Introduction This study aimed to investigate the anti-inflammatory, antioxidant, and anti-apoptotic properties of ursodeoxycholic (UDCA) and chenodeoxycholic (CDCA) bile acids in a rat model of endotoxin (lipopolysaccharide, LPS)-induced acute lung injury (ALI). Methods The study included six groups of Wistar rats exposed to different pretreatments. The control and endotoxin groups were pretreated with propylene glycol, a solvent for bile acids, while the other groups received UDCA or CDCA for 10 days. On the 10th day, an endotoxin injection was given to evaluate the impact of these pretreatments. Lung tissue sections were analyzed by immunohistochemistry, targeting the pro-inflammatory marker nuclear factor kappa B (NF-κB), the anti-apoptotic marker B-cell lymphoma 2 (BCL-2), pro-apoptotic markers BCL-2-associated X protein (BAX) and caspase 3, as well as the aquaporins 1 and 5 (AQP1 and AQP5). Oxidative stress was assessed in bronchoalveolar lavage fluid (BALF). Results and discussion This study demonstrates that UDCA and CDCA can mitigate endotoxin-induced lung injury in rats. These effects are achieved through modulation of AQP1 and AQP5 expression, reduction of oxidative stress, regulation of apoptotic pathways (BAX, caspase 3, BCL-2), and attenuation of pro-inflammatory activity of NF-κB. Although the results indicate a significant association between the expression of these proteins and histopathological changes, the potential influence of additional factors cannot be excluded. These findings suggest that UDCA and CDCA provide lung protection by acting through complex mechanisms involving inflammatory, oxidative, and apoptotic pathways.

Background: Myocardial injury (MI) is characterized by an increased level of at least one cardiac troponin. Experimental MI can be induced by isoprenaline, a β-adrenergic agonist, and it can lead to heart failure (HF). Liraglutide is glucagon-like 1 peptide receptor agonist used in diabetes management, but it has anti-inflammatory and antioxidative effects, which can be beneficial in treatment of HF. The aim of this study was to investigate the effects of liraglutide on isoprenaline-induced MI and prevention of HF. Methods: Male Wistar albino rats were divided into four groups: Con—received saline the first 2 days + saline the next 7 days; Iso—isoprenaline the first 2 days + saline the next 7 days; Lir—saline the first 2 days + liraglutide the next 7 days; Iso + Lir—isoprenaline the first 2 days + liraglutide the next 7 days. On day 10, blood samples were taken for biochemical analysis and oxidative stress marker evaluation, and hearts were isolated for pathohistological analysis. Cardiac function was assessed by electrocardiography (ECG) and echocardiography (ECHO). Results: Liraglutide treatment significantly attenuated oxidative stress, repaired ECG and ECHO parameters, and mitigated myocardial morphological changes induced by isoprenaline. Conclusions: Liraglutide restores cardiac function in isoprenaline-induced HF.

Psoriasis is a chronic inflammatory skin disease with relapsing nature. Estimates are that approximately 2–3% of the world’s population suffers from this disease. More severe forms of psoriasis are conditions of high inflammation, which is confirmed by the clinical picture and numerous inflammatory parameters such as C-reactive protein (CRP), cytokines and homocysteine, which vary with disease activity. The objective of this clinical study was to investigate the effect of GLP-1 receptor agonist semaglutide therapy on pro-inflammatory factors in the serum and the severity of the clinical picture of psoriasis in obese patients with type 2 diabetes mellitus (T2DM) on chronic metformin therapy. This randomized clinical study was conducted on 31 psoriatic patients with T2DM that were randomized into two groups: one that received semaglutide during the 12-week trial (n = 15), while the second was control (n = 16). The results demonstrated that the severity of the clinical picture of psoriasis, determined by the Psoriasis Area and Severity Index (PASI) score, was significantly better after the administration of semaglutide (the median baseline PASI score in patients treated with semaglutide was 21 (IQR = 19.8), while after 12 weeks of therapy the score was 10 (IQR = 6; p = 0.002). Also, the quality of life in the group of patients who received the drug, measured by the Dermatology Life Quality Index (DLQI), improved significantly after 3 months (a median baseline DLQI score in the semaglutide group was 14 (IQR = 5) at the beginning of the study, and after 12 weeks of treatment the median DLQI score was 4 (IQR = 4; p = 0.002)). The use of semaglutide led to a significant decrease in pro-inflammatory cytokines in the serum (IL6), as well as a significant decrease in CRP values (p < 0.05). A significant decrease in the body mass index (BMI) value in the semaglutide-treated group was also identified, as well as a significant decrease in the level of low-density cholesterol (LDL) (p < 0.05). In conclusion, semaglutide, based on its systemic anti-inflammatory characteristics, could contribute to the treatment of psoriatic obese patients with T2DM.

BACKGROUND Limited joint mobility is the proven risk factor for diabetic foot ulceration when present in the subtalar and first metatarsophalangeal joints. Evidence shows that a foot-related exercise program, combined with a health-promoting program, can improve the signs and symptoms of diabetic polyneuropathy, enhance gait, restore mobility in the foot and ankle joints, redistribute pressure while walking, and increase foot strength and function. As a result, these exercise programs can help mitigate the risk factors for diabetic foot ulceration. AIM To determine the effect of supervised stretching, strengthening, functional and walking exercises on joint mobility and muscle strength in patients with diabetic polyneuropathy. METHODS This was a randomized controlled trial conducted in a tertiary hospital. The study included 82 participants allocated into the intervention group (alpha-lipoic acid and exercise on 15 consecutive therapeutic days, n = 42) and control group (alpha lipoic acid only, n = 40). Muscle strength included dorsal and plantar flexors dynamometry and strength score, while range of motion included ankle, subtalar and first metatarsophalangeal joint goniometry. RESULTS Change of motion range was significantly higher in the intervention group compared to the control group regarding ankle joint on day 15 (9.9 ± 7.2 vs 0.1 ± 3.3; P = 0.006) and month 6 (2.8 ± 7.3 vs -0.9 ± 4.1; P < 0.001), subtalar joint on day 15 (7.5 ± 5.1 vs -0.25 ± 2.25; P < 0.001) and month 6 (3.9 ± 6.4 vs -0.13 ± 3.49; P < 0.001). Change in dorsal flexors was significantly higher in the intervention group compared to the control group on day 15 (2.62 ± 1.69 vs 0.10 ± 1.35; P < 0.001) and month 6 (0.66 ± 2.38 vs -0.75 ± 1.94; P = 0.004) as well as plantar flexors on day 15 (3.3 ± 1.6 vs 0.3 ± 1.5; P < 0.001) and month 6 (1.8 ± 2.2 vs -0.9 ± 2.1; P < 0.001). Muscle strength score change was significantly lower in the intervention group compared to the control group on day 15 (-1.45 ± 1.42 vs -0.03 ± 0.16; P < 0.001) and month 6 (-1.17 ± 1.53 vs 0.20 ± 0.56; P < 0.001). CONCLUSION Exercise in combination with alpha-lipoic acid can improve joint mobility, as well as strength of the foot and lower leg muscles in patients with diabetic polyneuropathy.

Background/Objectives: The importance of fixed-dose combinations (FDCs) for the treatment of hypertension is well established. However, from a stability perspective, FDCs present a challenge since the degradation of one active pharmaceutical ingredient (API) can be affected by the presence of another API. The aim of this study was to compare the degradation behaviors and evaluate the degradation kinetics of three antihypertensive drugs, perindopril tert-butylamine (PER), amlodipine besylate (AML), and indapamide (IND). Methods: The degradation processes were studied using the previously developed reverse phase high-performance liquid chromatographic (RP-HPLC) method after exposing each drug individually, as well as the combinations of two/three drugs, to different stress factors, such as light, oxidation, acidic, basic, or neutral pH values at different temperatures. Results: The results show that PER is most unstable under basic conditions and that AML displays a negative, while IND displays a positive effect, on PER stability when combined. AML is most affected by basic conditions and oxidation, and its stability is affected by both drugs positively; IND undergoes extreme photolysis, which is positively affected by AML but negatively by PER. Conclusions: Great care must be taken when formulating FDCs with these three drugs, as well as solutions or oral suspensions adjusted for geriatric or pediatric populations, since the stability of all three drugs is greatly affected by pH conditions, as well as light or oxidation factors and their interactions.

Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is a chronic and relapsing condition characterized by persistent inflammation of the gastrointestinal tract. The complex pathogenesis of IBD involves a combination of genetic, environmental, and immune factors, which complicates the achievement of long-term remission. Lower abdominal pain, stomach cramps, blood in stool, chronic diarrhea, fatigue, and unexpected weight loss are common presenting symptoms. Despite the range of therapies and medications, including anti-inflammatory and anti-diarrheal drugs, immunosuppressants, antibiotics, and analgesics aimed at managing symptoms and controlling inflammation, a definitive cure for IBD remains elusive. Current therapy targets inflammation, mainly cytokines, inflammatory receptors, and immune cells, however, there is a need for novel targets to improve clinical outcomes. To identify novel targets and interactions among various factors, we performed a network analysis using various cytokines, TLRs, and NLRP3 inflammasome as inputs. This analysis revealed orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) as a central hub gene interacting with multiple factors. While the role of ORMDL3 in IBD pathogenesis is not well-established, our findings and existing literature suggest that ORMDL3 plays a role in inflammation, impaired mitochondrial function, and disrupted autophagy, all contributing to the disease progression. Given its central role in these pathogenic processes, targeting ORMDL3 presents a promising therapeutic target. Modulating ORMDL3 activity could alleviate inflammation, restore mitochondrial function, and enhance autophagy, potentially leading to more effective treatments and improved outcomes for IBD patients.

Background The inadequacy of intensive care medicine in low-resource settings (LRS) has become significantly more visible after the COVID-19 pandemic. Recommendations for establishing medical critical care are scarce and rarely include expert clinicians from LRS. Methods In December 2023, the National Association of Intensivists from Bosnia and Herzegovina organized a hybrid international conference on the topic of organizational structure of medical critical care in LRS. The conference proceedings and literature review informed expert statements across several domains. Following the conference, the statements were distributed via an online survey to conference participants and their wider professional network using a modified Delphi methodology. An agreement of ≥ 80% was required to reach a consensus on a statement. Results Out of the 48 invited clinicians, 43 agreed to participate. The study participants came from 20 countries and included clinician representatives from different base specialties and health authorities. After the two rounds, consensus was reached for 13 out of 16 statements across 3 domains: organizational structure, staffing, and education. The participants favored multispecialty medical intensive care units run by a medical team with formal intensive care training. Recognition and support by health care authorities was deemed critical and the panel underscored the important roles of professional organizations, clinician educators trained in high-income countries, and novel technologies such as tele-medicine and tele-education. Conclusion Delphi process identified a set of consensus-based statements on how to create a sustainable patient-centered medical intensive care in LRS. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-024-05113-9.

Patients suffering from cholelithiasis have an increased risk of developing cardiovascular complications, particularly ischemic myocardial disease. Ursodeoxycholic acid (UDCA), already used in clinical practice for the treatment of cholelithiasis and related conditions, has proven antioxidative, anti-inflammatory, and cytoprotective effects. Therefore, the aim of this study was to investigate the cardioprotective effect of UDCA pre-treatment on isoprenaline-induced myocardial injury in rats. Male Wistar albino rats were randomized into four groups. Animals were pre-treated for 10 days with propylene glycol + saline on days 9 and 10 (control), 10 days with propylene glycol + isoprenaline on days 9 and 10 (I group), 10 days with UDCA + saline on days 9 and 10 (UDCA group), and 10 days with UDCA + isoprenaline on days 9 and 10 (UDCA + I group). UDCA pre-treatment significantly reduced values of high-sensitivity troponin I (hsTnI) and aspartate aminotransferase (AST) cardiac markers (p < 0.001 and p < 0.01, respectively). The value of thiobarbituric acid reactive substances (TBARS) was also decreased in the UDCA + I group compared to the I group (p < 0.001). UDCA also significantly increased glutathione (GSH) levels, while showing a tendency to increase levels of superoxide dismutase (SOD) and catalase (CAT). The level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, a key regulatory gene of inflammation, was diminished when UDCA was administered. A reduction of cardiac damage was also observed in the UDCA pre-treated group. In conclusion, UDCA pre-treatment showed a cardioprotective effect on isoprenaline-induced myocardial injury in rats, primarily by reducing oxidative stress and inflammation.

Abstract Academic medicine encompasses education, research and clinical practice, and plays a crucial role in advancing medical science and training physicians. However, the field faces a crisis, with fewer graduates pursuing academic careers. Family medicine emerged as an academic discipline in the second half of the 20th century, contributing significantly to science and primary healthcare. Despite its recognised status, the World Health Organization has yet to formally define it as an academic discipline. Nevertheless, the discipline must continually update its academic dimension in order to address future challenges. The international conference in Banja Luka, attended by deans or representatives of Medical Faculties in Southeast Europe, emphasized family medicine's role in primary healthcare and academic medicine, adopting the Banja Luka Declaration to promote family medicine as an independent academic discipline. The conference aims to inspire global support for family medicine as an academic discipline.

Diabetes mellitus and inflammatory bowel disease are chronic conditions with significant overlap in their pathophysiology, primarily driven by chronic inflammation. Both diseases are characterized by an aberrant immune response and disrupted homeostasis in various tissues. However, it remains unclear which disease develops first, and which one contributes to the other. Diabetes mellitus increases the risk of inflammatory bowel disease and inflammatory bowel disease may increase the risk of developing diabetes. This review focuses on comprehensively discussing the factors commonly contributing to the pathogenesis of diabetes mellitus and inflammatory bowel disease to draw a relationship between them and the possibility of targeting common factors to attenuate the incidence of one if the other is present. A key player in the intersection of diabetes mellitus and inflammatory bowel disease is the NLRP3 inflammasome, which regulates the production of pro-inflammatory cytokines leading to prolonged inflammation and tissue damage. Additionally, toll-like receptors via sensing microbial components contribute to diabetes mellitus and inflammatory bowel disease by initiating inflammatory responses. Gut dysbiosis, a common link in both diseases, further intensifies inflammation and metabolic dysfunction. Alterations in gut microbiota composition affect intestinal permeability and immune modulation, perpetuating a vicious cycle of inflammation and disease progression by changing protein expression. The overlap in the underlying inflammatory mechanisms has led to the potential of targeting mediators of chronic inflammation using anti-inflammatory drugs and biologics that benefit both conditions or attenuate the incidence of one in the presence of the other.

Considering the escalating global prevalence and the huge therapeutic demand for the treatment of hypertension, there is a persistent need to identify novel target sites for vasodilator action. This study aimed to investigate the role of TRPA1 channels in carvacrol-induced vasodilation and to design novel compounds based on carvacrol structure with improved activities. In an isolated tissue bath experiment, it was shown that 1 µM of the selective TRPA1 antagonist A967079 significantly (p < 0.001) reduced vasodilation induced by 3 mM of carvacrol. A reliable 3D-QSAR model with good statistical parameters was created (R2 = 0.83; Q2 = 0.59 and Rpred2 = 0.84) using 29 TRPA1 agonists. Obtained results from this model were used for the design of novel TRPA1 activators, and to predict their activity against TRPA1. Predicted pEC50 activities of these molecules range between 4.996 to 5.235 compared to experimental pEC50 of 4.77 for carvacrol. Molecular docking studies showed that designed molecules interact with similar amino acid residues of the TRPA1 channel as carvacrol, with eight compounds showing lower binding energies. In conclusion, carvacrol-induced vasodilation is partly mediated by the activation of TRPA1 channels. Combining different in silico approaches pointed out that the molecule D27 (2-[2-(hydroxymethyl)-4-methylphenyl]acetamide) is the best candidate for further synthesis and experimental evaluation in in vitro conditions.

Background 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 development 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% polyacrylamide gradient gel electrophoresis method was used to separate plasma HDL particles. Results The level of CTSS was significantly higher in NHL patients than in control subjects: 12.20 (9.75-14.57) vs 9.97 (8.44-10.99), P<0.001. In NHL patients, there was a positive correlation between CTSS and the proportions of HDL3a, HDL3b, and the sum of the HDL3 subclasses (r=0.506, P<0.001; r=0.411, P=0.006, r=0.335, P=0.026, respectively). In addition, the area under the receiver operating characteristic curve (AUC curve) of CTSS was 0.766 (CI: 0.655-0.856) for NHL patients. There was no significant difference in CTSS values between the control group and patients with HL, nor significant correlations between CTSS and HDL subclasses in the HL group. Conclusions CTSS is significantly elevated in patients with NHL and has the potential to be a new diagnostic bio - marker for the detection of NHL. Also, this study was the first to unveil the association between serum CTSS levels and the proportions of anti-apoptotic HDL3a and HDL3b subclasses in NHL patients.