ОС вредношћу од свих осталих тестираних једињења. Такође, упоредне анализе доза-одговор тестираних пет једињења са најнижим ОС и Тролокса показују да Тролокс има слабијуантиоксидативну активност од једињења М2, М7и М10.This is peer-reviewed version of the following article: M. R. Petković, J. M. Kotur-Stevuljević, P. M.
Jovanović, M. D. Jovanović, N. M. Mitrović, M. R. Simić, G. D. Tasić, and V. M.
Savić, J. Serb. Chem. Soc. (2024).
[https://doi.org/10.2298/JSC240515082P
Psychological Safety Competency Training During the Clinical Internship From the Perspective of Health Care Trainee Mentors in 11 Pan-European Countries: Mixed Methods Observational Study
No full textBackground: In the field of research, psychological safety has been widely recognized as a contributing factor to improving the quality of care and patient safety. However, its consideration in the curricula and traineeship pathways of residents and health care students is scarce. Objective: This study aims to determine the extent to which health care trainees acquire psychological safety competencies during their internships in clinical settings and identify what measures can be taken to promote their learning. Methods: A mixed methods observational study based on a consensus conference and an open-ended survey among a sample of health care trainee mentors from health care institutions in a pan-European context was conducted. First, we administered an ad hoc questionnaire to assess the perceived degree of acquisition or implementation and significance of competencies (knowledge, attitudes, and skills) and institutional interventions in psychological safety. Second, we asked mentors to propose measures to foster among trainees those competencies that, in the first phase of the study, obtained an average acquisition score of <3.4 (scale of 1-5). A content analysis of the information collected was carried out, and the spontaneity of each category and theme was determined. Results: In total, 173 mentors from 11 pan-European countries completed the first questionnaire (response rate: 173/256, 67.6%), of which 63 (36.4%) participated in the second consultation. The competencies with the lowest acquisition level were related to warning a professional that their behavior posed a risk to the patient, managing their possible bad reaction, and offering support to a colleague who becomes a second victim. The mentors’ proposals for improvement of this competency gap referred to training in communication skills and patient safety, safety culture, work climate, individual attitudes, a reference person for trainees, formal incorporation into the curricula of health care degrees and specialization pathways, specific systems and mechanisms to give trainees a voice, institutional risk management, regulations, guidelines and standards, supervision, and resources to support trainees. In terms of teaching methodology, the mentors recommended innovative strategies, many of them based on technological tools or solutions, including videos, seminars, lectures, workshops, simulation learning or role-playing with or without professional actors, case studies, videos with practical demonstrations or model situations, panel discussions, clinical sessions for joint analysis of patient safety incidents, and debriefings to set and discuss lessons learned. Conclusions: This study sought to promote psychological safety competencies as a formal part of the training of future health care professionals, facilitating the translation of international guidelines into practice and clinical settings in the pan-European context
Chlorine containing tetrahydropyrimidines: Synthesis, characterization, anticancer activity and mechanism of action
No full textThe aim of the presented research was to explore anticancer potential of eleven newly synthesized tetrahydropyrimidine derivatives. The compounds were synthesized via Biginelli multicomponent one-pot reaction using different derivatives of vanillin, ethyl 4-chloroacetoacetate and (N-methyl)urea. The cytotoxic effects of the compounds were examined on three human malignant cell lines (HeLa, K562, and MCF7), and normal lung fibroblasts MRC-5. The mechanisms of anticancer activity were examined for two compounds 4a and 4b which showed the strongest and selective cytotoxicity against chronic myelogenous leukaemia K562 cells (IC50 = 1.76 ± 0.09, and 1.66 ± 0.05, respectively). The changes of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were investigated in the K562 cell line, as well as oncomiRNA miR-10b, miR-23a described to have both features, depending on a specific type of malignancy, and miR-34a with mostly described as a tumour suppressor
The beneficial effects of N-methyl-D-aspartate receptor antagonism on experimental autoimmune encephalomyelitis in aged rats
No full textPurpose: Life expectancy is only slightly affected by multiple sclerosis (MS), and it is a disease that often lasts for severaldecades. The proportion of patients with late-onset MS has increased significantly and the mean age at diagnosis hasshifted towards older age. Older age at disease onset is associated with a shorter time to disability. Immune cells, such asmacrophages, microglia and lymphocytes, express N-methyl-D-aspartate receptors (NMDARs). Our aim was to elucidatethe effects of ageing on the role of NMDARs in the pathogenesis of experimental autoimmune encephalomyelitis (EAE).Methods: Young adult (3-month-old) and aged (24-month-old) female Dark Agouti rats were used in this study.Memantine, a non-competitive NMDAR antagonist, was administered by oral gavage for 7 consecutive days from thefirst day post-immunization (dpi) in the first set of experiments or from the 7th dpi in the second set of experiments.Mononuclear cells were isolated from the spinal cord or draining lymph nodes and analysed by flow cytometry. Spinalcord tissue was collected for RT-qPCR.Results: Administration of an NMDAR antagonist during the induction phase of EAE diminished the proportion of Th1and Th17 cells and increased the proportion of IL-10+regulatory T cells in the lymph nodes draining the site ofimmunization in aged rats. Memantine increased the proportion of CD163+and IL-10+cells within CD11b+cells in thedraining lymph nodes of aged rats, whereas these effects were absent in young rats. Treatment with memantine from the7th dpi resulted in a shift of microglia towards the anti-inflammatory M2 phenotype, characterized by an increase in theexpression of CD163 and a decrease in the expression of MHCII molecules, with an increase in the proportion of IL10+microglia and the expression level of arginase 1 in the spinal cord of aged rats at the peak of the disease.Conclusion: NMDARs contribute significantly to the pathogenesis of EAE in aged rats in both the induction and effectorphases. Our results suggest that targeting NMDARs in elderly MS patients may help to tailor treatment to the elderly MSpopulation
Assessment of the influence of formulation parameters on the physico-chemical properties of hypromellose-based film-forming solutions
No full textThere is great interest in development of film-forming systems for dermal (topical or transdermal) drug delivery (FFSDDD) due to their unique property to form a thin, continuous film upon administration to the skin surface, offering numerous advantages compared to conventional topical preparations. The primary research challenge in the FFSDDD development is the formulation of a carrier that represents a polymer solution in a volatile and non-volatile solvents mixture. We examined the influence of the film-forming polymer (hypromellose) concentration and the type and concentration of nonvolatile solvent (propylene glycol or macrogol 400) and volatile solvent (ethanol or isopropanol) on the physicochemical (pH and transmittance) and rheological properties of the film-forming solution (FFS) and the properties of the film formed. FFS containing 2.5% of hypromellose and 1.25% and 5% propylene glycol form films with the most desirable pH, appearance, viscosity, and flexibility, so they can be considered promising dermal drug delivery carriers.17th International Conference on Fundamental and Applied Aspects of Physical Chemistry, September 23-27, 2024 Belgrade, Serbi
Effects of early and delayed x-ray exposures on DNA damage in mesenchymal stem cells
No full textTechniques based on X-ray phase-contrast (XPC), have shown great potential for a number of biomedical applications due to their ability to provide soft tissue contrast through their reliance on alternative X-ray properties (refraction, scatter). It is shown that XPC can be used to image biomaterials and soft tissue. Exposure of cells and biomaterials to X-rays even at diagnostic doses may influence the final outcome. Essential to the development of this technique and its routine use is an understanding the potential radiation damage to the cells and tissue that may result from routine imaging. The overall aim of the study was to investigate the effects of early (immediately after irradiation) and delayed (24 hours after irradiation) X-ray exposures generated by low (15 mGy) and intermediate (150 mGy and 1.5 Gy) irradiation on mesenchymal stem cells (MSCs) using polychromatic X-ray imaging. We used the alkaline Comet assay to quantify DNA damage. Our data showed that 15 mGy did not increase the number of DNA-damaged cells after irradiation, while 150 mGy and 1.5 Gy caused a significant increase (p<0.01) in DNA-damaged cells compared to the control. It is noteworthy that 24 h after irradiation, DNA damage at intermediate doses returned to control levels, indicating that MSCs provide significant protection at the XPC irradiation dose studied. The current work provides additional evidence for the use of MSCs in the clinical setting and emphasizes the need to investigate the effects of low and intermediate doses of X-ray PC irradiation in the field of tissue engineering.7th Congress of the Serbian genetic society : October 2-5, 2024, Zlatibo
Modifikacija karakteristika mikrokristalne celuloze dobivene iz žetvenih ostataka tehnikom koprocesnog sušenja raspršivanjem
No full textDue to its good binding properties and high dilution capacity microcrystalline cellulose
(MCC) is the most common excipient in tablet formulation. However, its poor solubility
may negatively affect drug release rate. This study aims to modify characteristics of MCC
obtained from wheat crop residues (CRs) by coprocessing using spray drying technique to
ensure fast drug release from high drug loading tablets. MCC obtained from CRs (MCC CR)
was coprocessed with the addition of a glidant (MCC CP1) or with mannitol, a glidant, and
a disintegrant (MCC CP2). MCC CR, MCC CP1, MCC CP2 and commercial MCC (Ceolus®
PH101–CMCC) were tested for powder flowability, tableting behavior, and release of
ibuprofen (IBU) from high drug loading (50 and 70 %) tablets with MCC. Coprocessed samples
showed slightly lower flow rates (FR) (FR(MCC CP1) = 0.7 ± 0.07 g/s, FR(MCC CP2) = 0.98 ± 0.14
g/s) compared to the MCC CR sample (FR(MCC CRs) = 1.20 ± 0.13 g/s). The addition of mannitol
increased the brittle component of deformation (1), which is manifested by a slightly lower
net work of compression and in die elastic recovery for MCC CP2. Tablets meeting the
usual tensile strength criteria (TS > 2 MPa) (2) were obtained by compressing the MCC
CR, MCC CP1, and CMCC samples over the entire range of compression pressures used
(35–173 MPa), while slightly higher compression pressures were required for the MCC CP2
sample to produce tablets with TS > 2 MPa. The ejection stress was well below 3 MPa for all
samples, indicating good lubricating properties (2). Up to 25 % of IBU was released within 2
hours from tablets prepared with MCC CR and either 50 or 70 % of IBU. Immediate release
of IBU (>75 % of drug released within 45 minutes) was only achieved from tablets prepared
with MCC CP2 with 50 % drug loading. Faster release of IBU was achieved when MCC CP2
was used as a diluent compared to MCC CR, MCC CP1, and CMCC with both drug loadings.
Coprocessing of MCC obtained from CRs significantly improved IBU release from high
drug loading tablets while maintaining the good tableting properties of MCC
Procena dijagnostičke vrednosti serumskog katepsina S i njegove korelacije sa HDL podklasama kod pacijenata sa ne-Hodgkinovim limfomom
Get PDFBackground: Recent findings point to the key role of
cathepsin S (CTSS) in the survival of malignant cells, as
well as the significance of the anti-apoptotic properties of
high-density lipoprotein (HDL) that contribute to enhanced
cell survival. The purpose of this study is to analyse CTSS
as a potential biomarker in lymphoma. Also, in order to
better understand the role of CTSS in the origin and devel-
opment of lymphoma, its association with cystatin C (Cys
C), lipids, and inflammatory markers was analysed.
Methods: The study included 90 subjects: 11 Hodgkin (HL)
and 44 B-cell non-Hodgkin lymphoma (NHL) patients, as
well as 35 healthy subjects. CTSS was determined using
the Invitrogen ELISA kit (Thermo Fisher Scientific, Inc.,
Waltham, MA, USA). The non-denaturing 3%–31% poly-
acrylamide gradient gel electrophoresis method was used
to separate plasma HDL particles.Uvod: Novija otkri}a ukazuju na klju~nu ulogu katepsina S
(CTSS) u pre`ivljavanju malignih }elija, kao i na zna~aj anti-
apoptoti~kih osobina lipoproteina visoke gusto}e (HDL)
koje doprinose ve}em pre`ivljavanja }elija. Cilj ove studije
je analizirati CTSS kao potencijalni biomarker kod limfomu.
Tako|e, kako bi se bolje razumela uloga CTSS-a u nastan-
ku i razvoju limfoma, analizirana je njegova povezanost sa
cistatinom C (Cys C), lipidima i upalnim markerima.
Metode: U istra`ivanje je bilo uklju~eno 90 ispitanika: 11
bolesnika sa Hodgkinovim (HL) i 44 bolesnika sa B-}elij-
skim ne-Hodgkinovim limfomom (NHL), te 35 zdravih ispi-
tanika. Za merenje serumskog CTSS je kori{}en Invitrogen
ELISA kit (Thermo Fisher Scientific, Inc., Waltham, MA,
SAD). HDL subfrakcije su razdvojene metodom vertikalne
elektroforeze na gradijentu poliakrilamida
Integration of 3D-QSAR, molecular docking, and machine learning techniques for rational design of nicotinamide-based SIRT2 inhibitors
No full textSelective inhibitors of sirtuin-2 (SIRT2) are increasingly recognized as potential therapeutics for cancer and neurodegenerative diseases. Derivatives of 5-((3-amidobenzyl)oxy)nicotinamides have been identified as some of the most potent and selective SIRT2 inhibitors reported to date (Ai et al., 2016; Ai et al., 2023, Baroni et al., 2007). In this study, a 3D-QSAR (3D-Quantitative Structure-Activity Relationship) model was developed using a dataset of 86 nicotinamide-based SIRT2 inhibitors from the literature, along with GRIND-derived pharmacophore models for selected inhibitors. External validation parameters emphasized the reliability of the 3D-QSAR model in predicting SIRT2 inhibition within the defined applicability domain. The interpretation of the 3D-QSAR model facilitated the generation of GRIND-derived pharmacophore models, which in turn enabled the design of novel SIRT2 inhibitors. Furthermore, based on molecular docking results for the SIRT1–3 isoforms, two classification models were developed: a SIRT1/2 model using the Naive Bayes algorithm and a SIRT2/3 model using the k-nearest neighbors algorithm, to predict the selectivity of inhibitors for SIRT1/2 and SIRT2/3. External validation parameters of the selectivity models confirmed their predictive power. Ultimately, the integration of 3D-QSAR, selectivity models and prediction of ADMET properties facilitated the identification of the most promising selective SIRT2 inhibitors for further development