Maintenance Of Function Research Articles

DOP030 Mucosal deficiency of mitochondria-driven humoral immunity is linked to Crohn’s Disease

Abstract Background Secretory IgA (sIgA) is critical for the maintenance of the mucosal barrier function, preventing bacterial translocation and reducing the risk of chronic inflammation. Several decades of research have revealed a dysregulation of the B-cell compartment in inflammatory bowel disease (IBD) of yet unknown origin1,2. While increased serum levels of (auto)antibodies against S. cerevisiae or the intestinal M-cell expressed FimH receptor glycoprotein 2 (GP2) are observed in patients with Crohn’s disease (CD)3, some studies indicated an impaired generation of intestinal immunoglobulin-secreting plasma cells (PCs)4. To unravel the role of mucosal humoral immunity in CD pathogenesis, we aimed to provide an in-depth characterisation of colonic PC differentiation in patients with CD. Methods In-depth phenotyping of patients with CD in remission and non-IBD controls (hospitalised normals) was performed using multi-omics analyses (spatial single-cell proteomics, proteomics, metabolomics, and transcriptomics) of plasma or colon biopsy samples. Colonic switched memory B cells (sMBCs) were sorted from lamina propria mononuclear cells (LPMNCs) by magnetic-activated cell sorting and ex vivo differentiated into PCs. The impact of mitochondrial function on colonic PC maturation was studied in mitochondrial respiratory chain complex V-deficient ATP8 mutant mice and mice that underwent nutritional intervention. Results Despite a hyperactive colonic B-cell compartment, patients with CD displayed significantly diminished mucosal dimeric IgA (dIgA) and fecal IgA compared to non-IBD controls. Polymeric immunoglobulin receptor (PIGR) expression did not differ, excluding a defective epithelial transcytosis of dIgA. Spatial single-cell proteomics uncovered that colonic plasmablasts and immature CD19+CD45+ PCs were increased at the expense of the fully mature CD19-CD45- phenotype. Consistently, PCs generated ex vivo from CD-derived sMBCs revealed impaired capacity to differentiate into IgA-secreting PCs. Metabolic phenotyping indicated a colonic mitochondrial dysfunction in patients with CD that was also reflected in colonic PCs by increased expression of the cell-surface NADase CD38 in concert with decreased expression of mitochondrially encoded transcripts. Of note, splenic PCs isolated from ATP8 mutant mice displayed a hyperproliferative and low-differentiated phenotype, while colonic IgA-secreting PCs were reduced. Conversely, feeding mice an isocaloric glucose-free, high-protein diet, which promotes mitochondrial activity, increased colonic IgA levels. Conclusion In summary, this study links mitochondrial dysfunction to impaired PC differentiation in patients with CD, resulting in reduced levels of sIgA and thereby compromised mucosal barrier integrity.

P0196 Metabolic dysregulation in Crohn’s disease fibrosis: Targeting WISP1 to restore ECM homeostasis

Abstract Background In patients with Crohn’s disease (CD), homeostasis of the extracellular matrix (ECM) is significantly disrupted, frequently leading to severe complications such as intestinal stenosis. The maintenance of organ functionality depends on a delicate balance between inflammatory mediators, ECM production, and degradation processes. However, these mechanisms remain poorly understood. This study investigates the dynamic interplay between ECM homeostasis and metabolic pathways in CD, providing novel insights into their role in disease pathogenesis and potential therapeutic intervention. Methods Bulk RNA sequencing was performed to compare fibrotic and non-fibrotic intestinal tissues from CD patients undergoing ileocecal resection, aiming to identify key metabolic and ECM-related pathways. Primary matrix-producing fibroblasts were studied in 2D cultures and spheroids to characterize their metabolic activity, with a focus on fatty acid oxidation (FAO) and glycolysis through gene and protein analysis, metabolic assays, and fatty acid profiling (GC-FID). Chronic intestinal fibrosis was modelled in vivo using dextran sodium sulfate (DSS)-treated mice, allowing therapeutic evaluation of WISP1 neutralisation. The in vivo model was characterized using histological and clinical scoring, as well as gene and protein expression analysis. Results Gene set enrichment analysis revealed increased WNT signaling coupled with a reduction in fatty acid metabolism. Additionally, fibrotic tissue exhibited elevated levels of oleic acid and palmitate, indicative of increased lipid accumulation. WISP1, a WNT mediator, was identified as an adipokine and a key regulator of the metabolic shift from fatty acid oxidation to glycolysis. The disruption of FAO-related genes, including PPARγ, CPT1A, CPT2, and ACOX1, demonstrated reciprocal effects on fibroblast activity: pharmacological inhibition of FAO increased matrix production by fibroblasts, whereas activation of FAO via the PPARα agonist fenofibrate induced a catabolic fibroblast phenotype. This phenotype was characterized by suppressed ECM expression and enhanced ECM degradation via MMP1. Importantly, therapeutic neutralization of WISP1 significantly reduced fibrosis in a chronic DSS-induced colitis model. Conclusion This study presents a novel therapeutic strategy for managing fibrosis in Crohn’s disease. By pharmacologically neutralizing WISP1, this approach aims to correct the underlying metabolic dysfunction, thereby restoring metabolic balance and ECM homeostasis.

Anillin tunes contractility and regulates barrier function during Rho flare-mediated tight junction remodeling.

To preserve barrier function, cell-cell junctions must dynamically remodel during cell shape changes. We have previously described a rapid tight junction repair pathway characterized by local, transient activations of RhoA, termed "Rho flares," which repair leaks in tight junctions via promoting local actomyosin-mediated junction remodeling. In this pathway, junction elongation is a mechanical trigger that initiates RhoA activation through an influx of intracellular calcium and recruitment of p115RhoGEF. However, mechanisms that tune the level of RhoA activation and Myosin II contractility during the process remain uncharacterized. Here, we show that the scaffolding protein Anillin localizes to Rho flares and regulates RhoA activity and actomyosin contraction at flares. Knocking down Anillin results in Rho flares with increased intensity but shorter duration. These changes in active RhoA dynamics weaken downstream F-actin and Myosin II accumulation at the site of Rho flares, resulting in decreased junction contraction. Consequently, tight junction breaks are not reinforced following Rho flares. We show that Anillin-driven RhoA regulation is necessary for successfully repairing tight junction leaks and protecting junctions from repeated barrier damage. Together, these results uncover a novel regulatory role for Anillin during tight junction repair and barrier function maintenance.

Cathepsins: Novel opportunities for antibody therapeutics in cancer.

Cathepsins, the most abundant lysosomal proteases, have key functions in cell maintenance and homeostasis. They are overexpressed and hypersecreted in cancer and associated with poor prognosis. Secreted cathepsins display pro-tumour activities in the tumour microenvironment and thus represent interesting molecular targets in oncology. Recently, several antibody-based cancer therapies have targeted the pro-tumour activity of the extracellular cathepsin pool, altering several cancer hallmarks, but not the intracellular cathepsin levels that are often crucial for cell homeostasis. In this mini-review, we describe advances in antibodies against extracellular cathepsins in cancer, and their effect on the proteolytic cascade, matrix remodelling, proliferation, and modulation of the anti-cancer immune response. We also discuss the add-on value of combination strategies (anti-cathepsin antibodies with chemotherapy and/or biologics) that make anti-cathepsin antibodies a new opportunity for disease management.

Butyrolactone I blocks the transition of acute kidney injury to chronic kidney disease in mice by targeting JAK1.

Chronic kidney disease (CKD) is a disease that affects more than 850 million people. Acute kidney injury (AKI) is a common cause of CKD, and blocking the AKI-CKD transition shows promising therapeutic potential. Herein, we found that butyrolactone I (BLI), a natural product, exerts significant nephroprotective effects, including maintenance of kidney function, inhibition of inflammatory response, and prevention of fibrosis, in both folic acid- and ureteral obstruction-induced AKI-CKD transition mouse models. Notably, BLI showed greater blood urea nitrogen reduction and anti-inflammatory effects than telmisartan. Bioinformatics analysis and target confirmation assays suggested that BLI directly binds to JAK1, and kinase inhibition assay confirmed it is a potent JAK1inhibitor with an IC50 of 0.376µM. Experiments in JAK1-knockdown mice also proved that BLI targets JAK1 to work. Furthermore, BLI demonstrated nephroprotective effects and safety comparable to ivarmacitinib, the well-known JAK1 inhibitor. Mechanistically, BLI targets JAK1 and inhibits its phosphorylation and JAK-STAT activation, subsequently regulating the downstream signaling pathways to inhibit reactive oxygen species production, inflammation, and ferroptosis, thereby preventing the occurrence of kidney fibrosis and blocking the AKI-CKD transition process. This study demonstrates for the first time that BLI is a JAK1 inhibitor and a promising candidate for delaying CKD progression, which warrants further investigation.

Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic β-like cells and rather enhances gain in β cell identity gene sets.

Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti-diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models. Human iPSCs are differentiated into SC-islets by three-dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC-islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC-islets. SC-islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP. Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin. Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.

MiR-199a-3p mitigates simulated microgravity-induced cardiac remodeling by targeting MEF2C.

Microgravity-induced cardiac remodeling and dysfunction present significant challenges to long-term spaceflight, highlighting the urgent need to elucidate the underlying molecular mechanisms and develop precise countermeasures. Previous studies have outlined the important role of miRNAs in cardiovascular disease progression, with miR-199a-3p playing a crucial role in myocardial injury repair and the maintenance of cardiac function. However, the specific role and expression pattern of miR-199a-3p in microgravity-induced cardiac remodeling remain unclear. We separately utilized mouse tail suspension and rhesus monkey bedrest models to construct simulated microgravity conditions and observed significant cardiac remodeling and dysfunction in both species, accompanied by a marked downregulation of miR-199a-3p expression in their hearts. By generating cardiac-specific transgenic (TG) mice and subjecting them to tail suspension, we observed that the wild-type (WT) mice exhibited cardiac remodeling characterized by increased fibrosis, smaller cardiomyocytes, and reduced ejection fraction (EF). In contrast, the miR-199a-3p TG mice were able to counteract the cardiac remodeling induced by tail suspension, demonstrating that miR-199a-3p can protect against simulated microgravity-induced cardiac remodeling. Subsequently, we employed an AAV9-mediated delivery system for cardiac-specific overexpression of miR-199a-3p, significantly mitigating cardiac remodeling and dysfunction induced by simulated microgravity. Mechanistically, miR-199a-3p targets MEF2C, inhibiting its activation induced by simulated microgravity, thereby suppressing the associated cardiac remodeling. This research identifies miR-199a-3p as a promising therapeutic target with significant potential for precise protection against spaceflight-induced cardiovascular dysfunction.

Systematic analysis of molecular mechanisms of action of essential macro- and micronutrients on the neurotransmitter and vasodilator molecule nitric oxide (NO)

Maintaining adequate levels of nitric oxide (NO) in the blood and other body tissues is necessary for the regulation of vascular tone, blood pressure, maintenance of oxygen metabolism and endothelial function. NO is also involved in regulating the balance of excitatory (glutamate) and inhibitory (gamma-aminobutyric acid) neurotransmission. Nutritional factors profoundly affect NO metabolism. Systematic computer analysis of 26,103 publications by methods of topological approach to recognition allowed to identify the most crucial fields of clinical research assessing relationships between NO metabolism and nutrients: arginine-derived NO synthase-driven NO production, nitrate-containing products, folates and vitamin B12 in NO homeostasis (including the effects of modifications of the vitamin B12 molecule), other B vitamins (B1, B2, B7), antioxidant vitamins (C and E), hormone-like vitamins D3 and A, electrolytes magnesium and calcium, participation of the microbiome in NO production.

Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice

The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obscured by redundancy among the Nr4a family members and by their reported functions in Treg generation and maintenance. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to show that Nr4a1 and Nr4a3 are essential for the upregulation of Bcl2l11/BIM and thymic clonal deletion by self-antigen. Importantly, thymocytes lacking Nr4a1/3 acquire an anergy-like signature after escaping clonal deletion and Treg lineage diversion. We further show that the Nr4a family helps mediate a broad transcriptional program in self-reactive thymocytes that resembles anergy and may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.

Mitochondrial Porin Is Required for Versatile Biocontrol Trait-Involved Biological Processes in a Filamentous Insect Pathogenic Fungus.

The mitochondrial voltage-dependent anion channel (VDAC) is the major channel in the mitochondrial outer membrane for metabolites and ions. VDACs also regulate a variety of biological processes, which vary in the number of VDAC isoforms across different eukaryotes. However, little is known about VDAC-mediated biocontrol traits in biocontrol fungi. Here, the only VDAC isoform (BbOmm1) in the filamentous insect pathogenic fungus Beauveria bassiana was characterized, which was crucial for maintenance of mitochondrial homeostasis and function and important biocontrol traits. Besides serious impairment of fungal growth, conidiation, and germination, inactivation of BbOmm1 led to increased sensitivity/tolerance to oxidative and osmotic stresses and production of oosporein and other secondary metabolites, which corresponded to the mitochondrial damage, downregulation of membrane lipid and cell wall homeostasis-involved genes, and upregulation of detoxification genes and biosynthesis gene clusters of those metabolites. These results enrich our understanding of VDAC-mediated biocontrol traits in insect fungal pathogens.

A feedback loop between Paxillin and Yorkie sustains Drosophila intestinal homeostasis and regeneration

Balanced self-renewal and differentiation of stem cells are crucial for maintaining tissue homeostasis, but the underlying mechanisms of this process remain poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Pax, which is orthologous to mammalian PXN, coordinates the proliferation and differentiation of ISCs during both normal homeostasis and injury-induced midgut regeneration in Drosophila. Loss of Pax promotes ISC proliferation while suppressing its differentiation into absorptive enterocytes (ECs). Mechanistically, our findings demonstrate that Pax is a conserved target gene of the Hippo signaling pathway in both Drosophila and mammals. Subsequent investigations have revealed Pax interacts with Yki and enhances its cytoplasmic localization, thereby establishing a feedback regulatory mechanism that attenuates Yki activity and ultimately inhibits ISCs proliferation. Additionally, Pax induces the differentiation of ISCs into ECs by activating Notch expression, thus facilitating the differentiation process. Overall, our study highlights Pax as a pivotal component of the Hippo and Notch pathways in regulating midgut homeostasis, shedding light on this growth-related pathway in tissue maintenance and intestinal function.

Age and Sex-Based Differences in Therapy Preferences Among Patients with Cancer: Evidence from a Novel Therapy Preference Scale.

Patients' preferences are crucial to formulating personalized treatment plans. We developed a self-reported questionnaire, Therapy Preference Scale (TPS), to examine treatment preferences of patients with cancer. TPS has 30 questions-19 on patients' preferences on safety, quality of life, and treatment effectiveness, 8 questions on importance of various treatment characteristics, and 3 on patients' preferred intent of therapy, expenses, and life expectancy gain. We recruited 300 adults>18 years with a cancer diagnosis and categorized them into 4 age-by-sex groups (younger men<60 years, older men≥60 years, younger women<60 years, older women≥60 years). Kruskal-Wallis non-parametric ANOVA method was used to compare responses among 4 groups. Older women, compared to other groups, were more likely to value maintenance of cognitive function and ability to perform daily activities. Older women were more likely to risk having a shorter life expectancy rather than facing the risk of long-term cognitive impairments. Younger men and women were more likely to accept more effective treatment, even if it caused significant pain. A higher percentage of younger men, compared to other groups, valued maintaining sex life. Older men and women were more likely to prefer oral pills over intravenous therapy. Patient preferences may vary based on age and sex with older women prioritizing cognitive and physical function independence more frequently, whereas younger men and women willing to pursue more effective treatment options even with a greater risk of significant pain. TPS can elicit detailed preferences of an individual patient to facilitate shared decision-making with their oncologists.

Acute respiratory distress syndrome : Pathophysiology, definition and treatment strategies

Acute respiratory distress syndrome (ARDS) is defined as an acute inflammatory syndrome leading to increased pulmonary capillary leakage and subsequent interstitial and alveolar pulmonary edema. Hypoxia is the predominant symptom. The definition of ARDS comprises acute onset, bilateral patchy infiltration on chest X‑ray and areduction of the ratio of arterial partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2), which also determines the classification into mild (≤ 300), moderate (≤ 200) and severe (≤ 100) ARDS. Treating the underlying cause is the only causal treatment measure. The aim of adjunctive therapy is the maintenance of life or organ functions by ensuring an adequate gas exchange without further damaging the lungs. Adjunctive therapy consists mainly of individually adapted "protective" ventilation treatment and the prone position. In severest ARDS, the use of venovenous extracorporeal membrane oxygenation (VV-ECMO) can improve survival if strict criteria for indications and contraindications are followed.

Epigenetic Regulatory Processes Involved in the Establishment and Maintenance of Skin Homeostasis-The Role of Microbiota.

Epigenetic mechanisms are central to the regulation of all biological processes. This manuscript reviews the current understanding of diverse epigenetic modifications and their role in the establishment and maintenance of normal skin functions. In healthy skin, these mechanisms allow for the precise control of gene expression, facilitating the dynamic balance between cell proliferation and differentiation necessary for effective barrier function. Furthermore, as the skin ages, alterations in epigenetic marks can lead to impaired regenerative capacity and increased susceptibility to environmental stressors. The interaction between skin microbiota and epigenetic regulation will also be explored, highlighting how microbial communities can influence skin health by modulating the host gene expression. Future research should focus on the development of targeted interventions to promote skin development, resilience, and longevity, even in an ever-changing environment. This underscores the need for integrative approaches to study these complex regulatory networks.

REV7: a small but mighty regulator of genome maintenance and cancer development.

REV7, also known as MAD2B, MAD2L2, and FANCV, is a HORMA-domain family protein crucial to multiple genome stability pathways. REV7's canonical role is as a member of polymerase ζ, a specialized translesion synthesis polymerase essential for DNA damage tolerance. REV7 also ensures accurate cell cycle progression and prevents premature mitotic progression by sequestering an anaphase-promoting complex/cyclosome activator. Additionally, REV7 supports genome integrity by directing double-strand break repair pathway choice as part of the recently characterized mammalian shieldin complex. Given that genome instability is a hallmark of cancer, it is unsurprising that REV7, with its numerous genome maintenance roles, is implicated in multiple malignancies, including ovarian cancer, glioma, breast cancer, malignant melanoma, and small-cell lung cancer. Moreover, high REV7 expression is associated with poor prognoses and treatment resistance in these and other cancers. Promisingly, early studies indicate that REV7 suppression enhances sensitivity to chemotherapeutics, including cisplatin. This review aims to provide a comprehensive overview of REV7's myriad roles in genome maintenance and other functions as well as offer an updated summary of its connections to cancer and treatment resistance.

Detailed analysis of cystic lesions in patients after open fetal repair and postnatal myelomeningocele closure

PurposeWe sought to evaluate the incidence, natural history, and management of cystic spinal lesions following myelomeningocele/myeloschisis closure.MethodsWe performed a single-center retrospective review of all patients who underwent myelomeningocele/myeloschisis closure from 2013 to 2018 with follow-up to 5 years old.ResultsWe analyzed 100 fetal repairs and 81 postnatal closures from 305 total surgeries. Patients within this cohort systematically underwent serial MRI scans of the lumbar spine and had clinical follow-up until at least 5 years of age. Ninety-three (51.2%) developed radiographic evidence of cystic lesions with 28 (30.1%) requiring surgical intervention. Presence of cysts was higher in fetal repair (67/100, 67%) compared with postnatal (26/81, 32.1%; p < 0.01). Of the 93 patients with radiographic cysts, 28 (30.1%) underwent surgical resection at a median age of 27.6 months old ([Q1, Q3], [13.0, 48.6 months]). Fetal repair patients had a higher rate (26/67, 38.8%) of cysts requiring surgical resection compared with postnatal closure (2/26, 7.7%, p value < 0.01). Pathology demonstrated 18 of resected cysts were dermoid, 8 were epidermoid, and 2 were fibrous tissue. Post-operatively, no patients experienced a worsened ambulation status. Bladder compliance showed a non-significant trend toward improvement.ConclusionsCystic lesions in myelomeningocele/myeloschisis patients are common findings that result in nerve root tethering. We propose regular screening in both symptomatic and asymptomatic patients to circumvent nerve injury. Most cystic lesions do not require surgical resection though fetal repair is associated with a higher incidence of operative cysts. However, these lesions can be safely surgically resected with maintenance of ambulation and urologic function.

An investigation into the factors associated with pregnancy associated glycoproteins in milk in seasonal-calving pasture-based dairy cows.

Pregnancy associated glycoproteins (PAG) are secreted by trophoblast giant cells, and are detectable in blood and milk within the first month of gestation. The PAG concentration in blood and milk is believed to be one indicator of placental function and predictive of pregnancy maintenance. The objective of this retrospective study was to investigate factors associated with milk PAG S-N profiles in cows managed under a seasonal calving, pasture-based production system. Spring-calving dairy cows (n = 496) located in 3 Teagasc Research farms in Ireland were enrolled in the study. Milk samples were collected weekly from each cow from wk 5 to 21 after artificial insemination (AI) to determine milk PAG S-N values. Body condition score was measured every 2 weeks on a scale of 1 to 5 with 0.25 increments. Only cows that conceived to first AI and maintained pregnancy were retained for the final analysis (n = 247). Mixed models were used to evaluate the fixed effects of week after AI, BCS, dam fertility index (FI) and milk index (MI), milk yield category, sire, parity, calf sex and calf birthweight on weekly milk PAGS-N profile, initial peak PAG, nadir PAG and post nadir recovery peak PAG. Week after AI was associated with milk PAG S-N values, with initial peak values observed on (mean and 95% CI) wk 6.4 ([6.2, 6.5]) after AI, nadir values on wk 8.6 ([8.55, 8.90]) after AI followed by recovery thereafter. We observed associations between parity, dam FI, milk yield, sire of the gestating embryo/fetus, fetal sex, and full-term calf birthweight with different aspects of the PAG S-N profile. Cows with the greatest FI had greater milk PAG S-N values at wk 5 and 6 after AI compared with cows with intermediate FI and least FI. There was also an association with parity because parity 1 cows had greater milk PAG S-N values than parity 2 and parity 3 cows during the initial peak and nadir stages of the PAG profile. An effect of sire on nadir milk PAG S-N values was observed, with PAG S-N values ranging from 0.5 to 1.2 between sires. In summary, milk PAG concentrations were associated with dam genetic merit, phenotypic milk production, and fetal characteristics. Assuming a correlation between milk PAG S-N values and placental function, these data provide evidence for an effect of genetic selection for fertility traits on placental development and/or function.

Zinc and its binding proteins: essential roles and therapeutic potential.

Zinc is an essential micronutrient that participates in a multitude of cellular and biochemical processes. It is indispensable for normal growth and the maintenance of physiological functions. As one of the most significant trace elements in the body, zinc fulfills three primary biological roles: catalytic, structural, and regulatory. It serves as a cofactor in over 300 enzymes, and more than 3000 proteins require zinc, underscoring its crucial role in numerous physiological processes such as cell division and growth, immune function, tissue maintenance, as well as synthesis protein and collagen synthesis. Zinc deficiency has been linked to increased oxidative stress and inflammation, which may contribute to the pathogenesis of a multitude of diseases, like neurological disorders and cancer. In addition, zinc is a key constituent of zinc-binding proteins, which play a pivotal role in maintaining cellular zinc homeostasis. This review aims to update and expand upon the understanding of zinc biology, highlighting the fundamental roles of zinc in biological processes and the health implications of zinc deficiency. This work also explores the diverse functions of zinc in immune regulation, cellular growth, and neurological health, emphasizing the need for further research to fully elucidate the therapeutic potential of zinc supplementation in disease prevention and management.

Selective Labeling of Phosphatidylcholine to Track Their Translocation Between Organelles in Living Cells.

Phosphatidylcholine (PC) is a major phospholipid that forms biological membranes in eukaryotes. PC is mainly synthesized in the endoplasmic reticulum (ER) and Golgi apparatus and then transported to other organelle membranes via multiple mechanisms. Such interorganelle lipid transport is thought to play an important role in the maintenance of cell morphology, organelle functions, and homeostasis, though the details of this process have not yet been well investigated. This chapter describes a technology for the selective labeling and fluorescence imaging of PC in target organelles. This approach involves the metabolic incorporation of azidocholine, followed by a spatially restricted bioorthogonal click reaction that enables the visualization and quantitative analysis of interorganelle PC transport in live cells using confocal microscopy.

Role of vitamin A on the ocular surface.

Vitamin A is an essential fat-soluble vitamin that cannot be endogenously synthesized by the human body. Retinoic acid (RA) is the biologically active form of vitamin A. Utilizing both nuclear and non-nuclear receptor-mediated pathways, RA plays a crucial role in regulating various biological processes, including apoptosis, differentiation, and anti-inflammatory properties within the cornea and conjunctiva. In addition, RA has been demonstrated to exert a significant influence on anti-tumor mechanisms. Disruption of RA signaling can result in corneal defects, anophthalmia, and microphthalmia. However, the beneficial effects of RA are only observed when it is administered at appropriate dosages, and higher doses have an adverse impact. Ocular abnormalities are often early indicators of a vitamin A deficiency. The lacrimal gland secretes vitamin A onto the ocular surface, where it is metabolized into RA via two sequential steps. This article provides a comprehensive overview of how vitamin A is transformed and transported from the intestine to the ocular surface, ultimately contributing to the maintenance of the normal physiological function of the ocular surface.