Nimbin, a bioactive triterpenoid compound isolated from the neem tree (Azadirachta indica), is known for its anti-inflammatory, antioxidant, antimicrobial, and hepatoprotective properties. The study aimed to explore the impact of nimbin on cardiac markers, mitochondrial and lysosomal enzyme activities, as well as apoptotic signaling in rats induced with isoproterenol. The subcutaneous injection of isoproterenol (ISO) at a dosage of 85 mg/kg body weight over the last two consecutive days led to notable increased in the activities/levels of the cardiac markers, lysosomal glycohydrolases and cathepsins. Conversely, reductions in the functioning of mitochondrial tricarboxylic acid cycle enzymes and respiratory chain enzymes in ISO-induced rats. In ISO-induced rats, there was an augmentation in the expressions of Bax, caspase-3, caspase-9, and cytochrome c, along with a diminished level of Bcl-2. Administration of nimbin resulted in decreased activities/levels cardiac markers, lysosomal glycohydrolases, cathepsins and increased functioning of mitochondrial tricarboxylic acid cycle enzymes and respiratory chain enzymes. Additionally, decreased expressions of Bax, executioner caspases and cytochrome c, along with heightened expression of Bcl-2, were noted in rats treated with nimbin. This indicates that nimbin possesses cardioprotective properties and mitigates mitochondrial and lysosomal dysfunction in rats induced with ISO. Key words Myocardial infarction " Tricarboxylic acid (TCA) cycle enzymes " Cathepsin-D " Cardiac markers " Triterpenoid.

An important harmful side effect of the prolonged support of the left ventricle (LV) with an LV assist device (LVAD) in patients with advanced heart failure (HF) is development of cardiac atrophy. Our first aim was to evaluate if implantation of the four-branch spring expander into LV of the rat will exhibit greater attenuation of unloading-induced cardiac atrophy as compared with the three-branch spring expander. The second aim was to assess if sex-related differences are present in the development of unloading-induced cardiac atrophy in the failing hearts with implanted either three-branch or four-branch spring expander into the LV. Heterotopic heart transplantation in the rat (HTx) served as the model of heart unloading after LVAD implantation. HF was induced by volume overload achieved by creation of the aorto-caval fistula. The degree of cardiac atrophy was assessed as the weight ratio of the heterotopically transplanted heart to the control native heart. We found that enhancement of isovolumic loading by implantation of either type of spring expander into the LV reduced the degree of post-HTx cardiac atrophy in the failing hearts but the four-branch variant was significantly more effective. In addition, we found that there were no sex-related differences in the development of unloading-induced cardiac atrophy or in the attenuation of this process in the failing hearts. We propose that enhancing cardiac work by increasing isovolumic loading via implantation of the spring expander might be a reasonable approach to attenuate the unloading-induced cardiac atrophy in the failing hearts in both sexes. Key words Heart failure in rats " Cardiac atrophy " Aorto-caval fistula " Heterotopic heart transplantation " Three-branch spring expander " Four-branch spring expander.

Regarding cardiovascular (CV) risk, patients with type 1 diabetes mellitus (T1D) are a heterogeneous population with CV risk ranging from low to very high. For personalized prevention strategies, screening for subclinical atherosclerosis may be of clinical significance. However, more data is needed. Our study aimed to describe the prevalence of prognostically significant findings on invasive coronary artery examination in patients with subclinical atherosclerosis determined by non-invasive examination of the carotid and coronary arteries. Patients with T1D for at least 10 years, without a prior history of atherosclerotic CV disease or target organ damage, followed at a large tertiary hospital were enrolled. Non-invasive examinations included carotid ultrasound for carotid plaque detection and a CT for coronary artery calcium (CAC) score evaluation. Patients with the presence of >/=2 carotid plaques and/or CAC score of >/=400 were classified as very high risk (VHR). These VHR patients were subsequently evaluated using invasive coronary angiography (ICA) for the presence of obstructive coronary artery disease (CAD) and intracoronary optical coherence tomography (OCT) for the presence of thin-cap fibroatheroma (TCFA) and very high-risk plaque. Moreover, hemodynamic stenosis relevance was assessed by the vessel fraction flow ratio (vFFR). Sixty-two T1D patients aged 50.1+/-12.7 years, 53 % women were enrolled. The criteria of VHR were fulfilled in 12/62 (19.4 %) patients, of which 6 (50 % of VHR) had both CAC>/=400 and at least 2 atherosclerotic plaques in the carotid arteries, one patient (8 % of the VHR) fulfilled only the CAC criteria and 5 (42 % of VHR) only the carotid criteria. The median CAC score of the VHR group was 606.3 (175.3-1515) and the mean number of carotid plaques was 2.75+/-1.06. ICA showed obstructive CAD in 5/12 (41.7 %) patients, and 3/12 (25 %) had vFFR-positive lesions. Using OCT, TCFA was present in 7/12 (58.3 %) and a very high-risk plaque in 4/12 (33.3 %) patients. Among asymptomatic patients with T1D, the combination of coronary artery calcium score and carotid ultrasound identifies a very high-risk group, in which 58.3 % of patients had a thin-cap fibroatheroma and 33.3 % of patients had a very high-risk plaque. Patients identified by these non-invasive techniques may benefit from intensive risk factors management. Key words Type 1 diabetes mellitus " Coronary artery calcium score " Carotid ultrasound " Optical coherence tomography " Cardiovascular risk.

Postoperative cognitive dysfunction (POCD) substantially influences patient outcomes, with its pathophysiology potentially linked to neuroinflammation induced by surgical procedures and anesthesia. Previous research has indicated that esketamine may alleviate neuroinflammation. Therefore, elucidating the mechanisms through which esketamine modulates neuroinflammation to ameliorating POCD is crucial for advancing its clinical management. An in vivo model of POCD was established using C57BL/6J mice subjected to exploratory laparotomy. Cognitive performance was evaluated through the Morris water maze. Subsequently, hippocampal tissue samples were collected to measure changes in the levels of IL-1beta, IL-6, TNF-alpha, PARP1, SIRT1, LC3, and P62. In vitro experiments were performed using BV2 microglial cells treated with lipopolysaccharides (LPS) to induce inflammation and a PARP1 plasmid to create PARP1 overexpression (OvPARP1) models. These models were treated with esketamine, followed by assessment of changes in the previously mentioned indicators. Immunofluorescence microscopy was used to examine PARP1 expression, while transmission electron microscopy was used to analyze cellular autophagy. Exploratory laparotomy induced POCD and triggered neuroinflammation within the hippocampus of the mice. Treatment with esketamine alleviated POCD by inhibiting OvPARP1 expression and increasing SIRT1 levels, which promoted cellular autophagy and reduced neuroinflammation. Esketamine regulates the PARP1-SIRT1 pathway, thereby activating autophagy, reducing neuro-inflammation, and improving POCD. These findings provide novel insights into potential therapeutic strategies for the management of POCD. Key words Autophagy " Esketamine " Neuroinflammation " PARP1 " Postoperative cognitive dysfunction.

Ca2+-sensing receptors (CaSR) are G-protein coupled receptors activated by elevated concentrations of extracellular Ca2+. Cinacalcet, a positive allosteric CaSR modulator, is used as a calcimimetic to inhibit parathyroid hormone release and thus lower serum Ca2+ in hypercalcemic patients. There is a recent trend of repurposing cinacalcet in multiple applications such as anti-cancer actions, treatment of diarrhea and prevention of kidney cyst formation. In this study we investigated whether cinacalcet inhibited proliferation of endothelial cells (EC). Inhibition of EC proliferation offers an anti-angiogenesis mechanism in suppressing tumor growth. Cinacalcet at >/=18 µM caused mitochondrial membrane depolarization, suppressed proliferation and induced apoptosis in mouse bEND.3 EC. In 2 mM Ca2+-containing bath solution, cinacalcet (>/=18 µM) caused an initial rise in [Ca2+]i followed by fura-2 leakage. Similar results were obtained in Ca2+-free or 4 mM Ca2+-containing bath solution. Cinacalcet-elicited Ca2+ signal was unaffected by NPS 2143, a negative allosteric modulator of CaSR. Cinacalcet also increased Ni2+ leakage and trypan blue uptake into cells. Cinacalcet-induced membrane leakiness and cytotoxicity did not appear to be related to membrane fluidity changes. These data suggest cinacalcet, in a manner independent of CaSR stimulation and membrane fluidity perturbation, caused membrane leakiness, eventually leading to inhibition of EC proliferation and EC death. Key words Ca2+-sensing receptors " Endothelium " Cinacalcet " Ca2+ " Membrane permeability.

Stroke-prone spontaneously hypertensive rats (SHRSP) are widely used as a model to study cerebral small vessel disease (CSVD) and its association with chronic hypertension. This study investigated the relationship between metabolic, cardiovascular, and neuronal comorbidities in 32-week-old SHRSP rats versus Wistar-Kyoto (WKY) controls, with a focus on oxidative stress, inflammation, and metabolic alterations. Despite hypertension and cardiac and renal hypertrophy, no significant cerebral vascular changes or microbleeds and no cerebral edema were detected in SHRSP. NMR-based urinary metabolomics revealed reduced gut microbiome-derived metabolites, such as p-cresylglucuronide, hippurate, and phenylacetylglycine, alongside increases in methylamine and dimethylamine. These findings reflect gut dysbiosis and altered microbial composition in hypertensive conditions. Elevated markers of oxidative stress, including thiobarbituric acid-reactive substances, and increased expression of NADPH oxidase (NOX) 2 and NOX4 in peripheral tissues suggested oxidative damage in SHRSP rats. Astrocytic hyperreactivity, indicated by increased expression of glial fibrillary acidic protein in brain cortex and hippocampus, was suggestive of neuroinflammatory responses. Our findings highlight complex interplay between hypertension, metabolism, and neuroinflammation while underscoring the variability in SHRSP models. Key words SHRSP " Neuroinflammation " Oxidative stress " Metabolomics.

High mortality rates among patients with acute respiratory distress syndrome (ARDS) have been linked to pulmonary fibrosis. MicroRNAs exhibit significant potential in modulating pulmonary fibrosis. However, the specific role and underlying mechanisms of miR-93-5p in the context of ARDS-associated pulmonary fibrosis remain largely unexplored. Mitofusin 2 (Mfn2) is a highly conserved transmembrane GTPase. Our previous study demonstrated that the upregulation of Mfn2 can inhibit pulmonary fibrosis in ARDS mice. In this investigation, we identified upstream miRNAs regulating Mfn2 using bioinformatics tools such as TargetScan, miRDB, and microT-CDS. Based on the expression levels of these miRNAs in lung tissue from rats with LPS-induced ARDS, miR-93-5p was selected as the focus of our research. We modulated miR-93-5p expression in ARDS rats via tail vein injection of a miR-93-5p antagomir. Thereafter, we conducted pathological staining and molecular assays to examine the impact of miR-93-5p on pulmonary fibrosis in ARDS rats and to elucidate its potential mechanisms. The results demonstrated that the expression of miR-93-5p was significantly upregulated in the lung tissue of ARDS rats. LPS-induced ARDS rats exhibited severe pulmonary fibrosis, inflammation, and strong endoplasmic reticulum (ER) stress. Furthermore, Mfn2 expression exhibited a negative correlation with miR-93-5p expression. Inhibition of miR-93-5p markedly upregulated Mfn2 expression, attenuated ER stress and lung inflammation, and decreased collagen deposition. In conclusion, the inhibition of miR-93-5p upregulated Mfn2 expression and attenuated ER stress, consequently ameliorating pulmonary fibrosis in ARDS rats. Key words Acute respiratory distress syndrome " miR-93-5p " Pulmonary fibrosis " Endoplasmic reticulum stress " Mitofusin 2.

Promoting angiogenesis to enhance the success rate of parathyroid autotransplantation represents an effective strategy for improving patient outcomes following thyroid surgery. Eyes absent homolog 1 (EYA1) may be modulated by stromal vascular fraction (SVF) and adipose-derived stem cells (ADSCs) to facilitate angiogenesis. Phototherapy, which involves the use of artificial light source irradiation for disease prevention and treatment, has emerged as a promising approach. However, it remains unclear whether ADSCs pretreated with phototherapy can promote angiogenesis in the parathyroid gland through the regulation of EYA1. Primary human ADSCs (hADSCs) were isolated and identified. The impact of various wavelengths of light on the proliferation and secretion of angiogenic factors by hADSCs was assessed using a CCK-8 assay and an ELISA. Subsequently, the influence of light-pretreated hADSCs on HUVEC proliferation, migration, and angiogenesis was evaluated through CCK-8, Transwell, tube formation assays, and ELISA. Finally, qRT-PCR and Western blot analysis were employed to examine the effects of different wavelengths of light on the expression levels of differentiation-related transcription factors in hADSCs, including EYA1. To further elucidate the role of EYA1, an EYA1 interference plasmid (si-EYA1) and its negative control plasmid (si-NC) were transfected into hADSCs to determine whether silencing EYA1 would inhibit the promotion of HUVECs migration and angiogenesis by light-pretreated hADSCs. The results demonstrated that compared with green light (516 nm) and blue light (475 nm), red light (635 nm) irradiation significantly enhanced hADSCs proliferation and the secretion of angiogenic factors. Moreover, light-pretreated (red light) hADSCs markedly promoted HUVECs proliferation, migration, and angiogenesis. Additionally, red light irradiation significantly upregulated the mRNA and protein expression of EYA1, SIX1, TGF-beta1, and Wnt1 while downregulating the mRNA and protein expression of DACH1 in hADSCs. However, silencing EYA1 attenuated the promotive effect of light-pretreated hADSCs on HUVECs migration and angiogenesis. These findings suggest that phototherapy-pretreated hADSCs may enhance HUVECs migration and angiogenesis via the activation of EYA1 and increased secretion of angiogenic factors. Key words Phototherapy " Adipose-derived stem cells " Human umbilical vein endothelial cells " Angiogenesis " Migration " Eyes absent homolog 1.

Sustained poor survival rate in pancreatic ductal adenocarcinoma (PDAC) calls for an earlier diagnosis to assure curative treatment. New powerful biomarkers are necessary because the currently used CA19-9 is not sensitive enough to distinguish PDAC, especially from chronic pancreatitis (CP). Expressions of miRNA-21, -30 -192, -196, -200, and -423 were measured in 77 patients with PDAC, 26 patients with CP and 64 non-cancer/non-CP subjects (39 patients with type 2 diabetes mellitus and 25 control healthy persons). Eleven patients with PDAC had CP at the background. The expressions of all microRNAs were significantly 1.4-3.7 times higher in the PDAC group compared to non-cancer/non-CP subjects and 2.2-6.1 times higher compared to CP patients. No difference in miRNA expressions was found between diabetic and non-diabetic patients. CA19-9 did not distinguish CP from PDAC patients with the history of CP, whereas all six miRNAs were able to do it. Adding miR-196, -200 and -423 to current marker CA19-9 improved sensitivity by 7 % (to 93 %) and specificity by 8 % (to 89 %). MicroRNA-423 could significantly distinguish PDAC from CP with both sensitivity and specificity 96 %. Panel of six miRNAs could be used as reliable marker in differentiating PDAC from chronic pancreatitis with the most impressive difference in miR-196 and miR-423. Key words microRNA " Pancreatic ductal adenocarcinoma " Chronic pancreatitis " Biomarker " CA19-9.

This investigation attempted to discern the causal link of gut microbiota with osteoporosis, examining potential mediating factors, involving inflammatory markers and immune cell activity. Bidirectional two-sample univariable Mendelian randomization (UVMR) was used to decipher the causal link of gut microbiota with osteoporosis, verifying three core assumptions. External datasets were utilized to validate UVMR outcomes and implemented reverse analyses to identify potential reverse causality. Additionally, mediation effects were figured out through UVMR, estimating effect sizes and proportions for every qualifying mediator. It was attempted to precisely select instrumental variables (IVs), ensuring that those influenced by linkage disequilibrium (LD) or demonstrating weak correlations were excluded. The inverse-variance weighted (IVW) analysis unveiled 12 gut microbiota species that were remarkably linked with osteoporosis risk. Specifically, five families, involving Pasteurellaceae, could elevate the risk of osteoporosis, while another five, such as Oxalobacteraceae, were protective. Additionally, two inflammatory markers exhibited a remarkable linkage with osteoporosis following heterogeneity testing, and 37 distinct immune cell types were recognized as being relevant to the disease after adjusting for heterogeneity and pleiotropy. Reverse MR analysis confirmed the absence of reverse causality among gut microbiota, inflammatory factors, immune cells, and osteoporosis. Notably, mediation analysis unveiled that Cyanobacteria influenced HLA DR++ monocytes' percentage in leukocytes, contributing to osteoporosis's pathogenesis. The outcomes highlighted specific gut microbiota, inflammatory factors, and immune cells, noticeably contributing to osteoporosis's pathogenesis. The identified mediating pathways provided innovative insights into disease mechanisms and potential therapeutic targets. Key words Gut Microbiota " Inflammatory cytokines " Immune cell dynamics " Osteoporosis " Mendelian randomization.

We studied the effect of Methylpredisolone (MP) on ischemic brain edema after temporary occlusion of the middle cerebral artery for 90 min (MCAo90). We verified the presence of ischemic edema by determining the brain water content (BWC) by measuring dry/wet weight and by examining MRI - T2-weighted imaging, T2 relaxation times and apparent diffusion coefficient (ADC). In another group, animals were administered MP intraperitoneally 30 min after MCAo90, followed by 24 h reperfusion (MCAoMP). Edema changes were documented by the same MRI examinations. A statistically significant increase in BWC was found between the post-MCAo90 group of animals and the intact animals, demonstrating the presence of edema in the former group. A statistically significant increase in ADC was observed in the MCAo group, indicating the presence of vasogenic edema. A statistically significant difference was demonstrated between the MCAo and MCAoMP groups, with no statistically significant difference between the CG and MCAoMP groups, demonstrating a reduction in ischemic brain swelling after MP administration. The main effect of MP on ischemic brain edema is attributed to its antioxidant capacity. It can be assumed that this capacity of MP, with its complex impact on cellular metabolism, affects the movement of water in the brain and reduces ischemic brain edema. Key words Temporary occlusion of the middle cerebral artery " Brain water content " T2 relaxation " Apparent Diffusion Coefficient " Methylprednisolone.

Gouty arthritis is a type of inflammatory arthritis that is mediated by the deposition of monosodium urate crystals and is an important burden on healthcare worldwide. The aim of this comprehensive review is to discuss the most recent advances regarding the mechanisms of treatment for gout, from classic pharmacological interventions to emerging therapeutic strategies. The chapter dissects the pathophysiology of gout through hyperuricemia, crystal deposition, and inflammatory responses to form a basis for the discussion of current treatment approaches; pharmacological interventions are described-side by side with lifestyle modifications-including NSAIDs, colchicine, and xanthine oxidase inhibitors. Newer approaches to management are discussed, including the use of biologics targeting IL-1beta, newer agents in development, and personalized medicine. It also outlines the future directions in gout research, focusing on the development of novel imaging techniques, biomarkers for treatment response, and targeting novel pathways. This review serves as an overall guide for clinicians and researchers and all other stakeholders interested in further advancing the specialty of gouty arthritis. Key words Gouty arthritis " Serum urate " Hyperuricemia " Crystal deposition " Colchicine.

This study compares the interrelationships among different methods of determining predictive factors of cardiovascular risk: the Night-to-Day ratio (ND-R), Ambulatory Arterial Stiffness Index (AASI), Cardio-Ankle Vascular Index (CAVI), and Ankle-Brachial Index (ABI). A total of 8120 blood pressure measurements were obtained from 280 24h-ABPM records (29 values per daily record) of 20 patients who each provided two 7-day/24-hour monitoring sessions. For each of the two 7-day-24h-ABPM records, the ND-R and AASI were determined. CAVI and ABI were always examined at the beginning of each 7-day-24h-ABPM session. All 20 patients (12 men; 8 women; mean age 57+/-2.1 yrs; mean BMI 29.3+/-1.69 kg/m2; mean left ventricle ejection fraction 53+/-3.8 %) had chronic ischemic coronary artery disease. The correlation coefficients did not exceed 0.318. ND-R of SBP showed the highest methodological sensitivity, identifying 65 % of patients at increased risk, compared to 57.5 % for ND-R of DBP, 23.7 % for CAVI, and 2.5 % for AASI (up to 27.5 % by evaluating individual days). The different cardiovascular risk assessment methods (ND-R, AASI, CAVI and ABI) cannot be substituted for one another. No risk was demonstrated using ABI. Repeating the 7-day-24h-ABPM approximately 1 year apart (unless there is a change in medication or in clinical symptoms) revealed a significantly different results of the ND-R and AASI, which can be expected in approximately 25 % of patients. Key words Ambulatory blood pressure monitoring " Night-to-Day blood pressure ratio " Ambulatory Arterial Stiffness Index " Cardio-Ankle Vascular Index " Ankle Brachial Index " Ischemic heart disease.

Cardiac troponins are indispensable biomarkers for the diagnosis of acute myocardial infarction, but false-positive elevations that contradict the clinical picture remain a significant challenge in laboratory medicine. Analytical interferences may arise from macrotroponins, heterophile or anti-troponin antibodies, and the limited cardiac specificity of high-sensitivity troponin T (hs-cTnT) in skeletal muscle disease. Recent studies show that hs-cTnT is elevated in up to two-thirds of patients with myopathies, while high-sensitivity troponin I (hs-cTnI) is largely unaffected, underscoring the diagnostic advantage of hs-cTnI in this setting. A pragmatic diagnostic approach should combine clinical plausibility with stepwise laboratory testing. First, preanalytical factors such as sample mislabeling, fibrin clots, or hemolysis must be excluded and the measurement repeated. If the results remain incongruent, an alternative assay - ideally hs-cTnI - should be performed. Further evaluation may include heterophile-blocking reagents, polyethylene glycol precipitation to screen for macro-analytes, and, where available, confirmatory techniques such as gel filtration chromatography or immunoglobulin depletion (protein A/G). Although these strategies can help identify assay interference, there is no universally accepted gold standard. Awareness of false-positive elevations, careful interpretation of discordant troponin results, and effective collaboration between laboratories and clinicians are essential to prevent misdiagnosis and unnecessary interventions. Clear documentation of confirmed interferences further ensures safe patient management and provides guidance on which assays are reliable for future tests. Key words Cardiac troponin " Skeletal muscle disease " False-positive results " Analytical interference " Macrotroponin " Laboratory diagnostics.

The Social Brain is a distributed network of neuroanatomical regions and neurochemical systems that underpins the human capacity for social cognition, empathy, and interpersonal behavior. Social isolation (SI), defined as the objective reduction in social interaction, poses a significant threat to the integrity of this system. In this review, we synthesize evidence from human and animal studies to elucidate the biological, cognitive, and behavioral consequences of SI on the social brain. We describe how SI acts as a chronic stressor, disrupting structural connectivity, and altering neurotransmitter systems critical for social cognition. These disruptions manifest in altered social behavior, mentalization processes, and emotional reactivity, significantly contributing to increased vulnerability to psychiatric and neurodegenerative disorders, including depression, schizophrenia, substance use disorders, and Alzheimer's disease. Converging findings from studies of evolutionarily conserved mechanisms in rodent and primate models demonstrate that SI compromises neurodevelopment, attenuates neuroplasticity, and triggers maladaptive stress responses, highlighting that social deprivation has profound neurobiological and behavioral consequences that greatly overlap with the pathophysiological changes seen in neuropsychiatric disorders. Furthermore, we explore the role of indirect stressors resulting from SI such as touch deprivation and digital-era social disconnection as contemporary amplifiers of SI's neurobiological impact. In light of public health challenges such as the COVID-19 pandemic, we propose that SI should be recognized not only as a psychosocial condition but as a modifiable risk factor with transdiagnostic significance across psychiatry, neurology, and preventive medicine. Addressing SI through targeted interventions and policy measures is essential for promoting mental resilience and well-being. Key words Chronic Stress " Loneliness " Social Cognition " Socialization " Social Stress.

This study aimed to examine the protective and antioxidant properties of a Teucrium polium leaf extract against acute kidney damage caused by nicotine in male mice. A total of 24 male Swiss albino mice were divided into four groups. The control group (oral solution of 0.9 % NaCl), the positive control group (injections of nicotine at a dosage of 2.5 mg/kg b.w.), the third group (received 100 mg/kg b.w. ethanolic extract of T. polium), and the fourth group (nicotine injections at a dosage of 2.5 mg/kg b.w + 100 mg/kg b.w. ethanolic extract of T. polium). GC-MS analysis of the plant extract revealed the presence of 16 active compounds. Nicotine administration resulted in a significant increase in kidney biomarkers, namely urea, uric acid, and creatinine, by 50 %, 207 %, and 129 %, respectively, compared to the control group, indicating nephrotoxicity. However, treatment with the T. polium extract improved these parameters by 77 %, 79 %, and 83 %, respectively. Furthermore, the nicotine group exhibited elevated levels of nitric oxide (NO) and malondialdehyde (MDA), which are indicators of oxidative stress, as well as decreased levels of glutathione (GSH) and reduced activity of superoxide dismutase (SOD). Conversely, the administration of the T. polium extract reversed these effects, suggesting its potential to enhance the antioxidant defense system. This finding was also supported by the improvements observed in the kidney TUNEL assay sections and the preservation of histopathological integrity. In conclusion, the T. polium extract demonstrates protective effects against nicotine-induced kidney damage by modulating oxidative stress and antioxidant defense mechanisms.

MiR-9-5p is up-regulated in lupus nephritis (LN) patients and targets Foxo1 that is a protective factor against renal disorders. In the current study, the role of miR-9-5p/Foxo1 LN progression was assessed and the associated mechanism was explored. The levels of LN-associated miRs were firstly detected in MRL/lpr mice. Then the effect of miR-9-5p modulation on the viability of SV40 MES 13 cells was detected. MRL/lpr mice were treated with miR agomirs or antagonists, and effects on renal structure and function were assessed. MiR-9-5p was selected as the potential target, which was up-regulated in MRL/lpr mice, contributing to the suppressed expression of Foxo1. The modulation of miR-9-5p in vitro influenced the viability of SV40 MES 13 cells. The progression of LN in mice was also associated with the increased level of miR-9-5p and the decreased level of Foxo1. The administration of miR agomirs significantly impaired renal structure and function impairments associated with LN, along with the suppressed expression of Foxo1, while antagonists improved these features by up-regulating Foxo1 level. The current study demonstrated that miR-9-5p showed LN promoting effects, which depended on the inhibition of Foxo1.

Short bowel syndrome (SBS) is an intestinal disorder characterized by reduced length of the gut most due to intestinal resection, resulting in malabsorption, malnutrition, and water and electrolyte disturbances. Intestinal adaptation is a long-term process in which GIT hormones, growth peptides, cytokines etc. are involved. These mechanisms have not been fully clarified yet. The most important seem to be GLP-2 and other gut hormones. The aim of our study was to consider the changes of the levels of selected gut hormones and parameters of glucose homeostasis during the mixed liquid meal test in one year of follow up after the gut resection. Seventeen patients with SBS type I were included into our study. The meal test and measuring of selected parameters (GLP-2, GLP-1, ghrelin, insulin, glucagon, GIP, amylin) were conducted after 2 weeks, 6 and 12 months from its initiation, respectively. During one year of this study patients´ nutritional status improved due to sufficient parenteral nutrition, despite no change in body weight. Hormones possibly involved in intestinal adaptation (GLP-2, GLP-1, ghrelin) did not differ in meal test, neither levels nor AUC. Only higher insulin and glucose levels after one year of follow-up may indicate the beginning of intestinal adaptation process and improving intestinal functions. We conclude that impaired GLP-2 secretion is probably the main reason for the limited adaptation ability in patients with SBS type I.

Astaxanthin is a natural, small-molecule compound with anti-inflammatory and antioxidant properties that has broad potential for use in alleviating exercise fatigue. This study investigated whether astaxanthin can attenuate the onset of fatigue, prolong the time to exhaustion, and enhance post-exercise recovery using a rat model of chronic exercise fatigue. Twenty male rats were trained for 8 weeks to establish the chronic exercise fatigue model. During training, 10 rats were randomly assigned to receive astaxanthin intragastrically and 10 rats received soybean oil alone. After the intervention, 5 rats from each group were divided into astaxanthin (AX) and control groups. The remaining rats were divided into astaxanthin-exercise (AXE) and exercise control groups, respectively, and underwent exhaustive exercise. Astaxanthin alleviated chronic exercise fatigue by improving antioxidant capacity (^CAT, GSH-Px, GSH/GSSG; p<0.05-0.01) and mitochondrial function (^MMP, ST3/ST4; p<0.01-0.001). It prolonged exercise endurance (^time to exhaustion; p<0.001), reduced muscle damage (ˇBUN, CK; p<0.01) and accelerated recovery (^Liver glycogen, NEFA; p<0.001). Astaxanthin appears to improve skeletal muscle antioxidant capacity and mitochondrial function in chronic exercise fatigue in rats, providing a theoretical basis for fatigue management in exercise training.

Variation in response to clopidogrel represents a significant clinical challenge in patients with ischemic stroke. Genetic polymorphisms cytochrome P450 2C19 (CYP2C19) are a known cause of resistance to clopidogrel. Platelet microRNAs (miRNAs) can modulate the efficacy of antiplatelet therapy. This study focuses solely on clopidogrel because it is the most widely used alternative to aspirin in patients with aspirin intolerance or contraindications. Our aim was to investigate its pharmacogenomic and epigenetic modulation in a targeted and homogeneous cohort. CYP2C19 genotypes are commonly reported as *1/*1 (wild type), *1/*2 (intermediate metabolizer), *2/*2 (poor metabolizer) and *2/*3 (poor metabolizer). These denote the number and type of loss-of-function alleles that affect clopidogrel metabolism. Clopidogrel treatment is typically a component of broader secondary prevention strategies, including lifestyle modifications, statins, and control of blood pressure. Relevant bibliographic references have been added to support the background statements provided in the introduction and methodology. To evaluate the expression of selected platelet miRNAs (miR-126-3p, miR-19a-3p, miR-19b-3p, miR-22-3p, miR-185-5p) in patients with ischemic stroke in relation to the CYP2C19 genotype (*1/*1 ,*1/*2, *2/*2) during clopidogrel treatment. Seventy patients treated with clopidogrel (75 mg daily) were enrolled. Patients were genotyped for the CYP2C19 *2 and *3 alleles by real-time polymerase chain reaction (polymerase chain reaction (PCR)) and miRNA expression was measured in plasma. All abbreviations used throughout the manuscript have been defined at their first appearance for the sake of clarity. No significant differences in miRNA expression were found between the genotypic groups (p > 0.05). Patients with genotype *2/*2 (poor metabolizer) showed a trend towards higher levels of miR-126-3p and miR-185-5p (approximately 1.5 to 1.7 times) compared to *1/*1 (wild type). The clinical parameters did not differ significantly between the groups. Poor clopidogrel metabolizers can exhibit upregulation of some platelet miRNAs as a potential compensatory mechanism. This pilot study suggests a possible epigenetic modulation of the response to antiplatelet therapy through platelet miRNAs.

Paclitaxel (PTX), a commonly used chemotherapeutic, frequently leads to chemotherapy-induced peripheral neuropathy (CIPN), characterized by persistent pain and neuronal hypersensitivity. While its effects on peripheral nerves are well-documented, paclitaxel also influences central nervous system pathways, particularly spinal synaptic transmission, through Toll-like receptor 4 (TLR4) activation and subsequent sensitization of transient receptor potential vanilloid 1 (TRPV1) receptors. In this study, we used an in vitro model of paclitaxel-induced neuropathic pain to investigate the role of glial activation in TRPV1 receptor function. Using whole-cell patch-clamp recordings from superficial dorsal horn neurons in acute spinal cord slices, we evaluated the effects of minocycline (MX), a glial cell inhibitor, and ISO-1, a macrophage migration inhibitory factor (MIF) antagonist, on paclitaxel-induced synaptic changes. Our results demonstrate that acute paclitaxel application enhances nociceptive signaling and impairs capsaicin-induced TRPV1 receptor tachyphylaxis, leading to sustained hyperactivity. Minocycline preincubation effectively mitigated paclitaxel-induced sensitization, restoring normal nociceptive signaling, whereas acute minocycline treatment failed to prevent these changes. ISO-1 in vitro co-incubation with paclitaxel did not affect the paclitaxel-induced changes. These findings offer novel insight into the intricate interactions among neuroinflammatory mediators, glial cell activation, and TRPV1 receptor sensitization in paclitaxel-induced neuropathic pain. The differential effects of acute versus prolonged pre-incubation minocycline application suggest the importance of sustained glial inhibition for effective outcomes and neuropathic pain management.