Epithelial Changes Research Articles

A Novel Pathogenic Variant in the KRT3 Gene in a Family with Meesmann Corneal Dystrophy

Background/Objectives: to report a novel KRT3 Meesmann corneal dystrophy (MECD) mutation and its clinical findings in a Spanish family, thus completing the international database. Case series study. Methods: Two generations of three family members were studied. The clinical ophthalmologic evaluation was made including best-corrected visual acuity (BCVA), biomicroscopy with and without fluorescein, fundoscopy, Schirmer test I, non-invasive break-up time (NiBUT), and esthesiometry. In vivo confocal microscopy (IVCM), anterior segment optical coherence tomography (AS-OCT) with an epithelial map, and genetic analysis were also performed. Results: A novel heterozygous mutation in the KRT3 gene c.1527G>T (p. Glu509Asp) was identified. Biomicroscopy revealed bilateral multiple corneal intraepithelial cysts. IVCM showed numerous and relatively small microcysts (12–32 µm), hyperreflective materials, subepithelial nerve and Bowman’s layer alterations. AS-OCT scan revealed diffuse hyperreflectivity and the epithelial map displayed thickening of the corneal epithelium in the interpalpebral zone (proband: 52–68 µm and father’s proband: 55–71 µm) with a slightly thinned cornea. Conclusions: We identified a new mutation in the KRT3 gene–c.1527G>T (p. Glu509Asp) in a Spanish family with MECD. A comprehensive characterization of the clinical signs, using different techniques, especially an epithelial map, could be useful to diagnose and monitor epithelial changes by quantitative measures. Epithelial map changes provide better understanding of MECD differential epithelial behavior and its progression changes. Larger studies will be necessary to better understand these specific patterns and clinically evaluate new therapies.

Differential diagnoses of central serous chorioretinopathy : Is that really a central serous chorioretinopathy?

The accurate diagnosis of central serous chorioretinopathy (CSC) and its distinction from differential diagnoses is crucial for effective patient counseling and treatment. This is achieved through a targeted patient history and multimodal imaging, which distinguish CSC from other ocular diseases also characterized by subretinal fluid and changes in the retinal pigment epithelium. In this article we identify the key differential diagnoses of CSC and illustrate the characteristic differential diagnostic features of each disease. The differential diagnoses of CSC can be categorized into eight groups: 1)(neo)vascular choroidal diseases, 2)retinal diseases, 3)inflammatory diseases of the posterior segment, 4)benign and malignant ocular tumors, 5)malignant hematological diseases, 6)genetic disorders, 7)ocular developmental anomalies and 8)medication-related and toxic retinal changes.

Loss of PRICKLE1 leads to abnormal endometrial epithelial architecture, decreased embryo implantation, and reduced fertility in mice

Abstract Successful embryo implantation requires coordinated changes in the uterine luminal epithelium, including structural adaptations, apical-basal polarity shifts, intrauterine fluid resorption, and cellular communication. Planar cell polarity (PCP) proteins, essential for cell organization, are understudied in the context of uterine physiology and implantation. PRICKLE proteins, components of PCP, are suggested to play critical roles in epithelial polarization and tissue morphogenesis. However, their function in the polarized unicellular layer of endometrial epithelium, which supports embryo implantation, is unknown. We developed an endometrial epithelial-specific knockout (cKO) of mouse Prickle1 using Lactoferrin-iCre to investigate its’s role in uterine physiology. Prickle1 ablation in the endometrial epithelium of mice resulted in decreased embryo implantation by gestational day 4.5 leading to lower fertility. Three-dimensional imaging of the uterus revealed abnormal luminal folding, impaired luminal closure, and altered glandular length in mutant uteri. Additionally, we observed decreased aquaporin-2 expression, disrupted cellular architecture, and altered E-Cadherin expression and localization in the mutant uterine epithelium. Evidence of epithelial-mesenchymal transition (EMT) was found within luminal epithelial cells, further linking PRICKLE1 loss to uterine pathologies. Furthermore, altered polarity of cell division leading to incomplete cytokinesis and increase in binuclear or multinucleated cells suggests a crucial role for PRICKLE1 in the maintenance of epithelial architecture. Our findings highlight PRICKLE1's critical role in the PCP pathway within the uterus, revealing its importance in the molecular and cellular responses essential for successful pregnancy and fertility.

P0013 Protein-Energy Malnutrition Induces Microbiome-Dependent Long-Lasting Changes in Intestinal Epithelial Composition

Abstract Background Protein-energy malnutrition (PEM) in childhood is associated with increased susceptibility to infections, endocrine disorders, metabolic syndrome and organ dysfunction later in life1-4. However, the mechanisms behind these long-term effects are poorly understood. While the gut microbiome plays an important role in the aetiology of PEM, little is known about the long-term epithelial changes caused by the microbiome5-7. The aim of this project was to analyse the effects of PEM on the intestinal epithelium in the presence and absence of the microbiome. Methods Conventionally maintained (CONV-R) and germ-free (GF) mice were exposed to isocaloric PEM (0.7% protein) for 4 weeks, followed by a 6-week recovery period (20% protein). Multi-omics was used to analyse the effects of PEM. Changes in the composition of the intestinal epithelium were validated by immunostaining. An organoid differentiation model was used to analyse the hypotheses formulated under ex vivo PEM conditions. Results PEM caused a long-lasting reduction in body weight in CONV-R mice and extensive changes in the intestinal epithelium, including a significant depletion of Paneth cells, compared to GF mice. Furthermore, PEM disrupted microbiota composition and function, particularly affecting amino acid and lipid metabolism. Using a multi-omics approach, we identified the microbiota-derived PPAR-GDF15 axis as a critical mediator of PEM-induced Paneth cell dysfunction. These findings were validated using an ex vivo intestinal organoid model of PEM, which revealed that Paneth cell depletion requires not only the stress-induced cytokine GDF15 as a mediator of PEM, but also a secondary microbiota-dependent hit including lipid metabolites such as 9-HODE and 12,13-diHOME, which act as PPAR agonists. Conclusion PEM induces long-term microbiome-dependent changes in the intestinal epithelium. This malnutrition-microbiome-host axis may be a promising target for therapeutic intervention to counteract the persistent effects of malnutrition.

P0074 Colonic goblet cell dysfunction and gastric intestinal metaplasia in patients with anterior gradient 2 defects and infantile Inflammatory bowel disease

Abstract Background Biallelic anterior gradient 2 (AGR2) loss-of-function variants cause infantile-onset inflammatory bowel disease, alongside histological changes of the gastrointestinal epithelium. The underlying mechanisms on epithelial development and function are not understood. Methods We conducted single-cell RNA-sequencing of gastrointestinal biopsies and organoids from AGR2-deficient patients. Organoids were used for functional investigation of the epithelium and mucus layer by flow cytometry, confocal microscopy, and using a microfluidic organ-chip. Multiplexed imaging was used to characterise intestinal metaplasia in the antrum. Results AGR2-deficiency caused region-specific changes in epithelial cell populations. In the gastric antrum, AGR2-deficiency led to defective epithelial cell differentiation into premalignant metaplastic enterocytes associated with an up-regulation of gastric cancer markers. In the colon, despite a histological depletion of goblet cells, single-cell analysis demonstrated an over-abundance of goblet cells in AGR2-deficiency, exhibiting high ER-stress. We identified defective processing of MUC2 and reduced MUC2 storage in goblet cells without signs of crinophagy, suggesting a stress-induced secretion. Similar to AGR2-deficiency, in ulcerative colitis, goblet cells revealed high ER-stress and no reduction in cell numbers. Conclusion Our data highlight AGR2-deficiency as a genetic model of precancerous intestinal metaplasia in the gastric antrum. Apparent colonic goblet cell depletion in AGR2-deficiency and in ulcerative colitis is a histological artefact, representing a reduction of stored mucins in goblet cells via stress-induced mucus secretion.

P0359 Characteristics and long-term outcomes of biopsy proven serrated epithelial change in patients with inflammatory bowel disease: a retrospective analysis

Abstract Background Serrated epithelial change (SEC) is an increasingly recognised histologic finding in patients with inflammatory bowel disease (IBD) and may be associated with an increased risk of synchronous or metachronous colorectal dysplasia.1,2 The aims of this study were to characterise the clinical and histologic features of IBD patients with SEC and determine the incidence of dysplasia. Methods We performed a retrospective, observational, single-centre study at a tertiary referral hospital. IBD patients with SEC were identified by searching the pathology database for ‘serrated’, ‘epithelial’ and ‘change’ in pathology reports. The first colonic biopsy showing SEC between 2015 to 2023, was designated as the index SEC. SEC was defined as colonic mucosa with goblet cell-rich epithelium, disorganised crypt architecture and irregular serrations without distortion of basal aspects of crypts or features of dysplasia. Patients without follow-up colonoscopy or flexible sigmoidoscopy were excluded (see Figure 1). Clinical and histological data were extracted from electronic medical records and endoscopy reports. Results The cohort included 26 IBD patients (16 with Crohn’s Disease and 10 with ulcerative colitis), consisting of 14 males (53.8%) with a median age of 58 years at the time of the index SEC diagnosis. See Table 1 for patient characteristics. A total of 30 specimens with SEC were identified among the 26 patients, and all patients had at least one follow-up colonoscopy or flexible sigmoidoscopy. The mean disease duration was 15 years, and the median follow-up time was 24.5 months. SEC was detected on high-definition white light endoscopy in 61.5% of cases. SEC was primarily located in the cecum (30%), rectum (23.3%) and transverse colon (16.7%), detected on nodular or polypoid mucosa (60%), and exhibited multifocal distribution (19.2%). In patients with SEC, endoscopic and histologic inflammation was demonstrated in 50% and 46.2% of cases, respectively. One case (3.8%) of low-grade dysplasia in the caecum was observed in a patient with Crohn’s disease. Conclusion SEC was predominantly found as polypoid or nodular lesions proximal to the splenic flexure and associated with endoscopic and histologic inflammation. Larger, prospective, multi-centre studies are necessary to clarify the clinical implications of SEC in IBD, its potential role in carcinogenesis and dysplasia surveillance strategies.

The possible pathogenic mechanisms of microorganisms in infertility: a narrative review.

Infertility can harm a patient in physical, psychological, spiritual, and medical ways. This illness is unusual because it affects the patient's companion and the patient individually. Infertility is a multifactorial disease, and various etiological factors like infection are known to develop this disorder. Recently published studies reported that different bacteria, such as Chlamydia trachomatis, Mycoplasma spp., Ureaplasma urealyticum, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, can lead to infertility by immunopathological effects, oxidative stress, and adverse effects on sperm concentration, motility, morphology, and DNA condensation. Among viruses, Human papillomavirus and Herpes simplex virus reduce sperm progressive motility and sperm concentration. The viruses can lead to the atrophy of the germinal epithelium and degenerative changes in the testes. Candida albicans also harm sperm quality, motility, and chromatin integrity and induce apoptosis in sperm cells. Finally, Trichomonas vaginalis leads to distorted heads, broken necks, and acrosomes exocytosis in sperms. This parasite decreases sperm viability and functional integrity. Noteworthy, oxidative stress could have a role in many pathological changes in the reproductive system. Recent findings show that microorganisms can increase reactive oxygen species concentration inside the host cells, leading to oxidative stress and sperm distress and dysfunction. Therefore, this article explores the potential significance of critical bacteria linked to infertility and their pathogenic mechanisms that can affect sperm function and the female reproductive system.

Pathology of idiopathic pulmonary fibrosis with particular focus on vascular endothelium and epithelial injury and their therapeutic potential.

Idiopathic pulmonary fibrosis (IPF) remains a challenging disease with no drugs available to change the trajectory. It is a condition associated with excessive and highly progressive scarring of the lungs with remodelling and extracellular matrix deposition. It is a highly "destructive" disease of the lungs. The diagnosis of IPF is challenging due to continuous evolution of the disease, which also makes early interventions very difficult. The role of vascular endothelial cells has not been explored in IPF in great detail. We do not know much about their contribution to arterial or vascular remodelling, extracellular matrix changes and contribution to pulmonary hypertension and lung fibrosis in general. Endothelial to mesenchymal transition appears to be central to such changes in IPF. Similarly, for epithelial changes, the process of epithelial to mesenchymal transition seem to be the key both for airway epithelial cells and type-2 pneumocytes. We focus here on endothelial and epithelial cell changes and its contributions to IPF. In this review we revisit the pathology of IPF, mechanistic signalling pathways, clinical definition, update on diagnosis and new advances made in treatment of this disease. We discuss ongoing clinical trials with mode of action. A multidisciplinary collaborative approach is needed to understand this treacherous disease for new therapeutic targets.

Chinese herbal formula Regan Saibisitan alleviates airway inflammation of chronic bronchitis via inhibiting the JAK2/STAT3 pathway.

Regan Saibisitan (RGS) is a classic prescription used to treat cough, pneumonia, and other respiratory infections in Uygur medicine. It is a granule composed of 12 kinds of medicinal materials. However, the mechanism by which RGS regulates lung disease remains unclear. Chronic bronchitis (CB) is characterized by persistent, non-specific inflammation in the trachea, bronchial mucosa, and surrounding tissues mainly resulting from infectious or non-infectious factors. This study aimed to explore the function of RGS in alleviating airway inflammation associated with chronic bronchitis, and to examine the mechanisms by which RGS exerts its effects via the JAK 2/STAT 3 signaling pathway. The CB mouse model was established by cigarette smoking (CS) and intranasal administration of lipopolysaccharide (LPS, 20 μg), histological changes of bronchial epithelium, collagen deposition, mucus secretion in lung tissue and inflammatory factors were assayed. Transcriptomics analysis was performed to detect the differentially regulated genes in lung tissue of CB mice treated with RGS. The effect of RGS on JAK 2/STAT 3 pathway was investigated in CB mice and NCI-H292 cells treated with PMA using western blotting, ELISA, and immunohistochemical analysis. RGS treatment significantly improved the thickening of bronchial epithelium, decreased collagen deposition and secretion of mucus, and the levels of inflammatory factors in CB mice. Transcriptomics analysis showed that most of 402 differentially expressed genes in RGS-treated CB mice were related to inflammatory response. The results in CB mice and NCI-H292 cells showed that RGS reduced the phosphorylation level of JAK 2 and STAT 3. In addition, the use of JAK 2 inhibitor AG490 confirmed that JAK 2/STAT 3 pathway played a key role in the effects of RGS on CB. RGS suppresses inflammation and improves chronic bronchitis in NCI-H292 cells and CB mice, at least in part, via inhibiting the JAK 2/STAT 3 pathway. This study demonstrated that RGS could be a potential drug in treating CB disease.

Gold nanoparticles and induction of structural alteration and enhanced oxidative stress in rat lens.

There is an emerging wide use of nanotechnology in the medical fields. The information regarding distribution and clearance of gold nanoparticles (AuNPs) in the ocular tissue is insufficient. We investigated the cumulative effect of AuNPs on rat lens structure and their effect on the redox state and aquaporin-0 (AQP0) expression. Thirty-six male rats were distributed as follow: control, AuNPs-200 (200μg/kg/rat for 4-weeks) and AuNPs-500 (500μg/kg/rat for 4-weeks) groups. Rats were euthanized after 4-weeks, and the eye lenses were investigated for histological studies, transmission and scanning electron microscopic studies, immunohistochemistry for AQP0 and morphometric measures. Lens homogenates were investigated for tumour necrosis factor-alpha (TNF-α) and total reactive oxygen species levels by ELISA and for p-c-SRC by western-blot. AuNPs administration induced morphological and ultrastructural changes in rat lens. Degenerative changes in the lens epithelium, cytoplasmic vacuoles, distorted separated cortical lens fibers and loss of ball-and-socket junctions were observed. A significant reduction of AQP0-immune-staining with a significant elevation of TNF-α, total ROS and p-c-SRC content in rat lens homogenates were detected as compared to the control group. Repetitive spherical 20nm-sized AuNPs administration, especially at 500μg/kg/rat, induced structural changes in lens fibers of rats and increased oxidative stress level in the lens tissue.

Profound gastric mucosal changes and severe rebound acid hypersecretion after long-term Vonoprazan use: A case report.

Vonoprazan is a novel acid blocker with greater potency than proton pump inhibitors. A Japanese study reported no significant safety concerns over 5 years of Vonoprazan use; however, elevated serum gastrin and increased parietal cell and foveolar hyperplasia were observed, and long-term safety data beyond 5 years are limited. We report a case that used Vonoprazan for 6 years, complicated by significant gastric epithelial changes during treatment and acute duodenal mucosal lesionsfollowing its discontinuation. A 76-year-old, treated with proton pump inhibitors for over 10 years, was switched to Vonoprazan due to his worsening symptoms. After its use, hemorrhagic hyperplastic polyps became prominent. Given concerns about Vonoprazan's effect on the gastric epithelium, the medication was changed to high-dose H2 blocker therapy. Two months later, the patient complained of vomiting and black tarry stools. Esophagogastroduodenoscopy revealed a significant reduction of gastric polyps but multiple erosions and ulcers in the duodenum. This case indicates the potent effects of Vonoprazan on the gastric mucosa and the risk of severe rebound acid hypersecretion after its long-term use.

The geometric basis of epithelial convergent extension.

Shape changes of epithelia during animal development, such as convergent extension, are achieved through the concerted mechanical activity of individual cells. While much is known about the corresponding large-scale tissue flow and its genetic drivers, fundamental questions regarding local control of contractile activity on the cellular scale and its embryo-scale coordination remain open. To address these questions, we develop a quantitative, model-based analysis framework to relate cell geometry to local tension in recently obtained time-lapse imaging data of gastrulating Drosophila embryos. This analysis systematically decomposes cell shape changes and T1 rearrangements into internally driven, active, and externally driven, passive, contributions. Our analysis provides evidence that germ band extension is driven by active T1 processes that self-organize through positive feedback acting on tensions. More generally, our findings suggest that epithelial convergent extension results from the controlled transformation of internal force balance geometry which combines the effects of bottom-up local self-organization with the top-down, embryo-scale regulation by gene expression.

An immunocompetent human kidney on-a-chip model to study renal inflammation and immune-mediated injury.

Kidney damage and dysfunction is an emerging health issue worldwide resulting in high morbidity and mortality rates. Numerous renal diseases are recognized to be driven by the immune system. Despite this recognition, the development of targeted therapies has been challenging as knowledge of the underlying mechanism and complex interactions remains insufficient. Recent advancements in the field offer promising avenues for exploring the interplay between renal cells and immune cells and their role in the development of renal inflammation and diseases. This study describes the establishment of a human immunocompetent 3D in vitro co-culture model of the proximal tubule in a high-throughput microfluidic platform that can be used to study renal functionality and inflammatory processes. 
The model incorporated RPTEC in the top compartment and HUVECs in the bottom compartment cultured under flow and in direct contact with a collagen-I ECM gel resulting in the formation of polarized tubular structures. As an immune component, human primary monocytes of different donors were added to the lumen of the endothelium. Renal inflammation was successfully induced using complement activated serum (CAS) as evident by epithelial morphological changes, increased expression of adhesion molecules, release of pro-inflammatory cytokines, and reduced epithelial viability. Realtime migratory behavior of monocytes showed increased extravasation and migration towards the ECM and Renal compartment upon exposure to CAS with donor-to-donor differences observed. Finally, immune modulatory compounds showed efficacious inhibition of monocyte migration under inflammatory conditions in the microfluidic co-culture model. 
A successful co-culture model was established and can be applied to study renal functionality in health and disease but also for drug screening due to the compatibility of the platform with automation and relatively high throughput. Overall, the described proximal tubule model has high potential to fill the gap that currently exists to study renal inflammation preclinically.&#xD.

Deleterious Effects of Yoyo Dieting and Resistant Starch on Gastrointestinal Morphology.

Obesity is associated with structural deterioration in the gut. Yoyo dieting, which refers to repeated phases of dieting and non-dieting periods leading to cyclic weight loss and regain, is a common occurrence in individuals with obesity. However, there is limited evidence on how gut structures are affected in yoyo dieting. There is good evidence suggesting that increased intake of resistant starch (RS) may be beneficial in promoting structural improvements in the gut. This investigation aimed to explore the effect of yoyo dieting on gastrointestinal structure and whether RS has beneficial effects in improving obesity-related gastrointestinal damage. In this study, male and female C57BL/6 mice were assigned to six different diets for 20 weeks: (1) control diet, (2) high fat diet (HF), (3) yoyo diet (alternating HF and control diets every 5 weeks), (4) control diet with RS, (5) HF with RS, and (6) yoyo diet with RS. Distal colon was collected for epithelial barrier integrity measurement. The small and large intestines were collected for histological assessment. After 20 weeks, yoyo dieting resulted in increased colonic inflammation and exacerbated mucosal damage in comparison with continuous HF diet feeding. RS supplemented in HF and yoyo diets reduced mucosal damage in comparison to diets without RS. However, RS supplementation in a control diet significantly increased inflammation, crypt length, and goblet cell density. There were no significant differences in epithelial change and epithelial barrier integrity across diet groups. This study suggests that yoyo dieting worsens gut damage, and incorporating high levels of RS may be detrimental in the absence of dietary challenge.

Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase 1/2 Multicenter Study (HORIZON): 24-Month Safety and Efficacy Results: Subretinal Gene Therapy AGTC-501 for XLRP Ph 1/2 24M Results

PurposeTo evaluate the safety and efficacy of subretinal gene therapy using AGTC-501 (rAAV2tYF-GRK1-RPGR) in male participants with X-linked retinitis pigmentosa (XLRP). DesignPhase 1/2, open-label, dose-escalation study. MethodsSetting: Four centers in the United States. Patient or Study Population: Twenty-nine males with XLRP and confirmed pathogenic RPGR variants. Mean age was 31.6 years (range 15-55). Intervention: Subretinal injection of AGTC-501 at doses ranging from 2.48 × 1010 to 1.99 × 1012 vg/eye administered in one eye per participant. Subretinal injection sites initially targeted the peripheral retina and then transitioned to the macula with successive cohorts. Main Outcome Measures: Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), laboratory parameters, and immunological responses. Efficacy was evaluated by mesopic microperimetry mean sensitivity. ResultsAll 29 participants experienced ≥1 TEAE. Eleven (38%) experienced ≥1 grade 3 TEAE. Six (21%) experienced ≥1 ocular SAE related to AGTC-501, including retinal detachment (n=4), subcapsular cataract (n=1), and glaucoma (n=1). Two (6.9%) experienced non-ocular treatment-emergent SAEs. Immunological findings did not indicate safety concerns. Three of 4 participants at the highest dose exhibited concerning retinal pigment epithelial changes. Half the participants at the highest tolerated dose (6.8 × 1011vg/eye) maintained ≥7 dB improvement in ≥5 loci at 24 months. ConclusionsSubretinal AGTC-501 was generally well-tolerated. Despite all participants experiencing at least one TEAE, most of these events were mild in nature, exhibited complete resolution, and were associated with the subretinal injection procedure itself rather than the study agent. The highest dose exhibited an unfavorable risk-benefit profile due to the development of RPE changes. Although this group had the highest improvement in retinal sensitivity, our team has decided not to continue this dose in future clinical trials. Preliminary efficacy was observed at the maximum tolerated dose. Further studies are warranted to assess long-term safety and efficacy of AGTC-501 for XLRP treatment.

Changes in mucosal epithelia of marine Atlantic salmon (Salmo salar) under chronic heat stress

Changes in mucosal epithelia of marine Atlantic salmon (Salmo salar) under chronic heat stress

Pathology Findings and In-Life Correlates in the Nonclinical Development of Adeno-Associated Virus (AAV)-Based Retinal Gene Therapies.

Adeno-associated virus (AAV)-based vectors are the most frequently used platform for retinal gene therapy. Initially explored for the treatment of loss-of-function mutations underpinning many inherited retinal diseases, AAV-based ocular gene therapies are increasingly used to transduce endogenous cells to produce therapeutic proteins, thus producing site-specific biofactories. Relatively invasive ocular routes of administration (ROA) mean prominent procedure-related in-life, and histopathological findings may be observed with some regularity. Test article-related findings may vary with the ROA and cell populations transduced, with retinal pigmented epithelium (RPE) changes prominent (ranging from pigment alteration through degeneration, with or without associated degeneration of the overlying retina) with subretinal ROA, and more anterior changes (iris, ciliary body) generally observed with the intravitreal ROA. Ocular inflammation is the most frequent finding that occurs nonclinically and in patients, and is particularly pronounced with intravitreal administration. Extraocular findings may be observed in extraocular muscles, regional ganglia, or central visual pathways with multiple ocular ROA. Work is still needed to understand the mechanisms underpinning many of these ocular and extraocular findings. Emerging patient data is helping to clarify both the potential for translating nonclinical findings to predict possible human responses and the applicability of nonclinical biomonitoring methods to the clinical setting.

Effects of sublethal concentration of thiamethoxam formulation on the wild stingless bee, Partamona helleri Friese (Hymenoptera: Apidae): Histopathology, oxidative stress and behavioral changes

Bees are pollinators of native and cultivated plants around the world. However, several factors are contributing to the decrease in their populations in recent years, with emphasis on the increasing use of insecticides in agriculture. Thiamethoxam is a neonicotinoid neurotoxicant, which binds to nicotinic acetylcholine receptors, causing hyperexcitation, paralysis and death of insects. Although thiamethoxam's target is the nervous system, it can affect other organs through ingestion, such as the midgut, affecting non-target insects such as bees. Partamona helleri Friese (Hymenoptera: Apidae) is a stingless bee, pollinator of several native and cultivated botanical families, and can be exposed to sublethal concentrations of thiamethoxam. This study evaluated the side effects of chronic oral exposure to thiamethoxam on the midgut, oxidative stress and behavior of P. helleri workers. The bees were exposed orally, for 7 days, to the approximate sublethal concentration of thiamethoxam found in pollen grains (0.09 ng/g). The results demonstrated changes in the midgut epithelium of workers treated with thiamethoxam, such as cytoplasmic vacuolization, cellular protrusions, increased apocrine transfer, mitochondrial damage, decreased proteins and neutral polysaccharides and the presence of cells undergoing autophagy and apoptosis. Sublethal concentration of thiamethoxam also induced oxidative stress, evidenced by changes in the activities of detoxification enzymes and antioxidant markers. Finally, thiamethoxam affects the bee's behavior, driving the distance covered and walking speed of this insect. The results indicate that the exposure of P. helleri workers to sublethal concentration of thiamethoxam have negative impacts upon midgut morphology and physiology and behavioral traits.

Influence of Hypoxia on the Airway Epithelium

The necessity of oxygen for metabolic processes means that hypoxia can lead to serious cell and tissue damage. On the other hand, in some situations, hypoxia occurs under physiological conditions and serves as an important regulation factor. The airway epithelium is specific in that it gains oxygen not only from the blood supply but also directly from the luminal air. Many respiratory diseases are associated with airway obstruction or excessive mucus production thus leading to luminal hypoxia. The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction.

Chronic Exposure of Zebrafish to Iron and Aluminum: Evaluation of Reversal and Generational Transposition of Behavioral, Histopathological, and Genotoxic Changes.

This study aimed to report the effects of chronic exposure of zebrafish exposed to environmentally relevant concentrations of 0.5, 2.4, and 5.0 mg L-1 iron (Fe) and 0.2, 0.4, and 2.0 mg L-1 aluminum (Al). We also evaluated the reversal and generational transposition (F1) of possible histopathological, behavioral, and genotoxic changes in the species. Locomotion changes that may have been caused by the increase in the number of apoptotic cells and in the telencephalic mitochondrial activity were observed especially after the 30 days exposure to Al and persisted after recovery (30 days). We also observed histopathological changes, such as an increase in the number of intestinal goblet cells, even after the recovery period in these animals. Our results also showed that the Fe concentrations used were insufficient to cause genotoxicity, behavioral and intestinal epithelium changes. The adult offspring (F1) of animals exposed to Al showed changes in locomotion and in the amount of goblet cells, demonstrating that even in low concentrations this pollutant can harm subsequent generations in the aquatic biota. Animals demonstrate, in general, greater tolerance to Fe which may be related to the physiological demand of this metal by the body. Even so, all concentrations of both metals that caused some change in the species represent Brazilian environmental occurrences or Brazilian legislation. It highlights the need for updating the guidelines and constant monitoring of aquatic environments, since even in the face of a hypothetical decontamination of the environment, some changes could persist and affect different trophic levels.