Pathophysiology, Volume 31, Issue 1 (March 2024) – 13 articles

To molecularly characterize the impact of exercise on mitigating neoadjuvant treatment (NAT)-induced physical decline in pancreatic ductal adenocarcinoma (PDAC) patients, a multi-omics approach was employed for the analysis of plasma samples before and after a personalized exercise intervention. Consisting of personalized aerobic and resistance exercises, this intervention was associated with significant molecular changes that correlated with improvements in lean mass, appendicular skeletal muscle index (ASMI), and performance in the 400-m walk test (MWT) and sit-to-stand test. These alterations indicated exercise-induced modulation of inflammation and mitochondrial function markers. This case study provides proof-of-principal application for multiomics-based assessments of supervised exercise, thereby supporting this intervention as a feasible and beneficial intervention for PDAC patients to potentially enhance treatment response and patient quality of life. The molecular changes observed here underscore the importance of physical activity in cancer treatment protocols, advocating for the development of accessible multiomics-guided exercise programs for cancer patients. Full article

Opioid abuse in the United States has been increasing at an alarming rate over the past 20 years. Sex differences are documented for the rates of opioid-related overdoses, abuse patterns, and drug-induced physiological effects. In our previous study, we demonstrated that chronic oxycodone administration in young female rats is associated with neurodegeneration in the brain. Males and females are susceptible to neurodegenerative diseases via differing mechanisms. To investigate whether opioid exposure affects males and females differently, we treated young mice with chronic morphine. We observed that females had stronger antinociceptive responses to acute morphine and showed a delayed development of tolerance. Males had a higher basal Bax level in the brain that correlated with a higher number of apoptotic cells. Morphine increased Bax levels in both males and females without affecting the numbers of apoptotic cells. Morphine increased activated caspase 3 in axons and increased the MBP level in plasma only in females, suggesting a demyelination process. Our data suggest that males are protected from demyelination by having a higher basal BDNF level. Altogether, our results suggest that males and females have different molecular signaling underlying their patterns in the development of morphine tolerance and drug-induced neuronal degeneration. Full article

This article provides a summary of the 9th International Congress of the International Society for Pathophysiology (ISP 2023) which took place in Belgrade, Serbia, from 4 to 6 July 2023. It describes the main trends and the most promising areas of research in current pathophysiology, including investigations of new pathogenic pathways, and the identification of cellular and molecular mechanisms, target molecules, genetic mechanisms, and new therapeutic strategies. The present article also highlights the research conducted by leading scientific teams and national pathophysiological societies from various countries that adds to our understanding of the pathogenesis of diseases and pathological processes. Full article

Changes in lighting accompany modern urbanization trends and can lead to various pathologies based on circadian disturbances. In this study, we assessed the changes in the circadian rhythm of core body temperature (Tcore) and locomotor activity of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) following exposure to different lighting conditions: extended light phase of the day (16 h–8 h, 20 h–4 h, 24 h–0 h), light pollution, monochromatic light, and bright light therapy. The telemetry data was collected after experimental lighting conditions during periods with standard lighting (12 h of light and 12 h of darkness) and was processed using linear and cosinor analysis. The daily rhythms of rats’ parameters persisted in accordance with the standard lighting regime. Tcore changes were observed in both groups compared to the initial period: in WKY, a decrease in Tcore during the darkness and an increase during the light; in SHR, the opposite trend, with Tcore increased during the darkness and decreased during the light phase of the day. A relationship between Tcore and activity was observed with weak correlation. WKY exhibited more pronounced signs of adaptive variation and desynchronization compared to SHR, which could be associated with a wider range of functional capabilities of the organism without cardiovascular pathology. Full article

Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux. Full article

Abnormal nucleotide insertions of C9orf72, which forms a complex with Smith–Magenis syndrome chromosomal region candidate gene 8 (SMCR8) protein and WD repeat-containing protein 41 (WDR41) protein, are associated with an autosomal-dominant neurodegenerative frontotemporal dementia and/or amyotrophic lateral sclerosis type 1 (FTDALS1). The differentially expressed in normal and neoplastic cells (DENN) domain-containing C9orf72 and its complex with SMCR8 and WDR41 function as a guanine-nucleotide exchange factor for Rab GTP/GDP-binding proteins (Rab GEF, also called Rab activator). Among Rab proteins serving as major effectors, there exists Rab11a. However, it remains to be established which Rab protein is related to promoting or sustaining neuronal morphogenesis or homeostasis. In this study, we describe that the knockdown of Rab11a decreases the expression levels of neuronal differentiation marker proteins, as well as the elongation of neurite-like processes, using N1E-115 cells, a well-utilized neuronal differentiation model. Similar results were obtained in primary cortical neurons. In contrast, the knockdown of Rab11b, a Rab11a homolog, did not significantly affect their cell morphological changes. It is of note that treatment with hesperetin, a citrus flavonoid (also known as Vitamin P), recovered the neuronal morphological phenotypes induced by Rab11a knockdown. Also, the knockdown of Rab11a or Rab11b led to a decrease in glial marker expression levels and in morphological changes in FBD-102b cells, which serve as the oligodendroglial differentiation model. Rab11a is specifically involved in the regulation of neuronal morphological differentiation. The knockdown effect mimicking the loss of function of C9orf72 is reversed by treatment with hesperetin. These findings may reveal a clue for identifying one of the potential molecular and cellular phenotypes underlying FTDALS1. Full article

Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx. Full article

Anorexia nervosa (AN) remains a challenging condition in psychiatric management and its pathogenesis is not yet fully understood. An imbalance in the gut microbiota composition may contribute to its pathophysiology. This review aims to explore the link between the human gut microbiota and AN (objective 1) or refeeding syndrome in AN (objective 2). The online databases MEDLINE and PsycINFO were searched for relevant studies. A total of 14 studies met the inclusion and exclusion criteria and only answered objective 1. A total of 476 AN patients, 554 healthy-weight (HC) controls, and 0 patients with other psychiatric disorders were included. Compared to HC, there were consistently reduced abundances of Faecalibacterium prausnitzii and Roseburia inulinivorans, and increased Methanobrevibacter smithii, in AN patients. Changes in alpha diversity were inconsistent, while beta diversity increased in four of six studies. Our model suggests that an imbalance in gut microbiota composition leads to reduced short-chain fatty acids, contributing to a proinflammatory state in AN, which is also common in other psychiatric comorbidities. Microbial changes may also contribute to the semistarvation state through endocrine changes and altered energy utilization. Full article

For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm–Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut–bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described. Full article

An electrical storm (ES) is defined as the presence of at least three episodes of sustained ventricular tachycardia or ventricular fibrillation within 24 h. This patient had a previously known arterial hypertension, type II diabetes mellitus, and chronic kidney disease and has presented to the Emergency Department (ED) with symptoms of retrosternal chest pain lasting for several hours prior. The initial 12-lead electrocardiogram revealed ST segment elevation in the anterior leads (V1–V6). Emergent coronary angiography revealed an acute occlusion of the proximal left anterior descending artery (pLAD) and percutaneous coronary intervention was performed with successful implantation of one drug-eluting stent in the pLAD. On day 8 of hospitalization, the patient developed a refractory ES for which he received 50 DC shocks and did not respond to multiple lines of antiarrhythmic medications. Due to a failure of medical therapy, we decided to implant a temporary pacemaker and initiate ventricular overdrive pacing (VOP) that was successful in terminating ES. Following electrical stabilization, the patient underwent a successful ICD implantation. This case demonstrates that VOP can contribute to hemodynamic and electrical stabilization of a patient that suffers from refractory ES and this treatment modality might serve as a temporary bridge to ICD implantation. Full article

The use of catheter-based irreversible electroporation in clinical cardiac laboratories, termed pulsed-field ablation (PFA), is gaining international momentum among cardiac electrophysiology proceduralists for the non-thermal management of both atrial and ventricular tachyrhythmogenic substrates. One area of potential application for PFA is in the mitigation of ventricular tachycardia (VT) risk in the setting of ischemia-mediated myocardial fibrosis, as evidenced by recently published clinical case reports. The efficacy of tissue electroporation has been documented in other branches of science and medicine; however, ventricular PFA’s potential advantages and pitfalls are less understood. This comprehensive review will briefly summarize the pathophysiological mechanisms underlying VT and then summarize the pre-clinical and adult clinical data published to date on PFA’s effectiveness in treating monomorphic VT. These data will be contrasted with the effectiveness ascribed to thermal cardiac ablation modalities to treat VT, namely radiofrequency energy and liquid nitrogen-based cryoablation. Full article

Superantigens, i.e., staphylococcal enterotoxins and toxic shock syndrome toxin-1, interact with T cells in a different manner in comparison to conventional antigens. In fact, they activate a larger contingent of T lymphocytes, binding outside the peptide-binding groove of the major histocompatibility complex class II. Involvement of many T cells by superantigens leads to a massive release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma. Such a storm of mediators has been shown to account for tissue damage, multiorgan failure and shock. Besides conventional drugs and biotherapeutics, experiments with natural and biological products have been undertaken to attenuate the toxic effects exerted by superantigens. In this review, emphasis will be placed on polyphenols, probiotics, beta-glucans and antimicrobial peptides. In fact, these substances share a common functional denominator, since they skew the immune response toward an anti-inflammatory profile, thus mitigating the cytokine wave evoked by superantigens. However, clinical applications of these products are still scarce, and more trials are needed to validate their usefulness in humans. Full article

Background: There is a considerable overlap between the clinical presentation of post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many of their common symptoms can be linked to dysregulation of the autonomic nervous system (dysautonomia). This study aimed to objectively assess autonomic function in a general group of patients with PCC and in a group of patients with ME/CFS whose disease was not related to COVID-19. We hypothesize that the similarity in the chronic symptoms of patients with PCC and ME/CFS extends to objective autonomic nervous system abnormalities. Methods: Synchronous recordings of an electrocardiogram and continuous dynamics of blood pressure in the digital artery using the Penaz method were obtained using the spiroarteriocardiorhythmography method in 34 patients diagnosed with ME/CFS, in whom the onset of the disease was not associated with COVID-19, 29 patients meeting the PCC definition and 32 healthy controls. Heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) were assessed at rest and in tests with fixed respiratory rates. Indicators of baroreflex regulation (baroreflex effectiveness index and baroreflex sensitivity) were additionally determined at rest. Results: The total power and power of low-frequency and high-frequency of RR interval variability at rest as well as baroreflex sensitivity were significantly lower both in PCC and ME/CFS patients compared to healthy controls. Several diagnostic prediction models for ME/CFS were developed based on HRV parameters. During slow breathing, the HRV parameters returned to normal in PCC but not in ME/CFS patients. The correlation analysis revealed a close relationship of HRV, BPV parameters and baroreflex sensitivity with fatigue, but not with HADS depressive/anxiety symptoms in the ME/CFS and PCC patients. Conclusions: A similar pattern of HRV and baroreflex failure with signs of a pathological acceleration of age-dependent dysautonomia was identified in the ME/CFS and PCC patients. The clinical, diagnostic and therapeutic implications of these findings are discussed, in light of previously described relationships between inflammation, vascular pathology, atherosclerotic cardiovascular disease and autonomic dysfunction. Full article