The role of podocyte injury in the pathogenesis of Fabry disease nephropathy / O papel da injúria podocitária na patogênese da nefropatia da doença de Fabry

Abstract Renal involvement is one of the most severe morbidities of Fabry disease (FD), a multisystemic lysosomal storage disease with an X-linked inheritance pattern. It results from pathogenic variants in the GLA gene (Xq22.2), which encodes the production of alpha-galactosidase A (α-Gal), responsible for glycosphingolipid metabolism. Insufficient activity of this lysosomal enzyme generates deposits of unprocessed intermediate substrates, especially globotriaosylceramide (Gb3) and derivatives, triggering cellular injury and subsequently, multiple organ dysfunction, including chronic nephropathy. Kidney injury in FD is classically attributed to Gb3 deposits in renal cells, with podocytes being the main target of the pathological process, in which structural and functional alterations are established early and severely. This configures a typical hereditary metabolic podocytopathy, whose clinical manifestations are proteinuria and progressive renal failure. Although late clinical outcomes and morphological changes are well established in this nephropathy, the molecular mechanisms that trigger and accelerate podocyte injury have not yet been fully elucidated. Podocytes are highly specialized and differentiated cells that cover the outer surface of glomerular capillaries, playing a crucial role in preserving the structure and function of the glomerular filtration barrier. They are frequent targets of injury in many nephropathies. Furthermore, dysfunction and depletion of glomerular podocytes are essential events implicated in the pathogenesis of chronic kidney disease progression. We will review the biology of podocytes and their crucial role in regulating the glomerular filtration barrier, analyzing the main pathogenic pathways involved in podocyte injury, especially related to FD nephropathy.

Resumo O acometimento renal é uma das mais severas morbidades da doença de Fabry (DF), enfermidade multissistêmica de depósito lisossômico com padrão de herança ligada ao cromossomo X, decorrente de variantes patogênicas do gene GLA (Xq22.2), que codifica a produção de alfa-galactosidase A (α-Gal), responsável pelo metabolismo de glicoesfingolipídeos. A atividade insuficiente dessa enzima lisossômica gera depósitos de substratos intermediários não processados, especialmente do globotriaosilceramida (Gb3) e derivados, desencadeando injúria celular e, posteriormente, disfunção de múltiplos órgãos, incluindo a nefropatia crônica. A lesão renal na DF é classicamente atribuída aos depósitos de Gb3 nas células renais, sendo os podócitos o alvo principal do processo patológico, nos quais as alterações estruturais e funcionais são instaladas de forma precoce e severa, configurando uma podocitopatia metabólica hereditária típica, cujas manifestações clínicas são proteinúria e falência renal progressiva. Embora os desfechos clínicos tardios e as alterações morfológicas estejam bem estabelecidos nessa nefropatia, os mecanismos moleculares que deflagram e aceleram a injúria podocitária ainda não estão completamente elucidados. Podócitos são células altamente especializadas e diferenciadas que revestem a superfície externa dos capilares glomerulares, desempenhando papel essencial na preservação da estrutura e função da barreira de filtração glomerular, sendo alvos frequentes de injúria em muitas nefropatias. A disfunção e depleção dos podócitos glomerulares são, além disso, eventos cruciais implicados na patogênese da progressão da doença renal crônica. Revisaremos a biologia dos podócitos e seu papel na regulação da barreira de filtração glomerular, analisando as principais vias patogênicas envolvidas na lesão podocitária, especialmente relacionadas à nefropatia da DF.

Short-chain fatty acid on blood-brain barrier and glial function in ischemic stroke.

Stroke is the second most common cause of death and one of the most common causes of disability worldwide. The intestine is home to several microorganisms that fulfill essential functions for the natural and physiological functioning of the human body. There is an interaction between the central nervous system (CNS) and the gastrointestinal system that enables bidirectional communication between them, the so-called gut-brain axis. Based on the gut-brain axis, there is evidence of a link between the gut microbiota and the regulation of microglial functions through glial activation. This interaction is partly due to the immunological properties of the microbiota and its connection with the CNS, such that metabolites produced by the microbiota can cross the gut barrier, enter the bloodstream and reach the CNS and significantly affect microglia, astrocytes and other cells of the immune system. Studies addressing the effects of short-chain fatty acids (SCFAs) on glial function and the BBB in ischemic stroke are still scarce. Therefore, this review aims to stimulate the investigation of these associations, as well as to generate new studies on this topic that can clarify the role of SCFAs after stroke in a more robust manner.

Chitosan-Tricarbocyanine-Based Nanogels Were Able to Cross the Blood-Brain Barrier Showing Its Potential as a Targeted Site Delivery Agent.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood-brain barrier (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through the effective engineering of nanogels. The primary objective of the present report was to develop and characterize a biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition on the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS and tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NGs can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities' sizes fell into the nanoscale. CNN-CS-NG was found to be non-cytotoxic, as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration, using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS.

Beta-caryophyllene in psychiatric and neurological diseases: Role of blood-brain barrier.

Beta-caryophyllene is an abundant terpene in cannabis, cinnamon, black pepper, cloves, and citrus fruit, delivering a striking, woody-spicy, like cloves and a sweet fruity aroma. Beta-caryophyllene is a Food and Drug Administration-approved food additive with Generally Recognized as Safe status. Interestingly, several biologic activities have been described for beta-caryophyllene, including anti-inflammatory and analgesic effects, neuroprotection against cerebral ischemia and neuronal injury, protection of neurovascular unit against oxidative damage, glial activation and neuroinflammation and anticonvulsant effects. In this chapter, we intend to review the beneficial effects of beta-caryophyllene in the context of psychiatric and neurological diseases. Also, we will analyze the possibility that the blood-brain-barrier may be a central target underlying the beneficial actions of beta-caryophyllene.

Sleep loss impairs blood-brain barrier function: Cellular and molecular mechanisms.

Sleep is a physiological process that preserves the integrity of the neuro-immune-endocrine network to maintain homeostasis. Sleep regulates the production and secretion of hormones, neurotransmitters, cytokines and other inflammatory mediators, both at the central nervous system (CNS) and at the periphery. Sleep promotes the removal of potentially toxic metabolites out of the brain through specialized systems such as the glymphatic system, as well as the expression of specific transporters in the blood-brain barrier. The blood-brain barrier maintains CNS homeostasis by selectively transporting metabolic substrates and nutrients into the brain, by regulating the efflux of metabolic waste products, and maintaining bidirectional communication between the periphery and the CNS. All those processes are disrupted during sleep loss. Brain endothelial cells express the blood-brain barrier phenotype, which arises after cell-to-cell interactions with mural cells, like pericytes, and after the release of soluble factors by astroglial endfeet. Astroglia, pericytes and brain endothelial cells respond differently to sleep loss; evidence has shown that sleep loss induces a chronic low-grade inflammatory state at the CNS, which is associated with blood-brain barrier dysfunction. In animal models, blood-brain barrier dysfunction is characterized by increased blood-brain barrier permeability, decreased tight junction protein expression and pericyte detachment from the capillary wall. Blood-brain barrier dysfunction may promote defects in brain clearance of potentially neurotoxic metabolites and byproducts of neural physiology, which may eventually contribute to neurodegenerative diseases. This chapter aims to describe the cellular and molecular mechanisms by which sleep loss modifies the function of the blood-brain barrier.

Environmental Enrichment Prevents Gut Dysbiosis Progression and Enhances Glucose Metabolism in High-Fat Diet-Induced Obese Mice.

Obesity is a global health concern implicated in numerous chronic degenerative diseases, including type 2 diabetes, dyslipidemia, and neurodegenerative disorders. It is characterized by chronic low-grade inflammation, gut microbiota dysbiosis, insulin resistance, glucose intolerance, and lipid metabolism disturbances. Here, we investigated the therapeutic potential of environmental enrichment (EE) to prevent the progression of gut dysbiosis in mice with high-fat diet (HFD)-induced metabolic syndrome. C57BL/6 male mice with obesity and metabolic syndrome, continuously fed with an HFD, were exposed to EE. We analyzed the gut microbiota of the mice by sequencing the 16s rRNA gene at different intervals, including on day 0 and 12 and 24 weeks after EE exposure. Fasting glucose levels, glucose tolerance, insulin resistance, food intake, weight gain, lipid profile, hepatic steatosis, and inflammatory mediators were evaluated in serum, adipose tissue, and the colon. We demonstrate that EE intervention prevents the progression of HFD-induced dysbiosis, reducing taxa associated with metabolic syndrome (Tepidimicrobium, Acidaminobacteraceae, and Fusibacter) while promoting those linked to healthy physiology (Syntrophococcus sucrumutans, Dehalobacterium, Prevotella, and Butyricimonas). Furthermore, EE enhances intestinal barrier integrity, increases mucin-producing goblet cell population, and upregulates Muc2 expression in the colon. These alterations correlate with reduced systemic lipopolysaccharide levels and attenuated colon inflammation, resulting in normalized glucose metabolism, diminished adipose tissue inflammation, reduced liver steatosis, improved lipid profiles, and a significant reduction in body weight gain despite mice's continued HFD consumption. Our findings highlight EE as a promising anti-inflammatory strategy for managing obesity-related metabolic dysregulation and suggest its potential in developing probiotics targeting EE-modulated microbial taxa.

Effects of different cold plasma treatments on chemical composition, phenolics bioaccessibility and microbiota of edible red mini-roses.

This study evaluated the effect of dielectric barrier discharge (DBD) and glow discharge (glow) cold plasma treatments in color, sugars, organic acids, phenolics (concentration and bioaccessibility), antioxidant activity, volatiles, and microbiota of edible mini-roses. Plasma treatments did not affect the flowers' color, while they increased organic acids and phenolics. Flowers treated with DBD had a higher concentration of most phenolics, including hesperidin (84.04 µg/g) related to antioxidant activity, and a higher mass fraction of most volatiles, including octanal (16.46% after 5 days of storage). Flowers treated with glow had a higher concentration of pelargonidin 3,5-diglucoside (392.73 µg/g), greater bioaccessibility of some phenolics and higher antioxidant activity. Plasma treatments reduced the microbiota diversity in mini-roses. Regardless of the plasma treatment, phylum Proteobacteria, family Erwiniaceae, and genus Rosenbergiella were the dominant groups. Results indicate plasma treatments as promising technologies to improve the quality and increase phenolic and specific volatile compounds in mini-roses.

Can Diet Alter the Intestinal Barrier Permeability in Healthy People? A Systematic Review.

Dietary factors can modify the function of the intestinal barrier, causing permeability changes. This systematic review analyzed evidence on the link between diet or dietary interventions and changes in intestinal barrier permeability (IBP) in healthy individuals. A systematic search for primary studies was conducted using the virtual databases EMBASE, PubMed, Web of Science, CINAHL, and Scopus. This review adhered to PRISMA 2020 guidelines, assessing the methodological quality using the Newcastle-Ottawa scale for observational studies and ROB 2.0 for randomized clinical trials. Out of 3725 studies recovered, 12 were eligible for review. Chicory inulin and probiotics reduced IBP in adults with a moderate GRADE level of evidence. The opposite result was obtained with fructose, which increased IBP in adults, with a very low GRADE level of evidence. Only intervention studies with different dietary components were found, and few studies evaluated the effect of specific diets on the IBP. Thus, there was no strong evidence that diet or dietary interventions increase or decrease IBP in healthy individuals. Studies on this topic are necessary, with a low risk of bias and good quality of evidence generated, as there is still little knowledge on healthy populations.

From Immunity to Neurogenesis: Toll-like Receptors as Versatile Regulators in the Nervous System.

Toll-like receptors (TLRs) are among the main components of the innate immune system. They can detect conserved structures in microorganisms and molecules associated with stress and cellular damage. TLRs are expressed in resident immune cells and both neurons and glial cells of the nervous system. Increasing evidence is emerging on the participation of TLRs not only in the immune response but also in processes of the nervous system, such as neurogenesis and cognition. Below, we present a review of the literature that evaluates the expression and role of TLRs in processes such as neurodevelopment, behavior, cognition, infection, neuroinflammation, and neurodegeneration.

The potential of five c-miRNAs as serum biomarkers for Late-Onset Alzheimer's disease diagnosis: miR-10a-5p, miR-29b-2-5p, miR-125a-5p, miR-342-3p, and miR-708-5p.

The nervous system is rich in miRNAs, indicating an important role of these molecules in regulating processes associated with cognition, memory, and others. Therefore, qualitative and quantitative imbalances involving such miRNAs may be involved in dementia contexts, including Late-Onset Alzheimer's Disease (LOAD). To test the viability of circulating miRNAs (c-miRNAs) as biomarkers for LOAD, we proceed accordingly to the following reasoning. The first stage was to discover and identify profile of c-miRNAs by RNA sequencing (RNA-Seq). For this purpose, blood serum samples were used from LOAD patients (n = 5) and cognitively healthy elderly control group (CTRL_CH) (n = 5), all over 70 years old. We identified seven c-miRNAs differentially expressed (p ≤ 0.05) in the serum of LOAD patients compared to CTRL_CH (miR-10a-5p; miR-29b-2-5p; miR-125a-5p; miR-342-3p, miR-708-5p, miR-380-5p and miR-340-3p). Of these, five (p ≤ 0.01) were selected for in silico analysis (miR-10a-5p; miR-29b-2-5p; miR-125a-5p; miR-342-3p, miR-708-5p), for which 44 relevant target genes were found regulated by these c-miRNAs and related to LOAD. Through the analysis of these target genes in databases, it was possible to observe that they have functions related to the development and progress of LOAD, directly or indirectly connecting the different Alzheimer's pathways. Thus, this work found five promising serum c-miRNAs as options for biomarkers contributing to LOAD diagnosis. Our study shows the complex network between these molecules and LOAD, supporting the relevance of studies using c-miRNAs in dementia contexts.

The Pattern of GH Action in the Mouse Brain.

GH acts in numerous organs expressing the GH receptor (GHR), including the brain. However, the mechanisms behind the brain's permeability to GH and how this hormone accesses different brain regions remain unclear. It is well-known that an acute GH administration induces phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in the mouse brain. Thus, the pattern of pSTAT5 immunoreactive cells was analyzed at different time points after IP or intracerebroventricular GH injections. After a systemic GH injection, the first cells expressing pSTAT5 were those near circumventricular organs, such as arcuate nucleus neurons adjacent to the median eminence. Both systemic and central GH injections induced a medial-to-lateral pattern of pSTAT5 immunoreactivity over time because GH-responsive cells were initially observed in periventricular areas and were progressively detected in lateral brain structures. Very few choroid plexus cells exhibited GH-induced pSTAT5. Additionally, Ghr mRNA was poorly expressed in the mouse choroid plexus. In contrast, some tanycytes lining the floor of the third ventricle expressed Ghr mRNA and exhibited GH-induced pSTAT5. The transport of radiolabeled GH into the hypothalamus did not differ between wild-type and dwarf Ghr knockout mice, indicating that GH transport into the mouse brain is GHR independent. Also, single-photon emission computed tomography confirmed that radiolabeled GH rapidly reaches the ventral part of the tuberal hypothalamus. In conclusion, our study provides novel and valuable information about the pattern and mechanisms behind GH transport into the mouse brain.

W-GA nanodots restore intestinal barrier functions by regulating flora disturbance and relieving excessive oxidative stress to alleviate colitis.

Inflammatory bowel disease (IBD) may arise due to disruption of mucosal barriers as a result of dysregulation of the intestinal flora and excessive oxidative stress. The creation of nanomaterials with only microbiota-regulating effects often leads to inadequate therapeutic outcomes caused by the disruption of a healthy microbial balance and the emergence of tissue harm caused by excessive oxidative stress. This report describes the multifunctional activity of ultrasmall W-GA nanodots, which can precisely regulate the intestinal microbiome by inhibiting the abnormal expansion of Enterobacteriaceae during colitis and alleviating the damage caused by oxidative stress to the reconstructive microflora, ultimately restoring intestinal barrier function. W-GA nanodots have been synthesized through a simple coordination reaction and can be dispersed in various solvents in vitro, demonstrating favorable safety profiles in cells, significant clearance of reactive oxygen and nitrogen species (RONS), and increased cell survival in models of oxidative stress induced by hydrogen peroxide (H2O2). Through oral or intravenous administration, the W-GA nanodots were shown to be highly safe when tested in vivo, and they effectively reduced colon damage in mice with DSS-induced colitis by restoring the integrity of the intestinal barrier. W-GA nanodots have enabled the integration of microflora reprogramming and RONS clearance, creating a potent therapeutic strategy for treating gut inflammation. Consequently, the development of W-GA nanodots represents a promising strategy for enhancing the formation and preservation of the intestinal barrier to treat IBD by suppressing the growth of Enterobacteriaceae, a type of facultative anaerobic bacterium, and facilitating the effective removal of RONS. Ultimately, this leads to the restoration of the intestinal barrier's functionality. STATEMENT OF SIGNIFICANCE: An increasing number of nanoparticles are under development for treating inflammatory bowel disease. Although they can alleviate inflammation symptoms by regulating reactive oxygen and nitrogen species (RONS) and microbiota, their understanding of the mechanism behind microbiota regulation is limited. This study synthesized W-GA nanodots using a straightforward one-pot synthesis method. Simple synthesis holds significant promise for clinical applications, as it encompasses multiple nanoenzyme functions and also exhibits Enterobacteriaceae inhibitory properties.Thus, it contributes to ameliorating the current medical landscape of inflammatory bowel disease.

The Therapeutic Potential of Harpagophytum procumbens and Turnera subulata and Advances in Nutraceutical Delivery Systems in Neurodegenerative Diseases.

This review article covers the therapeutic potential of the plants Harpagophytum procumbens and Turnera subulata in the treatment of neurodegenerative diseases. Despite the recognition of their beneficial properties, there is notable shortage of specific clinical and in vitro studies on these species regarding neurodegenerative diseases. Compounds such as harpagosides and vite-xin-2-O-rhamnoside, found in Harpagophytum procumbens and Turnera subulata, respectively, as well as other antioxidants and anti-inflammatory agents, are associated with mechanisms of action that involve reducing oxidative stress and modulating the inflammatory response, indicating their therapeutic potential in these pathologies. Additionally, the use of nutraceuticals derived from medicinal plants has emerged as a promising approach, offering natural therapeutic alternatives. However, the pressing need for studies focusing on the pharmacokinetics, safety, and pharmacological interactions of these extracts for the treatment of neurodegenerative diseases is emphasized. This review also evaluated advances in nutraceutical delivery systems, highlighting technological innovations that can optimize the precise delivery of these compounds to patients. Such findings highlight the gaps in the study of these plants for the treatment of neurodegenerative diseases and, at the same time, the potential for opening new perspectives in the treatment of neurodegenerative diseases, providing expectations for innovative solutions in this critical domain of medicine.

Effect of Metformin on Sertoli Cell Fatty Acid Metabolism and Blood-Testis Barrier Formation.

Sertoli cells (SCs) are essential to maintaining germ cell development. Metformin, the main pharmacologic treatment for pediatric type 2 diabetes, is administered to children during SC maturation. The present study aimed to analyze whether metformin affects SC energy metabolism and blood-testis barrier (BTB) integrity. Primary SC cultures were used for the in vitro studies. In vivo effects were studied in Sprague-Dawley rats treated with 200 mg/kg metformin from Pnd14 to Pnd30. Metformin decreased fatty acid oxidation and increased 3-hydroxybutyrate production in vitro. Moreover, it decreased the transepithelial electrical resistance across the monolayer and induced ZO-1 redistribution, suggesting an alteration of cell junctions. In vivo, a mild but significant increase in BTB permeability and ZO-1 expression was observed in the metformin group, without changes in testicular histology and meiosis progression. Additionally, adult rats that received metformin treatment during the juvenile period showed no alteration in BTB permeability or daily sperm production. In conclusion, metformin exposure may affect BTB permeability in juvenile rats, but this seems not to influence spermatogenesis progression. Considering the results obtained in adult animals, it is possible to speculate that metformin treatment during the juvenile period does not affect testicular function in adulthood.

Deciphering epigenetic regulations in the inflammatory pathways of atopic dermatitis.

Atopic dermatitis, commonly referred to as atopic eczema, is a persistent inflammatory skin disorder that predominantly manifests in children but may endure into adulthood. Its clinical management poses challenges due to the absence of a definitive cure, and its prevalence varies across ethnicities, genders, and geographic locations. The epigenetic landscape of AD includes changes in DNA methylation, changes in histone acetylation and methylation, and regulation by non-coding RNAs. These changes affect inflammatory and immune mechanisms, and research has identified AD-specific variations in DNA methylation, particularly in the affected epidermis. Histone modifications, including acetylation, have been associated with the disruption of skin barrier function in AD, suggesting the potential therapeutic benefit of histone deacetylase inhibitors such as belinostat. Furthermore, non-coding RNAs, particularly microRNAs and long non-coding RNAs (lncRNAs), have been implicated in modulating various cellular processes central to AD pathogenesis. Therapeutic implications in AD include the potential use of DNA methylation inhibitors and histone deacetylase inhibitors to correct aberrant methylation patterns and modulate gene expression related to immune responses and skin barrier functions. Additionally, the emerging role of lncRNAs suggests the possibility of using small interfering RNAs or antisense oligonucleotides to inhibit lncRNAs and adjust their regulatory impact on gene expression. In conclusion, the importance of epigenetic elements in AD is becoming increasingly clear as studies highlight the contribution of DNA methylation, histone modifications and, control by non-coding RNAs to the onset and progression of the disease. Understanding these epigenetic changes provides valuable insights for developing targeted therapeutic strategies.

Blood-brain barrier biomarkers.

The blood-brain barrier (BBB) is a dynamic interface that regulates the exchange of molecules and cells between the brain parenchyma and the peripheral blood. The BBB is mainly composed of endothelial cells, astrocytes and pericytes. The integrity of this structure is essential for maintaining brain and spinal cord homeostasis and protection from injury or disease. However, in various neurological disorders, such as traumatic brain injury, Alzheimer's disease, and multiple sclerosis, the BBB can become compromised thus allowing passage of molecules and cells in and out of the central nervous system parenchyma. These agents, however, can serve as biomarkers of BBB permeability and neuronal damage, and provide valuable information for diagnosis, prognosis and treatment. Herein, we provide an overview of the BBB and changes due to aging, and summarize current knowledge on biomarkers of BBB disruption and neurodegeneration, including permeability, cellular, molecular and imaging biomarkers. We also discuss the challenges and opportunities for developing a biomarker toolkit that can reliably assess the BBB in physiologic and pathophysiologic states.

Implications of environmental nanoparticles on neurodegeneration.

The ubiquity of nanoparticles, sourced from both natural environments and human activities, presents critical challenges for public health. While offering significant potential for innovative biomedical applications-especially in enhancing drug transport across the blood-brain barrier-these particles also introduce possible hazards due to inadvertent exposure. This concise review explores the paradoxical nature of nanoparticles, emphasizing their promising applications in healthcare juxtaposed with their potential neurotoxic consequences. Through a detailed examination, we delineate the pathways through which nanoparticles can reach the brain and the subsequent health implications. There is growing evidence of a disturbing association between nanoparticle exposure and the onset of neurodegenerative conditions, highlighting the imperative for comprehensive research and strategic interventions. Gaining a deep understanding of these mechanisms and enacting protective policies are crucial steps toward reducing the health threats of nanoparticles, thereby maximizing their therapeutic advantages.

Amelioration of Neurochemical Alteration and Memory and Depressive Behavior in Sepsis by Allopurinol, a Tryptophan 2,3-Dioxygenase Inhibitor.

BACKGROUND: In response to inflammation and other stressors, tryptophan is catalyzed by Tryptophan 2,3-Dioxygenase (TDO), which leads to activation of the kynurenine pathway. Sepsis is a serious condition in which the body responds improperly to an infection, and the brain is the inflammation target in this condition. OBJECTIVE: This study aimed to determine if the induction of TDO contributes to the permeability of the Blood-Brain Barrier (BBB), mortality, neuroinflammation, oxidative stress, and mitochondrial dysfunction, besides long-term behavioral alterations in a preclinical model of sepsis. METHODS: Male Wistar rats with two months of age were submitted to the sepsis model using Cecal Ligation and Perforation (CLP). The rats received allopurinol (Allo, 20 mg/kg, gavage), a TDO inhibitor, or a vehicle once a day for seven days. RESULTS: Sepsis induction increased BBB permeability, IL-6 level, neutrophil infiltrate, nitric oxide formation, and oxidative stress, resulting in energy impairment in 24h after CLP and Allo administration restored these parameters. Regarding memory, Allo restored short-term memory impairment and decreased depressive behavior. However, no change in survival rate was verified. CONCLUSION: In summary, TDO inhibition effectively prevented depressive behavior and memory impairment 10 days after CLP by reducing acute BBB permeability, neuroinflammation, oxidative stress, and mitochondrial alteration.

Lactobacillus delbrueckii CIDCA 133 fermented milk modulates inflammation and gut microbiota to alleviate acute colitis.

Lactobacillus delbrueckii subsp. lactis CIDCA 133 is a health-promoting bacterium that can alleviate gut inflammation and improve the epithelial barrier in a mouse model of mucositis. Despite these beneficial effects, the protective potential of this strain in other inflammation models, such as inflammatory bowel disease, remains unexplored. Herein, we examined for the first time the efficacy of Lactobacillus delbrueckii CIDCA 133 incorporated into a fermented milk formulation in the recovery of inflammation, epithelial damage, and restoration of gut microbiota in mice with dextran sulfate sodium-induced colitis. Oral administration of Lactobacillus delbrueckii CIDCA 133 fermented milk relieved colitis by decreasing levels of inflammatory factors (myeloperoxidase, N-acetyl-ß-D-glucosaminidase, toll-like receptor 2, nuclear factor-κB, interleukins 10 and 6, and tumor necrosis factor), secretory immunoglobulin A levels, and intestinal paracellular permeability. This immunobiotic also modulated the expression of tight junction proteins (zonulin and occludin) and the activation of short-chain fatty acids-related receptors (G-protein coupled receptors 43 and 109A). Colonic protection was effectively associated with acetate production and restoration of gut microbiota composition. Treatment with Lactobacillus delbrueckii CIDCA 133 fermented milk increased the abundance of Firmicutes members (Lactobacillus genus) while decreasing the abundance of Proteobacteria (Helicobacter genus) and Bacteroidetes members (Bacteroides genus). These promising outcomes influenced the mice's mucosal healing, colon length, body weight, and disease activity index, demonstrating that this immunobiotic could be explored as an alternative approach for managing inflammatory bowel disease.

Enhanced oral and pulmonary delivery of biomacromolecules via amplified transporter targeting.

Ligand-modified nanocarriers can promote oral or inhalative administration of macromolecular drugs across the intestinal or pulmonary mucosa. However, enhancing the unidirectional transport of the nanocarriers through "apical uptake→intracellular transport→basolateral exocytosis" route remains a hot topic and challenge in current research. Forskolin is a naturally occurring diterpenoid compound extracted from the roots of C. forskohlii. In our studies, we found that forskolin could increase the transcellular transport of butyrate-modified nanoparticles by 1.67-fold and 1.20-fold in Caco-2 intestinal epithelial cell models and Calu-3 lung epithelial cell models, respectively. Further mechanistic studies revealed that forskolin, on the one hand, promoted the cellular uptake of butyrate-modified nanoparticles by upregulating the expression of monocarboxylic acid transporter-1 (MCT-1) on the apical membrane. On the other hand, forskolin facilitated the binding of MCT-1 to caveolae, thereby mediating butyrate-modified nanoparticles hijacking caveolae to promote the basolateral exocytosis of butyrate-modified nanoparticles. Studies in normal mice model showed that forskolin could promote the transmucosal absorption of butyrate-modified nanoparticles by >2-fold, regardless of oral or inhalative administration. Using semaglutide as the model drug, both oral and inhalation delivery approaches demonstrated significant hypoglycemic effects in type 2 diabetes mice model, in which inhalative administration was more effective than oral administration. This study optimized the strategies aimed at enhancing the transmucosal absorption of ligand-modified nanocarriers in the intestinal or pulmonary mucosa.