Pathophysiological Effects Research Articles

The CentiMarker Project: Standardizing Quantitative Alzheimer's disease Fluid Biomarkers for Biologic Interpretation.

Biomarkers have been essential to understanding Alzheimer's disease (AD) pathogenesis, pathophysiology, progression, and treatment effects. However, each biomarker measure is a representation of the biological target, the assay used to measure it, and the variance of the assay. Thus, biomarker measures are difficult to compare without standardization, and the units and magnitude of effect relative to the disease are difficult to appreciate, even for experts. To facilitate quantitative comparisons of AD biomarkers in the context of biologic and treatment effects, we propose a biomarker standardization approach between normal ranges and maximum abnormal AD ranges, which we refer to as CentiMarker, similar to the Centiloid approach used in PET. We developed a standardization scale that creates percentile values ranging from 0 for a normal population to 100 for the most abnormal measures across disease stages. We applied this scale to CSF and plasma biomarkers in autosomal dominant AD, assessing the distribution by estimated years from symptom onset, between biomarkers, and across cohorts. We then validated this approach in a large national sporadic AD cohort. We found the CentiMarker scale provided an easily interpretable metric of disease abnormality. The biologic changes, range, and distribution of several AD fluid biomarkers including amyloid-β, phospho-tau and other biomarkers, were comparable across disease stages in both early onset autosomal dominant and sporadic late onset AD. The CentiMarker scale offers a robust and versatile framework for the standardized biological comparison of AD biomarkers. Its broader adoption could facilitate biomarker reporting, allowing for more informed cross-study comparisons and contributing to accelerated therapeutic development.

Effect of Placental Derived Nucleoproteins on liver regeneration in DEN-induced liver fibrosis model

BackgroundPlacental Derived Nucleoproteins (PDNs) is commonly associated with the process of angiogenesis, and doesn't affect the healthy vasculature. PDNs are clinically estimated for the treatment of cancer cases and severe hepatic injuries. Thus, the pathophysiological effects of PDNs targeting liver fibrosis is a concern. ObjectivesTo assess the molecular, histopathological, and chemical impact of PDNs on liver regeneration in Diethylnitrosamine (DEN)-induced mice liver fibrosis. MethodsNormal untreated reference group of ten mice and two groups of induced liver cirrhosis using the recommended weekly dose of Diethylnitrosamine in total of eleven doses, initially 20 mg/kg body weight, and then 30 mg/kg in the third week, followed by 50 mg/kg for the last eight weeks, one of them combined treatment aligned with injection with total dose of extracted PDNs 25 mg/kg, in comparison to PDNs only treated group. An autopsy was performed after 22 weeks of the initial dose of DEN in each group. Molecular characterization of Alpha smooth muscle actin, TGFβ and NF-κB biomarkers for liver then liver function panel were analyzed and finally hepatopathological changes were observed using H&E stain and Sirius red stain. ResultsLiver enzymes, total bilirubin and total proteins in tissue in PDNs-DEN treated models were controlled in the direction of normal group and 50 % reduction of fibrosis in comparing to DEN-treated models. The cellular arrangement of fibrosis in the DEN entire groups were differentiated with high significant impact on the survival of mice. Increased levels of the biochemical markers in liver homogenate, loss of tissue architecture, and proliferation were observed in induced groups and down regulation of alpha smooth muscle actin, TGFβ and NF-κB. ConclusionThis finding demonstrates an improvement of Liver tissue induced fibrosis using DEN combined with PDNs. This strategy is to generate an animal model with a lower occurrence of fibrosis in a short time treatment regarding liver regeneration.

Temporal and Spatial Dynamics of Ischemic Stroke Lesions after Acute Therapy: A Comprehensive Edema Assessment Using Combined 1H- and 23Na-MRI.

Ischemic cerebral stroke initiates a complex cascade of pathophysiological events, involving various forms of molecular shifts and edema. Early intervention is pivotal in minimizing tissue loss and improving clinical outcomes. This study explores the temporal and spatial evolution of tissue sodium concentration (TSC) in acute ischemic lesions after acute therapy using 23Na-MRI in addition to conventional 1H-MRI. Prospectively, from examined 58 patients with acute ischemic stroke with a combined 1H/23Na-MRI within 72 h of symptom onset after receiving acute therapy, 31 patients were included in the evaluation of this study. After co-registration of the 23Na-MRI images to the morphological 1H-MRI images, manual segmentation of the ischemic lesions was performed, and the ADC and TSC measurements were quantified and correlated with the time of onset and lesion volume. The mean TSC in ischemic lesions correlated positively with lesion volume (r = 0.52, p = 0.002) and showed a significant association with the time of stroke onset (r = 0.8, p < 0.001). Patients who were treated only with intravenous rtPA showed homogenous sodium signal intensity in the ischemic lesions, whereas the patients who received mechanical recanalization exhibited distinctive sodium signal intensity patterns with focal significant TSC differences. The integration of 1H- and 23Na-MRI provides a nuanced understanding of temporal and spatial changes due to different types of edema in ischemic stroke lesions following acute treatment. Further exploration of these findings may enhance our understanding of stroke pathophysiology and guide personalized therapeutic interventions.

High salt intake and HIV infection on endothelial glycocalyx shedding in salt-sensitive hypertension.

The endothelial glycocalyx is closely associated with various physiological and pathophysiological events. Significant modification of the endothelial glycocalyx is an early process in the pathogenesis of cardiovascular disease. High dietary salt and HIV infection damages the endothelial glycocalyx causing endothelial dysfunction and increasing the risk for salt-sensitive hypertension and cardiovascular disease. The two factors, HIV infection and dietary salt are critical independent predictors of hypertension and cardiovascular disease and often synergize to exacerbate and accelerate disease pathogenesis. Salt-sensitive hypertension is more common among people living with HIV and is associated with risk for cardiovascular disease, stroke, heart attack and even death. However, the underlying mechanisms linking endothelial glycocalyx damage to dietary salt and HIV infection are lacking. Yet, both HIV infection/treatment and dietary salt are closely linked to endothelial glycocalyx damage and development of salt-sensitive hypertension. Moreover, the majority of individuals globally, consume more salt than is recommended and the burden of HIV especially in sub-Sahara Africa is disproportionately high. In this review, we have discussed the missing link between high salt and endothelial glycocalyx shedding in the pathogenesis of salt-sensitive hypertension. We have further elaborated the role played by HIV infection and treatment in modifying endothelial glycocalyx integrity to contribute to the development of hypertension and cardiovascular disease.

Ascorbyl palmitate (ASC16) as a potential inhibitor of toxicity induced by Crotalus durissus terrificus venom

It is well known that C. d. terrificus venom causes pathophysiological effects such as neuropathies, coagulopathies, and even death. Previous studies have reported that ASC16 can interact with monomeric phospholipases A2 from the venom of various snake species (e.g., Vipera russelli and Echis carinatus). As a result, ASC16 has been proposed as an inhibitor of the toxic effects induced by the heterodimeric complex (crotoxin) and other components of the venom of C. d. terrificus. To investigate this further, in silico studies were designed using the crotoxin (CTX) protein complex as a model, and experimental assays were conducted to evaluate the inhibitory effect of ASC16 on CTX, as well as on other venom enzymes such as thrombin-like enzyme (TLE), phosphodiesterase (PDE) and l-aminoxidase (LAAO). For in vitro assays, specific substrates were used, and lethal activity was measured over 48 h using an in vivo murine experimental model (CF01). In silico studies have indicated that the hydrophilic portion of ASC16 adopts a stable conformation while interacting with the catalytic site of crotoxin. At the highest concentrations, ASC16 significantly inhibited the activities of PLA2 (40.89 ± 0.09 %), TLE (11.03 ± 0.69 %), PDE (51.33 ± 2.83 %), and LAAO (56.79 ± 2.91 %). Furthermore, ASC16 neutralized the 2 LD50 lethality of crotalic venom. These findings lay the groundwork for designing promising adjuvants that can facilitate the incorporation of a larger quantity of proteins in immunization schemes. Consequently, this approach aims to achieve higher antibody titers, reduce the number of required immunizations, and minimize local damage in the producer animal.

Mathematical Modeling of Vedolizumab Treatment's Effect on Microbiota and Intestinal Permeability in Inflammatory Bowel Disease Patients.

Growing evidence suggests that impaired gut permeability and gut microbiota alterations are involved in the pathogenesis of Inflammatory Bowel Diseases (IBDs), which include Ulcerative Colitis (UC) and Crohn's Disease (CD). Vedolizumab is an anti-α4β7 antibody approved for IBD treatment, used as the first treatment or second-line therapy when the first line results in inadequate effectiveness. The aim of this study is to develop a mathematical model capable of describing the pathophysiological mechanisms of Vedolizumab treatment in IBD patients. In particular, the relationship between drug concentration in the blood, colonic mucosal permeability and fecal microbiota composition was investigated and modeled to detect and predict trends in order to support and tailor Vedolizumab therapies. To pursue this aim, clinical data from a pilot study on a cluster of 11 IBD patients were analyzed. Enrolled patients underwent colonoscopy in three phases (before (t0), after 24 weeks of (t1) and after 52 weeks of (t2 ) Vedolizumab treatment) to collect mucosal biopsies for transepithelial electrical resistance (TEER) evaluation (permeability to ions), intestinal permeability measurement and histological analysis. Moreover, fecal samples were collected for the intestinal microbiota analysis at the three time points. The collected data were compared to those of 11 healthy subjects at t0, who underwent colonoscopy for screening surveillance, and used to implement a three-compartmental mathematical model (comprising central blood, peripheral blood and the intestine). The latter extends previous evidence from the literature, based on the regression of experimental data, to link drug concentration in the peripheral blood compartment with Roseburia abundance and intestinal permeability. The clinical data showed that Vedolizumab treatment leads to an increase in TEER and a reduction in intestinal permeability to a paracellular probe, improving tissue inflammation status. Microbiota analysis showed increasing values of Roseburia, albeit not statistically significant. This trend was adequately reproduced by the mathematical model, which offers a useful tool to describe the pathophysiological effects of Vedolizumab therapy on colonic mucosal permeability and fecal microbiota composition. The model's satisfactory predictive capabilities and simplicity shed light on the relationship between the drug, the microbiota and permeability and allow for its straightforward extension to diverse therapeutic conditions.

Urinary Kidney Injury Molecule 1 and Urinary Monocyte Chemotactic Protein 1 as Novelbiomarkers for Early Detection of Sickle Cell Nephropathy

Abstract Background Sickle cell disease (SCD) is one of the most common genetic disorders, it not onlyhas hematological pathophysiological consequences, but also has systemic pathologicalmanifestations such as Sickle cell nephopathy(SN). There are no randomized control trials thatexamined the utility of screening test for renal disease in individuals with SCD. Aim of the Work To evaluate urinary monocyte chemoattractant protein-1 (MCP-1) and urinarykidney injury molecule 1 (KIM-1) as biomarkers for early detection of sickle cell nephropathy and correlate them with proteinuria and decline in estimate glomerular filtration rate ( eGFR). Patient and Methods This study was a cross sectional study, conducted at Pediatrics Hematology-Oncology Unit at Ain Shams University Children’s Hospital, where 45 children with sickle cell disease were enrolled aged 6 months - 16 years. Urine samples were collected to measure MCP-1and KIM-1 levels and compared to age and sex matched control. Results There was a statistically significant difference found between control group and patients’group regarding the level of MCP-1 in urine as it was found higher in patients than control group with median(IQR) values of 600 pg/ml (300–780) vs. 47.5 pg/ml (30–80, p < 0.001). Regarding the level of KIIM-1 in urine, it was found higher in patients than control group with median (IQR)values of 2.8 ng/ml (1.6–5.6) vs. 0.4 ng/ml (0.4–0.55, p<0.001) respectively. Conclusion Our data shows a distinct biomarker pattern in children with SCD, identifying KIM-1and MCP-1 as two potential biomarkers of early SN and its progression.

CD34+ Hematopoietic Stem Cell Count as a Novel Predictor of Vascular Event in Sickle Cell Disease Patients

Abstract Background Sickle cell disease (SCD) is one of the most common genetic disorders, it not only has hematological pathophysiological consequences, but also has systemic pathological manifestations such as vascular events (VEs). Prior studies have described that VEs are associated with poor outcomes in the short term and decreased quality of life in patients over the long term. There is no standardized method for predicting vascular injury in Sickle cell disease patients. Aim of the Work Our aim is to evaluate circulating CD34 as a novel predictive marker of occurrence of vascular event in Children with Sickle Cell Disease in their steady state and relate levels to severity of VEs in the following 6 months. Patient and Methods This study was an exploratory study, conducted at Pediatrics Hematology- Oncology Unit at Ain Shams University Children’s Hospital, where 50 children with sickle cell disease were enrolled at their steady state (defined as 2 months free from any Vascular Event prior to the study), aged 6 months - 16 years. Flow cytometry was done for quantification of circulating CD34+ at inclusion and compared to age and sex matched control and patients were followed up for 6 months for vascular events. Results There is statistically significant higher level of CD34+ among SCD patients compared to age and sex matched control with p value < 0.001.Circulating CD34+ showed significantly higher level in patients who developed systemic vascular events after 6 months of follow up with p value 0.022. There was no statistically significant correlation between circulating CD34+ and severity of peripheral vascular events (or any need for hospitalization) on follow up. Conclusion CD34+ cell count at steady state may be a promising biomarker of further vascular event in children with SCD.

Microbial signatures and continuum in endometrial cancer and benign patients

BackgroundEndometrial cancer is a multifactorial disease with inflammatory, metabolic and potentially microbial cues involved in disease pathogenesis. The endometrial cancer microbiome has been poorly characterised so far and studies have often overestimated bacterial biomass due to lack of integration of appropriate contamination controls. There is also a scarcity of evidence on the functionality of microbial microenvironments in endometrial cancer. This work addresses that knowledge gap by interrogating the genuine, contamination-free microbial signatures in the female genital tract and rectum of women with endometrial cancer and the mechanistic role of microbiome on carcinogenic processes.ResultsHere we sampled different regions of the reproductive tract (vagina, cervix, endometrium, fallopian tubes and ovaries) and rectum of 61 patients (37 endometrial cancer; 24 benign controls). We performed 16S rRNA gene sequencing of the V1–V2 hypervariable regions and qPCR of the 16S rRNA gene to qualitatively and quantitatively assess microbial communities and used 3D benign and endometrial cancer organoids to evaluate the effect of microbial products of L. crispatus, which was found depleted in endometrial cancer patients following primary analysis, on endometrial cell proliferation and inflammation. We found that the upper genital tract of a subset of women with and without endometrial cancer harbour microbiota quantitatively and compositionally distinguishable from background contaminants. Endometrial cancer was associated with reduced cervicovaginal and rectal bacterial load together with depletion of Lactobacillus species relative abundance, including L. crispatus, increased bacterial diversity and enrichment of Porphyromonas, Prevotella, Peptoniphilus and Anaerococcus in the lower genital tract and endometrium. Treatment of benign and malignant endometrial organoids with L. crispatus conditioned media exerted an anti-proliferative effect at high concentrations but had minimal impact on cytokine and chemokine profiles.ConclusionsOur findings provide evidence that the upper female reproductive tract of some women contains detectable levels of bacteria, the composition of which is associated with endometrial cancer. Whether this is a cause or consequence of cancer pathophysiology and what is the functional significance of this finding remain to be elucidated to guide future screening tools and microbiome-based therapeutics.7srhokZSHNZrvrGZNmjDS4Video

Lung Hyperinflation as Treatable Trait in Chronic Obstructive Pulmonary Disease: A Narrative Review.

Lung hyperinflation (LH) is a common clinical feature in patients with chronic obstructive pulmonary disease (COPD). It results from a combination of reduced elastic lung recoil as a consequence of irreversible destruction of lung parenchyma and expiratory airflow limitation. LH is an important determinant of morbidity and mortality in COPD, partially independent of the degree of airflow limitation. Therefore, reducing LH has become a major target in the treatment of COPD over the last decades. Advances were made in the diagnostics of LH and several effective interventions became available. Moreover, there is increasing evidence suggesting that LH is not only an isolated feature in COPD but rather part of a distinct clinical phenotype that may require a more integrated management. This narrative review focuses on the pathophysiology and adverse consequences of LH, the assessment of LH with lung function measurements and imaging techniques and highlights LH as a treatable trait in COPD. Finally, several suggestions regarding future studies in this field are made.

Modifications and Optimization of an Autologous Intracerebral Hemorrhage Rat Model

Objective: To date, no novel drug therapies have proven effective in improving outcomes after intracerebral hemorrhage (ICH). This has been slowed, in part, by a lack of reliable preclinical models that recapitulate the pathophysiological consequences of ICH. Limited descriptions of the methodology of preclinical models may play a role in this failed translation. The current study aimed to improve the autologous blood injection model of ICH and provide a comprehensive methodology to facilitate a reliable preclinical model that bridges the translational research gap. Methods: A modified single-injection protocol for an autologous-blood ICH model was developed and tested. This rodent ICH model produces injury in the basal ganglia of adult rats via a stereotaxically-assisted right-sided single-injection of fresh autologous whole blood. A comprehensive step-wise description of the methodology is presented and documented in a written and visual format with supporting pictorialmaterial, to prevent common mistakes that result in failed hematoma formation.Rates of successful hematoma formation using the single-injection protocol, outlined here, were compared to those using the traditional double-injection protocol.

Thalassemia Disorders: A Scoping Insight toward Management and Patient Care Prospects

Abstract Thalassemia (TH) is a group of inherited autosomal recessive blood disorders that are among the most common genetic diseases in the world and originate in the Mediterranean. The condition is caused by a number of genetic defects, and depending on the severity of the disease, untreated individuals may develop clinical complications such as skeletal deformities and growth retardation, splenomegaly, extramedullary hematopoiesis, heart failure, and endocrine complications. Based on a growing understanding of the sequential pathophysiological events, this study provides a scoping review of currently applied treatment, new attractive and potentially novel therapies that are starting to immerge for TH. Furthermore, because this genetic disorder necessitates long-term care, preventing the homozygous state is a critical tool in management alongside preventative measures toward patient care.

FEATURES OF ANESTHESIA IN PATIENTS WITH SPECIAL NEEDS. PART 1

The non-medical use of cannabis can negatively impact the morpho-functional state of almost all organs and systems of the human body. During acute intoxication and established drug dependence, it can unevenly distort the effects of drugs for local and general anesthesia, leading to life-threatening complications. Part 1 of this review presents the results of acute and chronic cannabis use on homeostasis. Cerebral vasospasm and atherosclerosis are identified as major etiological factors for cannabis-related cerebrovascular diseases. Young to middle-aged individuals (30–50 years), male gender (male-to-female ratio 3.7:1), and chronic use (86%) are significant independent predictors of neurovascular toxicity, cerebral hypoperfusion, and stroke. Cannabis smoking causes damage to the respiratory mucosa similar to tobacco. Regular cannabis smokers can expect irritation of the upper respiratory tract, swelling, obstruction, chronic cough, bronchitis, lung emphysema, and bronchospasm. Some reports advocate the use of dexamethasone during surgery to alleviate these symptoms. The detrimental effects of chronic cannabis use on liver and kidney functions are somewhat overstated. Disturbances in immune system, thermoregulation, blood clotting, and carbohydrate metabolism in the absence of anesthetic precautions can significantly complicate the patient's condition in the perioperative period. Cannabinoids can interact with drugs from various groups. Awareness of the pathophysiological and biochemical consequences of cannabis use allows anesthesiologists to anticipate and effectively manage perioperative complications in this patient category

Proximal tubule hypertrophy and hyperfunction: a novel pathophysiological feature in disease states.

The role of proximal tubules (PTs), a major component of the renal tubular structure in the renal cortex, has been examined extensively. Along with its physiological role in the reabsorption of various molecules, including electrolytes, amino acids and monosaccharides, transcellular transport of different hormones and regulation of homeostasis, pathological events affecting PTs may underlie multiple disease states. PT hypertrophy or a hyperfunctioning state, despite being a compensatory mechanism at first in response to various stimuli or alterations at tubular transport proteins, have been shown to be critical pathophysiological events leading to multiple disorders, including diabetes mellitus, obesity, metabolic syndrome and congestive heart failure. Moreover, pharmacotherapeutic agents have primarily targeted PTs, including sodium-glucose cotransporter 2, urate transporters and carbonic anhydrase enzymes. In this narrative review, we focus on the physiological role of PTs in healthy states and the current understanding of the PT pathologies leading to disease states and potential therapeutic targets.

Exploring Extravasation in Cancer Patients.

Extravasation, the unintended leakage of intravenously administered substances, poses significant challenges in cancer treatment, particularly during chemotherapy and radiotherapy. This comprehensive review explores the pathophysiology, incidence, risk factors, clinical presentation, diagnosis, prevention strategies, management approaches, complications, and long-term effects of extravasation in cancer patients. It also outlines future directions and research opportunities, including identifying gaps in the current knowledge and proposing areas for further investigation in extravasation prevention and management. Emerging technologies and therapies with the potential to improve extravasation prevention and management in both chemotherapy and radiotherapy are highlighted. Such innovations include advanced vein visualization technologies, smart catheters, targeted drug delivery systems, novel topical treatments, and artificial intelligence-based image analysis. By addressing these aspects, this review not only provides healthcare professionals with insights to enhance patient safety and optimize clinical practice but also underscores the importance of ongoing research and innovation in improving outcomes for cancer patients experiencing extravasation events.

The radiated breast and autologous reconstruction: benefits and alternatives

Despite advancements in research and technology, breast cancer remains the second leading cause of cancer-related mortality affecting women worldwide. Radiation therapy is a widely recommended adjunct to surgery due to its significant role in reducing loco-regional recurrence. Its use, however, is not without consequences. Radiation triggers a series of pathophysiologic events leading to tissue injury; reactive oxygen species incites (1) vascular damage and chronic hypoxia; (2) an inflammatory response; and (3) activation of myofibroblasts to induce fibrosis. As a result, radiotherapy interferes with wound healing and negatively impacts the quality of the skin. These pathophysiologic consequences complicate the sequence of breast reconstruction and require surgeons to consider timing and the type of reconstruction (autologous vs. implant), with respect to radiotherapy to improve patient outcomes. In this article, we briefly review radiation-induced tissue effects and their impact on breast reconstruction. More specifically, we comment on the traditional use of autologous tissue, microsurgical technical pearls for irradiated fields, reconstructive timing paradigms, and lymphedema prevention. With continued progress, derivation, and innovation, plastic and reconstructive surgery has consistently advanced and revolutionized both medicine and surgery. This review considers the future implications of breast reconstruction and how it will impact patients, healthcare, and the field. While not an exhaustive review, we aim to provide a comprehensive discussion and insights. In summary, the authors discuss the possibilities of a paradigm shift in breast reconstruction, emphasizing the need for surgeons to have an armamentarium capable of all breast reconstruction options for the best possible patient outcomes.

LPA-Induced Thromboxane A2-Mediated Vasoconstriction Is Limited to Poly-Unsaturated Molecular Species in Mouse Aortas.

We have previously reported that, in aortic rings, 18:1 lysophosphatidic acid (LPA) can induce both vasodilation and vasoconstriction depending on the integrity of the endothelium. The predominant molecular species generated in blood serum are poly-unsaturated LPA species, yet the vascular effects of these species are largely unexplored. We aimed to compare the vasoactive effects of seven naturally occurring LPA species in order to elucidate their potential pathophysiological role in vasculopathies. Vascular tone was measured using myography, and thromboxane A2 (TXA2) release was detected by ELISA in C57Bl/6 mouse aortas. The Ca2+-responses to LPA-stimulated primary isolated endothelial cells were measured by Fluo-4 AM imaging. Our results indicate that saturated molecular species of LPA elicit no significant effect on the vascular tone of the aorta. In contrast, all 18 unsaturated carbon-containing (C18) LPAs (18:1, 18:2, 18:3) were effective, with 18:1 LPA being the most potent. However, following inhibition of cyclooxygenase (COX), these LPAs induced similar vasorelaxation, primarily indicating that the vasoconstrictor potency differed among these species. Indeed, C18 LPA evoked a similar Ca2+-signal in endothelial cells, whereas in endothelium-denuded aortas, the constrictor activity increased with the level of unsaturation, correlating with TXA2 release in intact aortas. COX inhibition abolished TXA2 release, and the C18 LPA induced vasoconstriction. In conclusion, polyunsaturated LPA have markedly increased TXA2-releasing and vasoconstrictor capacity, implying potential pathophysiological consequences in vasculopathies.

The Clot Thickens: Differential Coagulotoxic and Cardiotoxic Activities of Anguimorpha Lizard Venoms.

Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful for predation than defence (such as paralytic neurotoxicity). This study aimed to ascertain the effects of Heloderma, Lanthanotus, and Varanus lizard venoms on the coagulation and cardiovascular systems. Anticoagulant toxicity was demonstrated for the Varanus species studied, with the venoms prolonging clotting times in human and bird plasma due to the destructive cleavage of fibrinogen. In contrast, thromboelastographic analyses on human and bird plasmas in this study demonstrated a procoagulant bioactivity for Heloderma venoms. A previous study on Heloderma venom using factor-depleted plasmas as a proxy model suggested a procoagulant factor was present that activated either Factor XI or Factor XII, but could not ascertain the precise target. Our activation studies using purified zymogens confirmed FXII activation. Comparisons of neonate and adult H. exasperatum, revealed the neonates to be more potent in the ability to activate FXII, being more similar to the venom of the smaller species H. suspectum than the adult H. exasperatum. This suggests potent FXII activation a basal trait in the genus, present in the small bodied last common ancestor. This also indicates an ontogenetic difference in prey preferences in the larger Heloderma species paralleing the change in venom biochemistry. In addition, as birds lack Factor XII, the ability to clot avian plasma suggested an additional procoagulant site of action, which was revealed to be the activation of Factor VII, with H. horridum being the most potent. This study also examined the effects upon the cardiovascular system, including the liberation of kinins from kininogen, which contributes to hypotension induction. This form of toxicity was previously described for Heloderma venoms, and was revealed in this study was to also be a pathophysiological effect of Lanthanotus and Varanus venoms. This suggests that this toxic activity was present in the venom of the last common ancestor of the anguimorph lizards, which is consistent with kallikrein enzymes being a shared toxin trait. This study therefore uncovered novel actions of anguimorph lizard venoms, not only contributing to the evolutionary biology body of knowledge but also revealing novel activities to mine for drug design lead compounds.

Inteleukin-6 secretion during pathophysiological events of pregnancy – preterm birth, preeclampsia, fetal growth restriction, gestational diabetes mellitus

Cytokines play a role in nearly all reproductive and pregnancy processes. These proteins are expressed in various body fluids and tissues related to reproduction. Interleukin-6 (IL-6) stands out as one of the best-characterized members of the cytokine family. This protein has an immense and imperfectly understood impact on both normal and pathological aspects of human pregnancy. IL-6 exerts a wide range of effects on the immune system, and it plays crucial roles in regulating inflammation processes and homeostasis. Herein, we summarize current knowledge on IL-6 secretion during pathophysiological events of pregnancy: preterm birth, preeclampsia, fetal growth restriction and gestational diabetes mellitus. Cytokines, particularly interleukin-6, play crucial roles in regulating pregnancy physiology. Maintaining IL-6 homeostasis is essential for the health of both the mother and fetus. IL-6 supports pregnancy by influencing uterine receptivity, trophoblast function, and immune interactions at the feto–maternal interface. Disrupted IL-6 expression may contribute to various pregnancy complications. A deeper understanding of IL-6 regulation can help detect dysregulation and potentially optimizing pregnancy outcomes. Addressing knowledge gaps identified in this review is vital for improving current practices and enhancing pregnancy outcomes.

Detailed role of SR-A1 and SR-E3 in tumor biology, progression, and therapy.

The first host defense systems are the innate immune response and the inflammatory response. Among innate immune cells, macrophages, are crucial because they preserve tissue homeostasis and eradicate infections by phagocytosis, or the ingestion of particles. Macrophages exhibit phenotypic variability contingent on their stimulation state and tissue environment and may be detected in several tissues. Meanwhile, critical inflammatory functions are played by macrophage scavenger receptors, in particular, SR-A1 (CD204) and SR-E3 (CD206), in a variety of pathophysiologic events. Such receptors, which are mainly found on the surface of multiple types of macrophages, have different effects on processes, including atherosclerosis, innate and adaptive immunity, liver and lung diseases, and, more recently, cancer. Although macrophage scavenger receptors have been demonstrated to be active across the disease spectrum, conflicting experimental findings and insufficient signaling pathways have hindered our comprehension of the molecular processes underlying its array of roles. Herein, as SR-A1 and SR-E3 functions are often binary, either protecting the host or impairing the pathophysiology of cancers has been reviewed. We will look into their function in malignancies, with an emphasis on their recently discovered function in macrophages and the possible therapeutic benefits of SR-A1 and SR-E3 targeting.