Pathological Effects Research Articles

Blocking HXA3-mediated neutrophil elastase release during S. pneumoniae lung infection limits pulmonary epithelial barrier disruption and bacteremia.

Streptococcus pneumoniae (Sp), a leading cause of community-acquired pneumonia, can spread from the lung into the bloodstream to cause septicemia and meningitis, with a concomitant three-fold increase in mortality. Limitations in vaccine efficacy and a rise in antimicrobial resistance have spurred searches for host-directed therapies that target pathogenic immune processes. Polymorphonuclear leukocytes (PMNs) are essential for infection control but can also promote tissue damage and pathogen spread. The major Sp virulence factor, pneumolysin (PLY), triggers acute inflammation by stimulating the 12-lipoxygenase (12-LOX) eicosanoid synthesis pathway in epithelial cells. This pathway is required for systemic spread in a mouse pneumonia model and produces a number of bioactive lipids, including hepoxilin A3 (HXA3), a hydroxy epoxide PMN chemoattractant that has been hypothesized to facilitate breach of mucosal barriers. To understand how 12-LOX-dependent inflammation promotes dissemination during Sp lung infection and dissemination, we utilized bronchial stem cell-derived air-liquid interface (ALI) cultures that lack this enzyme to show that HXA3 methyl ester (HXA3-ME) is sufficient to promote basolateral-to-apical PMN transmigration, monolayer disruption, and concomitant Sp barrier breach. In contrast, PMN transmigration in response to the non-eicosanoid chemoattractant fMLP did not lead to epithelial disruption or bacterial translocation. Correspondingly, HXA3-ME but not fMLP increased release of neutrophil elastase (NE) from Sp-infected PMNs. Pharmacologic blockade of NE secretion or activity diminished epithelial barrier disruption and bacteremia after pulmonary challenge of mice. Thus, HXA3 promotes barrier disrupting PMN transmigration and NE release, pathological events that can be targeted to curtail systemic disease following pneumococcal pneumonia.

Amorphous calcium carbonate as a novel potential treatment for osteoarthritis in dogs: a pilot clinical study.

Amorphous calcium carbonate (ACC) is a potential new treatment for canine osteoarthritis (OA) with novel mechanisms based on local pH modulation and targeting bone remodeling, inflammation, and pain. The aim of this pilot exploratory clinical study was to obtain initial data on the potential efficacy and safety of ACC in OA dogs and to determine if further investigation was appropriate using similar assessment methods. In this prospective, randomized, double-blind, controlled pilot study, 41 client-owned dogs were allocated in a 2:1 ratio to ACC: placebo given orally for 56 days. Efficacy assessments included improvements in pain and mobility using owner questionnaires [Canine Brief Pain Inventory (CBPI), Client Specific Outcome Measure (CSOM), and Veterinary Orthopedic Scores (VOS)]. Safety in the study population was monitored by veterinary examinations, clinical pathology, and adverse events. Fifty-three dogs were screened, of which 41 enrolled and served for the safety assessment. Thirty-six dogs were found evaluable for initial efficacy assessment. Three dogs given placebo (21.4%) and one given ACC (4.5%) were removed before day 56 due to owner-perceived pain and were considered treatment failures. There were no serious adverse events or clinically significant treatment-related effects in the study. Overall, ACC was found safe in the small study population. On day 56, proportionally more ACC than placebo dogs were treatment successes based on CBPI (45.5% vs. 21.4%) and CSOM (63.6% vs. 30.8%, respectively); however, these differences were not statistically significant (p = 0.15 and 0.06, respectively). On day 56, within the ACC group but not the placebo group, the CBPI, CSOM, and VOS assessments were lower compared to day 0 and day 14 (p < 0.05). The relatively small number of dogs limited the statistical power of the pilot study in evaluating the efficacy and safety of ACC. Study results support the conduct of larger, appropriately powered studies using similar assessments to confirm whether ACC may be a safe and effective treatment for OA in dogs.

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.

Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration.

The double-stranded RNA-binding protein Staufen1 (STAU1) regulates a variety of physiological and pathological events via mediating RNA metabolism. STAU1 overabundance was observed in tissues from mouse models and fibroblasts from patients with neurodegenerative diseases, accompanied by enhanced mTOR signaling and impaired autophagic flux, while the underlying mechanism remains elusive. Here, we find that endogenous STAU1 forms dynamic cytoplasmic condensate in normal and tumor cell lines, as well as in mouse Huntington's disease knockin striatal cells. STAU1 condensate recruits target mRNA MTOR at its 5'UTR and promotes its translation both in vitro and in vivo, and thus enhanced formation of STAU1 condensate leads to mTOR hyperactivation and autophagy-lysosome dysfunction. Interference of STAU1 condensate normalizes mTOR levels, ameliorates autophagy-lysosome function, and reduces aggregation of pathological proteins in cellular models of neurodegenerative diseases. These findings highlight the importance of balanced phase separation in physiological processes, suggesting that modulating STAU1 condensate may be a strategy to mitigate the progression of neurodegenerative diseases with STAU1 overabundance.

Ecological consequences of hidden pathology by larval digeneans in South American mollusks

The study of digeneans and their association with mollusks commenced in Europe and South America during the mid-19th to early 20th centuries. Digenean infestation can severely degrade host tissue, leading to diminished energy resources and eventual host mortality. However, these parasites can also induce various non-lethal effects, including changes in growth rates, survival rates, and reproductive capabilities, alongside physiological and behavioral alterations. While numerous studies have explored the ecological effects of digeneans on hosts in Europe and North America, our understanding of these dynamics in South America, particularly in first intermediate hosts, remains limited. Therefore, this paper aims to provide an overview of ecological investigations into digenean-mollusk systems in South America, emphasizing the importance of robust sampling designs and statistical analyses to address key ecological inquiries. Although fascinating examples exist of parasitism influencing different hierarchical levels of digenean-mollusk systems, particularly at the individual, population, and community levels, documentation of their ecosystem-level impacts is comparatively sparse. As South American studies of digenean-mollusk systems from an ecological perspective are still in their early stages, there is immense potential for uncovering unique ecological patterns in this largely unexplored region, propelling us toward further developmental strides in the parasite ecology.

Effect of Optogenetic Stimulation Parameters on Firing Rate of Basal Ganglia Neurons in Parkinsonian State BG and RT Networks

Purpose: Parkinson's disease is a neurodegenerative disorder that affects the basal ganglia of the brain, which plays an important role in movement. Basal Ganglia-Thalamic network model including Subthalamic nucleus, Globus Pallidus externa, Globus Pallidus interna and Thalamus neurons. Optogenetics is a combination of optical and genetic tools used to stimulate basal ganglia neurons by light-sensitive ion channels (opsins) to eliminate the pathological effects of Parkinson's disease. Materials and Methods: To analyze the effect of optogenetic stimulation on Parkinsonian nervous systems, two complete models of BG and RT (including STN, GPe, Gpi, and TH neurons) have been selected and developed for Parkinson’s disease and to apply three and four-state optogenetic stimulation. For this purpose, ChETA, ChRwt, and NpHR opsins have been selected in three-state and four-state stimulations and different stimulation conditions according to different parameters in both models have been investigated. Results: To evaluate the performance of two models for each gene in three- and four-state stimulation conditions with different values of basic parameters, the value of error index is calculated and stimulation conditions that created an error index equal to zero have been introduced as optimal conditions. Based on the results, frequencies of 20 and 200 Hz in the four-state ChRwt model and frequency of 80 Hz in the three-state ChETA model have been introduced as optimal genes, frequencies, and models. To verify the developed model, the obtained results have been compared with the results of experimental studies. Conclusion: In optimal conditions, STN provides excitatory input and GPe provide appropriate inhibitory input to GPi, and GPi can provide appropriate inhibitory input to TH, and as a result, its function improves and pathological effects of Parkinson's disease disappear. The response of GPe neurons is consistent with the experimental results and the response of other neurons is also similar to the response of GPe neurons.

Neferine inhibits BMECs pyroptosis and maintains blood–brain barrier integrity in ischemic stroke by triggering a cascade reaction of PGC-1α

Blood–brain barrier disruption is a critical pathological event in the progression of ischemic stroke (IS). Most studies regarding the therapeutic potential of neferine (Nef) on IS have focused on neuroprotective effect. However, whether Nef attenuates BBB disruption during IS is unclear. We here used mice underwent transient middle cerebral artery occlusion (tMCAO) in vivo and bEnd.3 cells exposed to oxygen–glucose deprivation/reoxygenation (OGD/R) injury in vitro to simulate cerebral ischemia. We showed that Nef reduced neurobehavioral dysfunction and protected brain microvascular endothelial cells and BBB integrity. Molecular docking, short interfering (Si) RNA and plasmid transfection results showed us that PGC-1α was the most binding affinity of biological activity protein for Nef. And verification experiments were showed that Nef upregulated PGC-1α expression to reduce mitochondrial oxidative stress and promote TJ proteins expression, further improves the integrity of BBB in mice. Intriguingly, our study showed that neferine is a natural PGC-1α activator and illustrated the mechanism of specific binding site. Furthermore, we have demonstrated Nef reduced mitochondria oxidative damage and ameliorates endothelial inflammation by inhibiting pyroptosis to improve BBB permeability through triggering a cascade reaction of PGC-1α via regulation of PGC-1α/NLRP3/GSDMD signaling pathway to maintain the integrity of BBB in ischemia/reperfusion injury.

Early and enduring: Targeting the endothelium for blood-brain barrier protection

The disruption of the blood-brain barrier marks a pivotal early pathological event in ischemic stroke that significantly contributes to subsequent permanent damage. Here we delve into the ramifications of a study conducted by Xu and colleagues, which underscores the essential role of the protein peroxiredoxin-4 in cerebrovascular endothelial cells. Peroxiredoxin-4 was shown to preserve blood-brain barrier integrity during the early stages after cerebral ischemia and reperfusion, ultimately leading to improved long-term outcomes.

Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age

Little is known about the possibility of reversing age-related biological changes when they have already occurred. To explore this, we have characterized the effects of reducing insulin/IGF-1 signaling (IIS) during old age. Reduction of IIS throughout life slows age-related decline in diverse species, most strikingly in the nematode Caenorhabditis elegans. Here we show that even at advanced ages, auxin-induced degradation of DAF-2 in single tissues, including neurons and the intestine, is still able to markedly increase C. elegans lifespan. We describe how reversibility varies among senescent changes. While senescent pathologies that develop in mid-life were not reversed, there was a rejuvenation of the proteostasis network, manifesting as a restoration of the capacity to eliminate otherwise intractable protein aggregates that accumulate with age. Moreover, resistance to several stressors was restored. These results support several new conclusions. (1) Loss of resilience is not solely a consequence of pathologies that develop in earlier life. (2) Restoration of proteostasis and resilience by inhibiting IIS is a plausible cause of the increase in lifespan. And (3), most interestingly, some aspects of the age-related transition from resilience to frailty can be reversed to a certain extent. This raises the possibility that the effect of IIS and related pathways on resilience and frailty during aging in higher animals might possess some degree of reversibility.

Sub-acute pathological effects of calcium carbide as an artificial fruit ripening agent on various organs of albino mice

Introduction. Calcium carbide is the most commercially used artificial fruit ripener because it is inexpensive to produce though, involving the use of hazardous elements and can easily be purchased in local markets. This study aimed at investigating the architectural changes of organs extracted from albino mice fed with fruits that were ripened with calcium carbide. Material and methods. About 40 mice of both males and females, weighing between 18g-25g were randomly used for this study. They were divided into five (5) groups, made up of six mice namely Groups 1, 2, 3, 4 &amp; 5 respectively. A set of unripe mature pawpaw and banana were ripened with calcium carbide (CCRP &amp; CCRB) and were fed orally to groups 3 and 5 respectively for four weeks with water. Another set of the unripe mature pawpaw and banana were ripened naturally (NRP &amp; NRB) without subjecting them to any artificial ripening processes and were fed orally to groups 2 and 4 mice respectively for four weeks with water. Rat feed and water were also given to the control group 1. Results. Increased body weights were observed in the calcium carbide ripened banana (CCRB) treated group when compared to the other groups (control and calcium carbide ripened pawpaw). Histological sections revealed increased numbers of inflammatory cells, presence of collapsed epithelial layer, ruptured muscle, disorganized clara cells, aggregation of fibroblasts in the lungs; mild interstitial edema in the brain between the cardiocytes: mononuclear cell infiltration with cloudy swelling of the renal epithelium; dendritic cells in the brain. Discussion and conclusions. According to this study, eating fruits that are ripened with calcium carbide has adverse related health effects thus negatively altering the histological architecture of the organs such as the lungs, liver, kidney, heart as well as the brain. Fruit vendors must therefore use caution when applying calcium carbide and adhere to international regulations that strictly limit its use.

Hyperprolactinemia of various genesis in premenopause: effect on cardiovascular risks, a practical aspect

The pathological aspects of hyperprolactinemia have been well studied to date and primarily affect changes in the reproductive system. Regardless of the genesis of hyperprolactinemia, negative changes include, first of all, dysmenorrhea and hyperan drogenism. Changes in the mammary glands include galactorrhea, mastopathy, and the development of breast cancer. The pathological effects of hyperprolactinemia on other organs and systems, including the cardiovascular system, have been studied less. Few existing studies suggest that elevated prolactin levels can potentially affect cardiovas cular risks and provoke myocardial remodeling, arterial hypertension, hyperhomocys teinemia, and disorders of the plasma lipid profile. Menopausal women are particularly vulnerable in this regard, as the cardioprotective role of estrogens is significantly re duced during this period. In this article, we examined the effect of hyperprolactinemia on the formation of cardiovascular disorders in premenopausal women. The purpose of the study was to evaluate the effect of hyperprolactinemia on the genesis of cardiovascular pathology in premenopausal women. Materials and methods: three groups of premenopausal patients were examined. The patients of the first group (n=26) had previously been diagnosed with pituitary adenoma and were treated with cabergoline, maintaining the target prolactin level for at least two years. According to pituitary MRI, prolactinoma and elevated prolactin levels were de tected in the patients of the second group (n=21), but these patients did not take prolac tin-lowering therapy for various reasons. The third group consisted of the patients with idiopathic hyperprolactinemia who did not receive prolactin-lowering therapy (n=19). The patients of all three groups underwent general clinical examination, determination of the daily blood pressure profile, ECG, echocardiography, determination of the level of lipidogram, homocysteine, and other markers of cardiovascular risk. The results of the study showed that regardless of its genesis, pathological hyperprolactinemia influences the development of cardiovascular pathology in premenopausal women.

Novel insights into STIM1's role in store-operated calcium entry and its implications for T-cell mediated inflammation in trigeminal neuralgia.

This investigation aims to elucidate the novel role of Stromal Interaction Molecule 1 (STIM1) in modulating store-operated calcium entry (SOCE) and its subsequent impact on inflammatory cytokine release in T lymphocytes, thereby advancing our understanding of trigeminal neuralgia (TN) pathogenesis. Employing the Gene Expression Omnibus (GEO) database, we extracted microarray data pertinent to TN to identify differentially expressed genes (DEGs). A subsequent comparison with SOCE-related genes from the Genecards database helped pinpoint potential target genes. The STRING database facilitated protein-protein interaction (PPI) analysis to spotlight STIM1 as a gene of interest in TN. Through histological staining, transmission electron microscopy (TEM), and behavioral assessments, we probed STIM1's pathological effects on TN in rat models. Additionally, we examined STIM1's influence on the SOCE pathway in trigeminal ganglion cells using techniques like calcium content measurement, patch clamp electrophysiology, and STIM1- ORAI1 co-localization studies. Changes in the expression of inflammatory markers (TNF-α, IL-1β, IL-6) in T cells were quantified using Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) in vitro, while immunohistochemistry and flow cytometry were applied in vivo to assess these cytokines and T cell count alterations. Our bioinformatic approach highlighted STIM1's significant overexpression in TN patients, underscoring its pivotal role in TN's etiology and progression. Experimental findings from both in vitro and in vivo studies corroborated STIM1's regulatory influence on the SOCE pathway. Furthermore, STIM1 was shown to mediate SOCE-induced inflammatory cytokine release in T lymphocytes, a critical factor in TN development. Supportive evidence from histological, ultrastructural, and behavioral analyses reinforced the link between STIM1-mediated SOCE and T lymphocyte-driven inflammation in TN pathogenesis. This study presents novel evidence that STIM1 is a key regulator of SOCE and inflammatory cytokine release in T lymphocytes, contributing significantly to the pathogenesis of trigeminal neuralgia. Our findings not only deepen the understanding of TN's molecular underpinnings but also potentially open new avenues for targeted therapeutic strategies.

An Updated Canvas of the RFC1-mediated CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome).

Proliferation of specific nucleotide sequences within the coding and non-coding regions of numerous genes has been implicated in approximately 40 neurodegenerative disorders. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a neurodegenerative disorder, is distinguished by a pathological triad of sensory neuropathy, bilateral vestibular areflexia and cerebellar impairments. It manifests in adults gradually and is autosomal recessive and multi-system ataxia. Predominantly, CANVAS is associated with biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene. Although various motifs have been identified, only a subset induces pathological consequences, by forming stable secondary structures that disrupt gene functions both in vitro and in vivo. The pathogenesis of CANVAS remains a subject of intensive research, yet its precise mechanisms remain elusive. Herein, we aim to comprehensively review the epidemiology, clinical ramifications, molecular mechanisms, genetics, and potential therapeutics in light of the current findings, extending an overview of the most significant research on CANVAS.

Comparative cytotoxicity of Acanthamoeba castellanii-derived conditioned medium on human corneal epithelial and stromal cells

Soluble factors in the secretome of Acanthamoeba castellanii play crucial roles in the pathogenesis of Acanthamoeba keratitis (AK). Investigating the pathological effects of A. castellanii-derived conditioned medium (ACCM) on ocular cells can provide insights into the damage inflicted during AK. This study examined ACCM-induced cytotoxicity in primary human corneal stromal cells (CSCs) and a human SV40 immortalized corneal epithelial cell line (ihCECs) at varying ACCM concentrations (25 %, 50 %, 75 %, and 100 %). MTT, AlamarBlue, Sulforhodamine B, lactate dehydrogenase, and Caspase-3/7 activation assays were used to assess the impact of ACCM on the cell viability, proliferation and apoptosis. Additionally, fluorescent staining was used to reveal actin cytoskeleton changes. ACCM exposure significantly decreased cell viability, increased apoptosis, and disrupted the actin cytoskeleton, particularly at higher concentrations and longer exposures. Proteases were found to mediate these cytopathogenic effects, highlighting the need for characterization of A. castellanii proteases as key virulence factors in AK pathogenesis.

Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology: a cohort study

BackgroundAutopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.MethodsA total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.ResultsAcross the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.ConclusionsOur findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Stated patient preferences for overnight at-home diagnostic assessment of sleep disorders

PurposeThe diagnostic workup for assessment of sleep disorders commonly involves overnight testing to assess sleep patterns and pathological events. So far, little is known about preferences for provision of home sleep tests to patients with sleep disorders. This study aims to close this gap by eliciting preferences for home sleep testing using a discrete choice experiment (DCE).MethodsA DCE with seven attributes of at-home sleep testing and three levels per attribute was developed using a fractional factorial design. Patients with and without previous sleep testing experience were recruited from two large sleep centers in Germany. Coefficients for attribute levels were calculated using a conditional logit model to estimate their influence on choice decisions and calculate the relative importance of each attribute.Results305 patients (54.5 ± 13,1 years, 65.3% male) were enrolled, and 288 surveys with complete data included for analysis. Attributes with greatest relevance were Waiting time to discuss sleep study results; Waiting time to conduct sleep study, and Sleep quality during measurement. Of lowest importance was Diagnostic accuracy of sleep study, followed by Effort to apply sleep study device. Significant heterogeneity in choice behavior was found, including differences by gender, willingness-to-pay for sleep studies, and previous experience with sleep studies. Preferred location for conducting sleep testing was at-home in 50.7% and in-lab in 46.9%.ConclusionsPreferences and relative importance of home sleep test attributes vary among different subgroups. Considering those preferences can be important for clinicians and policymakers when designing care pathways and planning of testing policies for sleep disorders.

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Molecular Signatures of Senescence in Periodontitis: Clinical Insights.

Most of the elderly population is afflicted by periodontal diseases, creating a health burden worldwide. Cellular senescence is one of the hallmarks of aging and associated with several chronic comorbidities. Senescent cells produce a variety of deleterious secretions, collectively termed the senescence-associated secretory phenotype (SASP). This disrupts neighboring cells, leading to further senescence propagation and inciting chronic inflammation, known as "inflammaging." Detrimental repercussions within the tissue microenvironment can trigger senescence at a younger age, accelerate biological aging, and drive the initiation or progression of diseases. Here, we investigated the biological signatures of senescence in healthy and diseased gingival tissues by assessing the levels of key senescence markers (p16, lipofuscin, and β-galactosidase) and inflammatory mediators (interleukin [IL]-1β, IL-6, IL-8, matrix metalloproteinase [MMP]-1, MMP-3, and tumor necrosis factor-α). Our results showed significantly increased senescence features including p16, lipofuscin, and β-galactosidase in both epithelial and connective tissues of periodontitis patients compared with healthy sites in all age groups, indicating that an inflammatory microenvironment can trigger senescence-like alterations in younger diseased gingival tissues as well. Subsequent analyses using double staining with specific cell markers noted the enrichment of β-galactosidase in fibroblasts and macrophages. Concurrently, inflammatory mediators consistent with SASP were increased in the gingival biopsies obtained from periodontitis lesions. Together, our findings provide the first clinical report revealing susceptibility to elevated senescence and inflammatory milieu consistent with senescence secretome in gingival tissues, thus introducing senescence as one of the drivers of pathological events in the oral mucosa and a novel strategy for targeted interventions.

Disease characterization in cloned foals in Colombia, the effect of placental pathologies on the success and survival of cloned foalsfrom two different cell lines

Cloned foals born in the different cloning programs in the USA, Argentina, and recently in Colombia have experienced several pathological entities during their pregnancy and neonatal period. These entities include abortions, stillbirths, hypoxic-ischemic encephalopathy, large umbilical remanent, and angular deformity on the fore limb. The objectives of this study were to determine whether cloned foals suffer similar diseases and have the same mortality rate as noncloned ones and the differences between cloned foals from two different cell lines (fibroblastic and bone marrow cells) and, to establish whether mares carrying cloned foals from different cell lines have ultrasonographic, paraclinical, and hormonal profile parameters equal to traditional pregnancies and to determine whether there are differences between the cloned foals from the two different cell lines. In the analysis of the continuous variables, significant mean differences were established in the three groups of mares in PCV, hemoglobin, erythrocyte count, MCV, MCH, serum proteins and globulins, and in lymphocyte counts p&lt;0.05. A risk analysis was made for morbidity and mortality associated with the cell origin of the clone and its pregnancy using chi-square sequential tests and logistic regression, and it was considered statistically significant at p&lt; 0.05. A principal component analysis of the paraclinical findings of the mares with the outcome of the foal and the paraclinical parameters of the foals divided by the origin of gestation was performed to evaluate the components of the response variable and their dynamics. Thirty-four pregnancies of clones of fibroblastic origin, 26 of clones of bone marrow origin, and 32 of non-clones were studied. The presentation of placental diseases compatible with placentitis was significantly more frequent (p= 0.026) in mares with cloned foals from fibroblastic cell lines. Neonatal sepsis was determined to be the most frequent disease and was diagnosed more commonly in foals of fibroblastic cell origin—an increase in the risk (OR 37) (p=0.0006). The risk of death was positive and significant with the fibroblast cell line foals (OR: 9.1. P&lt;0.01) compared to the cloned foals of marrow cell origin and non-cloned foals. The risk of death can be predicted in the neonatal period, and some indicators found in this study, such as signs related to placentitis, are associated with increased neonatal mortality and are more frequent in foals of fibroblastic cell origin.

Emerging Roles of Galectin-3 in Pulmonary Diseases.

Galectin-3 is a multifunctional protein that is involved in various physiological and pathological events. Emerging evidence suggests that galectin-3 also plays a critical role in the pathogenesis of pulmonary diseases. Galectin-3 can be produced and secreted by various cell types in the lungs, and the overexpression of galectin-3 has been found in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), pulmonary fibrosis diseases, lung cancer, lung infection, chronic obstructive pulmonary disease (COPD), and asthma. Galectin-3 exerts diverse effects on the inflammatory response, immune cell activation, fibrosis and tissue remodeling, and tumorigenesis in these pulmonary disorders, and genetic and pharmacologic modulation of galectin-3 has therapeutic effects on the treatment of pulmonary illnesses. In this review, we summarize the structure and function of galectin-3 and the underlying mechanisms of galectin-3 in pulmonary disease pathologies; we also discuss preclinical and clinical evidence regarding the therapeutic potential of galectin-3 inhibitors in these pulmonary disorders. Additionally, targeting galectin-3 may be a very promising therapeutic approach for the treatment of pulmonary diseases.