Pathophysiology

Background: A dysregulated proinflammatory microenvironment is considered one of the reasons why current therapies of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) do not secure disease control. Therefore, the development of BCR-ABL1-independent therapies is encouraged. Renalase (RNLS) is a multifunctional protein that exhibits both enzymatic and non-enzymatic cytokine-like properties, along with potent anti-inflammatory and anti-apoptotic effects. It is expressed in various tissues, including tumors. Methods: We investigated the levels of RNLS in the blood of CML patients in the chronic phase, treatment naïve patients, and those in remission under TKI treatment (either imatinib or nilotinib) and compared them to healthy individuals. Results: Renalase concentration was markedly decreased in treatment-naive CML patients compared to other groups (p = 0.000), while lower levels in the TKI group were not statistically significant compared to controls. The levels correlated negatively with the total leukocyte and neutrophil count (p < 0.05), while a positive correlation was present with CRP levels in treatment naïve patients. Conclusions: Dynamic regulation of RNLS expression and activity is coupled with transcription factors NF-κB and STAT3. Interpretation of our results might rely on differential requirements of activated STATs (STAT3/5) during CML clone development and maintenance, including the observation of RNLS rise upon TKI introduction. Overall, our research provides new insights into the field of hematological malignancies. Unlike other malignancies studied, RNLS plasma levels are significantly decreased in CML. In future perspectives, RNLS could potentially serve as a diagnostic, prognostic, or therapeutic option for these patients. Full article

Chronic Kidney Disease of Unknown Etiology (CKDu) is a worldwide hidden health threat that is associated with progressive loss of kidney functions without showing any initial symptoms until reaching end-stage renal failure, eventually leading to death. It is a growing health problem in Asia, Central America, Africa, and the Middle East, with identified hotspots. CKDu disease mainly affects young men in rural farming communities, while its etiology is not related to hypertension, kidney stones, diabetes, or other known causes. The main suspected causal factors are heat-stress, dehydration, exposure to agrochemicals, heavy metals and use of hard water, infections, mycotoxins, nephrotoxic agents, altitude, and genetic factors. This review gives an overview of CKDu and sheds light on its medical history, geographic distribution, and worldwide prevalence. It also summarizes the suspected causal factors, their proposed mechanisms of action, as well as the main methods used in the CKDu prior detection and surveillance. In addition, mitigation measures to reduce the burden of CKDu are also discussed. Further investigation utilizing more robust study designs would provide a better understanding of the risk factors linked to CKDu and their comparison between affected regions. Full article

Post-Traumatic Stress Disorder (PTSD) is a multifaceted psychiatric disorder triggered by traumatic events, leading to prolonged psychological distress and varied symptoms. Rat models have been extensively used to explore the biological, behavioral, and neurochemical underpinnings of PTSD. This review critically examines the strengths and limitations of commonly used rat models, such as single prolonged stress (SPS), stress–re-stress (S-R), and predator-based paradigms, in replicating human PTSD pathology. While these models provide valuable insights into neuroendocrine responses, genetic predispositions, and potential therapeutic targets, they face challenges in capturing the full complexity of PTSD, particularly in terms of ethological relevance and translational validity. We assess the degree to which these models mimic the neurobiological and behavioral aspects of human PTSD, highlighting areas where they succeed and where they fall short. This review also discusses future directions in refining these models to improve their utility for translational research, aiming to bridge the gap between preclinical findings and clinical applications. Full article

Histomorphometric measurements of the wall thickness and internal diameter of the macrovessels of the chorionic villi of placentas from pregnancies complicated by preeclampsia or fetal growth restriction in comparison with normotensive pregnancy. Methods: The research included placentas from singleton pregnancies complicated by preeclampsia and/or fetal growth restriction, women delivered in medical institutions in Karaganda city (Kazakhstan). Placentas were divided into three groups: PE (n = 59), isolated FGR (n = 24), and PE with FGR (n = 41). The control group consisted of normotensive pregnancies, compared by gestation period. Placental examination and selection of placental tissue fragments were carried out in accordance with the consensus recommendations of the Amsterdam Placental Workshop Group. The sections were stained with hematoxylin and eosin and Masson trichrome. Morphometric measurements were performed using ImageJ software version 1.52p. Results: Our data showed that, in the PE group, there was a significant decrease in the wall thickness of the proximal and distal vessels with an increase in internal diameter compared with the control group (p < 0.01). In the PE + FGR group, there was a thickening of the wall of the proximal part of the vessels with a decrease in their lumen and a decrease in the wall thickness of the vessels with an increase in the lumen in the distal part compared with the control group (p < 0.01). Conclusions: Two histopatterns of placental macrovessels in preeclampsia were revealed: the histophenotype of diffuse (proximal and distal) ectatic macroangiopathy with a thin vascular wall with a decrease in the thickness of the muscle layer and the histophenotype of proximal fibromuscular sclerosis with vascular obliteration/spasm and distal ectatic macroangiopathy. We believe that significant structural differences in vascular remodeling may reflect the different temporal and spatial nature of the pathological factor. Future research is needed to investigate the associations between histopatterns of placental vascular remodeling in preeclampsia and long-term perinatal/maternal outcomes. Full article

Aim: To investigate the anti-inflammatory, antioxidant, and diabetic wound healing properties of the novel topical formulation [Ferulic acid-loaded nanoemulgel (DLMGO-G)]. Methods: Ferulic acid nanoemulsion developed with lemongrass oil is investigated in diabetic wound healing. Further nanoemulsion is incorporated into 1% carbopol^® 934 to obtain the DLMGO-G. Nanoemulsion was characterized for particle size, and polydispersity index (PDI) was obtained by Malvern Zetasizer (Zetasizer Nano ZS, Malvern, AL, USA), and morphology by TEM (JEM 1400, JOEL, Akishima, Japan). Furthermore, in vitro cell line and in vivo studies were carried out. Results: The developed nanoemulsion showed a globule size of 28.04 ± 0.23 nm and PDI of 0.07 ± 0.01. The morphology of nanoformulations by TEM confirmed the spherical and uniform nature. Further, the nanoformulation in in vitro cell line experiments revealed that the IC50 value was increased by 1.52 times compared to the drug solution. The treatment groups have shown that fibroblast morphologies were spindle-shaped, suggesting that nanoformulation was compatible with the cells and developed normally on nanoformulation. It also reduced ROS with improved internalization more than the control group. The in vitro wound healing model also revealed that nanoformulation had better wound healing activity. In the in vivo diabetic wound studies on male SD rats, the levels of inflammatory markers such as TNF-α, IL-6, IL-22, and IL-1β declined significantly when treated with DLMGO-G. IL-10 levels significantly increased compared to the diseased group, and MMP-9 levels were remarkably decreased compared to the diseased group. Furthermore, histopathological studies showed the regeneration and granulation of tissues. Conclusions: Thus, these findings indicate that FA-loaded nanoemulgel greatly accelerates the healing of wounds in diabetic rats. Full article

Background/Objectives: Vitamin D (VD) deficiency has been associated with increased risk of gestational disorders affecting the endocrine system, immune system, and neurodevelopment in offspring. Recent studies have focused on the interaction between toxic elements and micronutrients during pregnancy. This review analyzes the potential relationships between VD levels and heavy metals in pregnant women and their offspring. Methods: A systematic review was conducted according to PRISMA 2020 guidelines, using databases such as PubMed, ScienceDirect, Cochrane Library, and Google Scholar. Boolean operators ‘AND’ and ‘OR’ were applied with terms like ‘pregnancy’, ‘vitamin D’, ‘heavy metals’, and ‘newborns’. Results: From 4688 articles, 14 studies were selected based on relevance and quality. These studies measured the levels of metals like lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As), in biological samples including maternal blood, umbilical cord blood, placenta tissue, and meconium during different stages of pregnancy, showing an inverse relationship between VD deficiency and heavy metal concentrations, which could be related to the incidence of preterm birth. Conclusions: The review highlights the importance of maintaining adequate VD levels during pregnancy, suggesting that sufficient VD may mitigate the adverse effects of heavy metal exposure, potentially reducing pregnancy-related complications. Full article

Background/Objectives: Alzheimer’s disease (AD) remains incurable, highlighting the need for new and diverse animal models to better understand its complex mechanisms. This study compares various injected animal models of AD, focusing on the main theories that explain the disease; Methods: Female Wistar rats (10-months old) were administered intracebroventricularly by artificial cerebrospinal fluid (aCSF) (Control), beta amyloid Aβ1-42 (BA), okadaic acid (OKA), lipopolysaccharides (LPS), buthionine sulfoximine (BSO) or by a mixture of these different molecules (MLG). Cognitive performance was assessed one week or one month after stereotaxic surgery; Results: Our results, show that only the Aβ and the MLG induced a persistence and progressive deficits in the working memory, recognition memory and spatial memory in rats. As the hippocampus (HIP) and the prefrontal cortex (PFC) are particularly involved in memory behavior, we analyzed long-term neuroadaptations in these brain subregions using spectrophotometric and histological methods to assess oxidative stress changes and neuronal loss, respectively. We found that the behavioral impairments in memory and learning were accompanied by irreversible oxidative stress changes and neurodegenerescence, particularly in the HIP; Conclusions: This study provides promising data on the modeling of AD in order to develop an effective therapeutic approach. Full article

Introduction: Our objective in this article was to develop a predictive model for obesity in the third trimester of pregnancy using the plasma and clinical biomarkers that are managed within the Chromosomopathies Programme in the Andalusian Public Healthcare System. Methods: The epidemiological design was observational, of the unmatched case–control type. The geographical environment was the Seville Primary Healthcare District (DSAP Sevilla). The information was collected between 2011 and 2021. The reference cohort consisted of women who had carried a pregnancy to term. The variables and biomarkers studied correspond to those managed within the primary-care Pregnancy Integrated Care Pathway (ICP). Unconditional binary logistic regression (BLR) models were created, with the outcome variable being whether or not the women were obese in their third trimester of pregnancy. Results: A total of 423 controls and 104 cases of obesity were obtained for women in their third trimester who had not been obese in their first trimester. The average age for the sample group (P50) was 34 years old. The final, most parsimonious model included the variables PAPP-A (p = 0.074), beta-hCG (p = 0.1631), and systolic blood pressure (SBP) (p = 0.085). ROC curve = 0.75 (C.I. at 95%: 0.63–0.86). Discussion: The results of this research can only be extrapolated to primary care and to pregnancies with no complications. PAPP-A has been shown in our research to be a significant predictor of obesity risk in the third trimester of pregnancies with no complications (OR = 0.53; C.I. at 95%: 0.39–0.66; p = 0.04 in the single-variant study; OR = 0.58; C.I. at 95%: 0.29–0.93; p = 0.074 in the multi-variant analysis). This predictive capacity is further enhanced from an operational perspective by beta-hCG and 12-week SBP. Full article

Critical illness (CI) triggers complex disruptions in the growth hormone (GH)/insulin-like growth factor (IGF) axis, significantly affecting the dynamics of insulin-like growth-factor-binding proteins (IGFBPs). Among these, IGFBP-2 shows a sustained elevation during CI, which inversely correlates with serum levels of IGF-1, IGFBP-3, and the acid-labile subunit (ALS). Although IGFBP-2 does not directly interact with ALS, it may influence the availability of IGFs by competing with other IGFBPs for binding to IGF-1 and IGF-2. Research suggests that this persistent elevation of IGFBP-2 is largely driven by cytokine activity during CI, reflecting an adaptive response rather than a direct result of GH/IGF axis dysregulation. The clinical importance of IGFBP-2 is emphasized by its correlation with disease severity in conditions like sepsis and coronavirus disease 2019 (COVID-19), where its levels are markedly elevated compared to healthy controls and are similar to those observed in sepsis from various causes. Beyond its role in endocrine regulation, IGFBP-2 appears to play a part in metabolic and inflammatory pathways. Elevated IGFBP-2 levels have been linked to increased mortality and longer hospital stays, indicating its potential utility as a prognostic marker. Furthermore, measuring plasma IGFBP-2 may have other diagnostic applications, aiding in the assessment of CI when traditional biomarkers are inconclusive. Full article

Background: Thrombophilia, a predisposition to develop blood clots, is very common and can have serious sequelae. Aim: This study aimed to determine the prevalence of three thrombophilia-related genetic variants—factor V Leiden (FVL), prothrombin (F2) G20210A, and MTHFR C677T—in the Qatari population and their associations with self-reported thrombosis. Methods: We analysed samples from 408 Qatari participants [304 controls and 104 with self-reported thrombosis (deep vein thrombosis, pulmonary embolus, or ischaemic stroke)] from the Qatar Biobank. FVL (rs6025), F2 (rs1799963), and MTHFR (rs1801133) variants were genotyped using TaqMan assays. Results: Participants with self-reported thrombosis were older and more likely to be female. FVL A allele carriage (GA + AA vs. GG) was significantly higher in thrombosis cases (OR 3.6, p = 0.0002). In addition, individuals carrying FVL AA and GA genotypes had a lower mean platelet volume on average than those with the GG genotype (p = 0.03). MTHFR C677T did not show a similar association, and the F2 G20210A variant was too rare for analysis. Conclusions: There were significant differences in FVL A allele carriage between individuals with a history of thrombosis and the control group. Future research should explore the complex interplay between genetics and environment in thrombosis risk within this population. Full article

Angiogenesis is a process involved in the formation of new blood capillaries from pre-existing ones. It is regulated by several anti-angiogenic molecules involved in tumor growth and metastasis. The endothelial angiopoietin Ang-Tie/PI3K/AKT growth receptor pathway is necessary for healthy vascular development. The activation of AKT is controlled by a multistep process involving phosphoinositide 3-kinase (PI3K). This article aims to provide an overview of the role and mechanism of the Ang-Tie/PI3K/AKT signaling pathways and the potential of flavonoids as anti-angiogenic drugs. Flavonoids have shown great potential in preventing angiogenesis by targeting signaling pathways and exhibit additional anti-cancer properties. Research studies have revealed that the currently available anti-angiogenic drugs do not meet the safety and efficacy standards for treating tumor growth. Phytocompounds have long been a valuable resource for the development of novel therapeutic drugs. This article explores recent findings explaining the role and mechanism of the Ang-Tie/PI3K/AKT signaling pathways, as well as the interaction of flavonoids with angiogenic signaling pathways as a novel therapeutic approach. Several investigations have shown that synergistic studies of natural phytocompounds have great potential to target these pathways to inhibit tumor growth. Therefore, flavonoid-based medications may offer a more effective synergistic strategy to treat cancer. Full article

Manual ventilation, most commonly with a bag-valve mask, is a form of short-term ventilation used during resuscitative efforts in emergent and out-of-hospital scenarios. However, compared to mechanical ventilation, manual ventilation is an operator-dependent skill that is less well controlled and is highly subject to providing inappropriate ventilation to the patient. This article first reviews recent manual ventilation guidelines set forth by the American Heart Association and European Resuscitation Council for providing appropriate manual ventilation parameters (e.g., tidal volume and respiratory rate) in different patient populations in the setting of cardiopulmonary resuscitation. There is then a brief review of clinical and manikin-based studies that demonstrate healthcare providers routinely hyperventilate patients during manual ventilation, particularly in emergent scenarios. A discussion of the possible mechanisms of injury that can occur during inappropriate manual hyperventilation follows, including adverse hemodynamic alterations and lung injury such as acute barotrauma, gastric regurgitation and aspiration, and the possibility of a subacute, inflammatory-driven lung injury. Together, these injurious processes are described as manual-ventilation-induced lung injury (MVILI). This review concludes with a discussion that highlights recent progress in techniques and technologies for minimizing manual hyperventilation and MVILI, with a particular emphasis on tidal-volume feedback devices. Full article

Polycystic ovary syndrome (PCOS) is the most common complex endocrinological condition of women that is associated with infertility and metabolic disorders during the reproductive period. Recently, a great deal of research has focused on the etiopathogenesis of this disorder and the modulation of therapeutic approaches. There are still many controversies in the choice of therapy, and metformin is one of the most commonly used agents in the treatment of PCOS. Considering the link between metabolic disorders and PCOS, glycemic status is crucial in these patients, and sodium-glucose cotransporter type 2 inhibitors (SGLT2is) represent a potentially promising new therapeutic approach. These drugs have been shown to improve glucose metabolism, reduce adipose tissue, decrease oxidative stress, and protect the cardiovascular system. These data prompted us to investigate the effects of empagliflozin (EMPA) in a PCOS rat model and compare them with the effects of metformin. We confirmed that EMPA positively affects somatometric parameters, glucose and lipid metabolism, and the levels of sex hormones, as well as reduces oxidative stress and improves ovarian function and morphology. Administration of EMPA at doses of 5 mg/kg, 15 mg/kg, and 45 mg/kg during a 4-week treatment period improved, as induced by estradiol valerate and a high-fat diet, the metabolic and reproductive statuses in a PCOS rat model. The best effects, which were comparable to the effects of metformin, were achieved in groups receiving the middle and highest applied doses of EMPA. These results may prompt further clinical research on the use of EMPA in patients with PCOS. Full article

One of the hallmarks of Alzheimer’s disease (AD) is the deposition of amyloid-β (Aβ) within the extracellular spaces of the brain as plaques and along the blood vessels in the brain, a condition also known as cerebral amyloid angiopathy (CAA). Clusterin (CLU), or apolipoprotein J (APOJ), is a multifunctional glycoprotein that has a role in many physiological and neurological conditions, including AD. The apolipoprotein E (APOE) is a significant genetic factor in AD, and while the primary physiological role of APOE in the brain and peripheral tissues is to regulate lipid transport, it also participates in various other biological processes, having three basic human forms: APOE2, APOE3, and APOE4. Notably, the APOE4 allele substantially increases the risk of developing late-onset AD. The main purpose of this review is to examine the roles of CLU and APOE in AD pathogenesis in order to acquire a better understanding of AD pathogenesis from which to develop targeted therapeutic approaches. Full article

Early changes in lung tissue following ionizing radiation (IR) initiate processes that may lead to either regeneration or fibrosis. Intercellular junction proteins play a crucial role in the organization and function of epithelial tissues, both under normal conditions and after injuries. Alterations in the expression and localization of these proteins can influence the fate of epithelial cells. This study aims to investigate the effects of IR on lung tissue structure, as well as on the levels and distribution of intercellular junction proteins. Wistar rats were subjected to total X-ray irradiation at doses of 2 and 10 Gy. Lung tissue samples were collected for Western blot and histological analysis 72 h post-IR. IR at doses of 2 and 10 Gy led to structural changes in lung tissue and elevated levels of E-cadherin. The 10 Gy IR resulted in increased claudin-4 and occludin in lung parenchyma, decreased claudin-8 and claudin-12 in bronchial epithelium and endothelium, and suppression of apoptosis. Data evaluation indicated that alterations in the protein composition of intercellular junctions are essential processes in lung tissue at early stages after IR, and at least some of these alterations are associated with adaptation. Full article

Elevated levels of Inter-alpha-trypsin-inhibitor heavy chain 4 (ITIH4) have grabbed attention in rheumatoid arthritis (RA) pathogenesis, though its precise mechanisms remain unexplored. To elucidate these mechanisms, a comprehensive strategy employing network pharmacology and molecular docking was utilized. RA targets were sourced from the DisGeNET Database while interacting targets of ITIH4 were retrieved from the STRING and Literature databases. Venny 2.1 was used to identify overlapping genes, followed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) through Cytoscape 3.10.2 software, and molecular docking was performed in the ClusPro server. The study identified 18 interacting proteins of ITIH4 associated with RA, demonstrating their major involvement in the chemokine signaling pathway by enrichment analysis. Molecular docking of ITIH4 with the 18 proteins revealed that C-X-C chemokine-receptor type 4 (CXCR4), a major protein associated with chemokine signaling, has the highest binding affinity with ITIH4 with energy −1705.7 kcal/mol forming 3 Hydrogen bonds in the active site pocket of ITIH4 with His441, Arg288, Asp443 amino acids. The effect of ITIH4 on CXCR4 was analyzed via knockdown studies in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), demonstrating the significant downregulation of CXCR4 protein expression validated by Western blot in RA-FLS. In conclusion, it was speculated that CXCR4 might serve as a potential receptor for ITIH4 to activate the chemokine signaling, exacerbating RA pathogenesis. Full article

Background: The pathophysiological mechanism underlying pregnancy complications is not entirely known. Although it is currently impossible to predict the occurrence of redox imbalance, it is possible to identify women with a high or medium risk of developing this disease prior to a negative outcome by non-invasive diagnostic methods. The Aim: This study aimed to examine the possible role of the parameter of oxidative stress (OS) measured in early pregnancy in the screening/treatment of obesity and its complications during pregnancy. Methods: This research was designed as a prospective observational cross-sectional clinical study which included 40 non-obese and 31 obese pregnant women between 11 and 13 g.w. who were managed in the Department of Obstetrics, University Clinical Center Kragujevac in Serbia. We collected anthropometric and clinical indicators, maternal and pregnancy factors, and measured prooxidative parameters from blood samples. Results: We observed significantly increased levels of the superoxide anion radical, hydrogen peroxide and the index of lipid peroxidation in the Obese group in comparison with the Non-Obese group and significantly decreased bioavailability of nitrites in the Obese group in comparison with the Non-Obese group. Conclusions: The determination of systemic parameters of OS in early pregnancy could be a good methodological approach in the screening/treatment of obesity during pregnancy and this approach should be followed for the screening of endothelial dysfunction in pregnancy which needs further monitoring and/or treatment. Full article

High systolic blood pressure and increased blood pressure variability after the onset of ischemic stroke are associated with poor clinical outcomes. One of the key determinants of blood pressure is arteriolar size, determined by vascular smooth muscle tone and vasodilatory and vasoconstrictor substances that are released by the endothelium. The aim of this study is to outline alterations in vasomotor function in isolated peripheral arteries following ischemic stroke. The reactivity of thoracic aortic segments from male C57BL/6 mice to dilators and constrictors was quantified using wire myography. Acetylcholine-induced endothelium-dependent vasodilation was impaired after ischemic stroke (LogIC50 Sham = −7.499, LogIC50 Stroke = −7.350, p = 0.0132, n = 19, 31 respectively). The vasodilatory responses to SNP were identical in the isolated aortas in the sham and stroke groups. Phenylephrine-induced vasoconstriction was impaired in the aortas isolated from the stroke animals in comparison to their sham treatment counterparts (Sham LogEC50= −6.652 vs. Stroke LogEC50 = −6.475, p < 0.001). Our study demonstrates that 24 h post-ischemic stroke, peripheral vascular responses are impaired in remote arteries. The aortas from the stroke animals exhibited reduced vasoconstrictor and endothelium-dependent vasodilator responses, while the endothelium-independent vasodilatory responses were preserved. Since both the vasodilatory and vasoconstrictor responses of peripheral arteries are impaired following ischemic stroke, our findings might explain increased blood pressure variability following ischemic stroke. Full article

Cathepsin S (CatS) is a proteolytic enzyme and a member of the cysteine protease family of proteolytic enzymes. Cathepsins S, K, and L are particularly similar in terms of their amino acid sequences and interactions with substrates, and this has made it difficult to develop inhibitors with specificity for either CatS, CatK, or CatL. The involvement of CatS in various disease pathophysiologies (autoimmune disorders, cardiovascular diseases, cancer, etc.) has made it a very important target in drug development. Efforts have been made since the early 1990s to develop a specific CatS inhibitor without any major success. Following many failed efforts to develop an inhibitor for CatS, it was discovered that interactions with the amino acid residues at the S2 and S3 pockets of CatS are critical for the identification of CatS-specific inhibitors. Amino acid residues at these pockets have been the target of recent research focused on developing a non-covalent, reversible, and specific CatS inhibitor. Methods applied in the identification of CatS inhibitors include molecular modeling, in-vitro screening, and in-vivo studies. The molecular modeling process has proven to be very successful in the identification of CatS-specific inhibitors, with R05459072 (Hoffmann-La Roche) and LY3000328 (Eli Lilly Company) which has completed phase 1 clinical trials. CatS inhibitors identified from 2011 to 2023 with promising prospects are discussed in this article. Full article