Secretory Components Research Articles

The PulE ATPase is required for twitching motility and DNA donation during Thermus thermophilus transjugation.

Thermus thermophilus can acquire DNA through natural competence and through transjugation, a mechanism that involves a two-step process of DNA secretion (push) and DNA internalization (pull) between mating cells of related species. The natural competence apparatus (NCA) is required in the recipient mate for the pull step. However, how the DNA exits of the donor cell is only partially known. The putative DNA translocase TdtA, encoded in mobile genetic element ICETh1 of T. thermophilus HB27, was shown to be required for DNA donation as reported by (Blesa et al.2017a). This ring-shaped hexameric ATPase binds to the membrane and likely interacts with yet unknown secretory components that allow the extrusion of DNA through the membrane; thus, a genetic screening to identify additional putative secretory components was performed. Here, we describe that mutants in gene TT_C1844, which encodes a putative AAA-ATPase named PulE, do not synthesize the recently described "narrow" type 4 pili required for twitching motility and made up of the major PilA5 pilin. Concomitantly, pulE mutants also exhibited DNA donation defects during transjugation, suggesting a role of narrow pili in the donation process. However, single pilA5 null mutants still function as DNA donors in transjugation experiments, so we conclude that the need for PulE in transjugation is independent of its role in narrow pili synthesis and twitching motility.

Antibacterial effects of human mesenchymal stem cells and their derivatives: a systematic review.

The growing problem of antimicrobial resistance (AMR) poses a significant challenge to public health; This is partly due to the lack of advancements in the development of novel antibiotics and the pressing need for alternative treatment options. Mesenchymal stem cells (MSC) possess secretory components that enhance the immune response and peptides that disrupt the bacteria constitution. The isolation of various human tissues has facilitated the investigation of the diverse potentials of MSC and their components. Further research is needed to fully understand the spectrum and efficacy of these elements and their differences. The primary aim of this study was to perform a thorough review of the current literature related to the antimicrobial properties of MSC and their associated components. The objective was to establish an insight into the results and effects of utilizing MSC in relation to bacterial colonization, and to present an overview of previously documented findings. This systematic literature review was conducted using the PubMed, Embase, and Web of Science databases. Data on the effect of MSC or their derivatives were measured by calculating the percentage of bacterial counts reduction after treatment with MSC in comparison to the control. A total of 3,911 articles were screened, and 31 eligible publications were selected for inclusion in the analysis. In the current systematic review, the majority of the experimental designs showed positive outcomes in terms of bacterial load reduction when MSC or their derivatives were used, with bone marrow being the most effective tissue. The rest of the findings exhibited heterogeneity in the spectrum of outcomes that could be attributed to the effects of using various tissues derived MSC in both in vivo and in vitro studies. The findings of our study indicate the potential antibacterial characteristics of MSC. The direct antimicrobial activity of these cells was demonstrated by our results, which quantitatively showed a decrease in bacterial growth after treatment with MSC. However, additional research is required to clarify the factors that determine the efficacy of their antimicrobial activity and their various components.

Nicotine induces senescence in spermatogonia stem cells by disrupting homeostasis between circadian oscillation and rhythmic mitochondrial dynamics via the SIRT6/Bmal1 pathway

Infertility is intricately linked with alterations in circadian rhythms along with physiological decline and stem cell senescence. Yet, the direct involvement of circadian mechanisms in nicotine-induced injury to the testes, especially the senescence of spermatogonia stem cells (SSCs), is not well comprehended. This study revealed that nicotine exposure induced testis injury by triggering SSCs senescence along with the upregulation of senescence marker genes and senescence-associated secretory phenotype components. Moreover, nicotine treatment caused mitochondrial hyper-fusion, increased oxidative stress, and DNA damage. Exposure to nicotine was found to suppress the expression of sirtuin 6 (SIRT6), which accelerated the senescence of spermatogonia stem cells (SSCs). This acceleration led to increased acetylation of brain and muscle ARNT-like protein (Bmal1), consequently reducing the expression of Bmal1 protein. Conversely, the overexpression of Bmal1 alleviated mitochondrial hyper-fusion and senescence phenotypes induced by nicotine. Overall, this study unveiled a novel molecular mechanism behind nicotine-induced disorders in spermatogenesis and highlighted the SIRT6/Bmal1 regulatory pathway as a potential therapeutic target for combating nicotine-associated infertility.

Egr1 regulates regenerative senescence and cardiac repair.

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin-FAK-ERK-Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.

MORPHOLOGICAL STRUCTURE OF THE BRONCHIAL WALL WITHOUT LUNG PATHOLOGY IN ADULTS

The selection of this particular subject is motivated by the necessity to examine the cellular composition of the respiratory epithelium. Within the respiratory epithelium lies a sophisticated tissue network that plays a crucial role in safeguarding the mucous lining of the respiratory passage. Goblet cells and submucosal glands situated in the layers serve as the primary origins of mucus. The mucociliary transport system of the respiratory passage is established through the collaboration of mucociliary cilia and secretory components. Although information regarding the bronchial epithelial layer is scarce, research studies have delved into the microscopic configuration of this layer and the age-related attributes of its transport function.

Application of dental pulp stem cells for bone regeneration.

Bone defects resulting from severe trauma, tumors, inflammation, and other factors are increasingly prevalent. Stem cell-based therapies have emerged as a promising alternative. Dental pulp stem cells (DPSCs), sourced from dental pulp, have garnered significant attention owing to their ready accessibility and minimal collection-associated risks. Ongoing investigations into DPSCs have revealed their potential to undergo osteogenic differentiation and their capacity to secrete a diverse array of ontogenetic components, such as extracellular vesicles and cell lysates. This comprehensive review article aims to provide an in-depth analysis of DPSCs and their secretory components, emphasizing extraction techniques and utilization while elucidating the intricate mechanisms governing bone regeneration. Furthermore, we explore the merits and demerits of cell and cell-free therapeutic modalities, as well as discuss the potential prospects, opportunities, and inherent challenges associated with DPSC therapy and cell-free therapies in the context of bone regeneration.

THE ANTIBACTERIAL POTENTIAL OF EUKARYOTIC MARINE MICROALGAE AGAINST PATHOGENS FROM CHICKEN, DOG AND AQUACULTURE

Antibiotic resistance is an emerging concern, leading to the search for alternative antibacterial agents. Scientists looking for potential alternatives to antibiotics see promise in the antimicrobial propensity of microalgae. We investigated the antibacterial potentials of Tetraselmis, Chlorella, and Nannochloropsis against pathogenic bacteria from chicken, dogs, and fish. We identified E. coli, Stenotrophomonas sp., Streptococcus sp., Staphylococcus sp., Aeromonas sp. and Lysinibacillus sp. by colony characteristics, Gram staining and VITEK-2 tests. Results demonstrated that Tetraselmis was highly sensitive against Stenotrophomonas sp. (p < 0.0001) and E. coli (p < 0.001) from chicken, and Staphylococcus sp. (p < 0.01) from dogs. Moreover, Chlorella was highly sensitive against E. coli (p < 0.0001) from dogs. All the bacteria isolated from chicken were moderate to highly sensitive to Chlorella. Nannochloropsis was marginally sensitive to all the bacteria isolated from chickens and dogs. The minimum inhibitory concentration values indicate that a minimum of 10 mg/ml of Tetraselmis can suppress the growth of Aeromonas sp. from fish and Chlorella can suppress E. coli and Stenotrophomonas sp. from chicken. Results indicate that native microalgae may have an active somatic or secretory components that prevent bacterial cell division and/or induce lysis. Advanced studies should be performed to identify the active component for the development of newer and sustainable antimicrobial drugs.

Progranulin-deficient macrophages cause cardiotoxicity under hypoxic conditions

Myocardial infarction (MI) induces structural and electrical cardiac remodeling in response to ischemic insult, causing lethal arrhythmias and sudden death. Progranulin (PGRN) is a glycoprotein mainly expressed in macrophages that modulates the immune responses. In this study, we investigated the direct influence of PGRN knockout (Grn−/−) macrophages on post-MI pathophysiology. An MI mouse model was established by ligating the left coronary artery for RNA sequencing and electrocardiographic analysis. Bone marrow-derived macrophages (BMDMs) were injected into mice and supernatant was collected for the measurement of reactive oxygen species (ROS) levels and extracellular flux analysis. Administration of Grn−/− BMDMs prolonged the QT intervals in the MI mouse model. Moreover, genes highly expressed in macrophages were upregulated in Grn−/− heart after MI. Post-hypoxic supernatant of Grn−/− BMDMs increased the oxygen–glucose deprivation-induced cardiomyocyte death. Grn−/− BMDMs exhibited increased ROS production, oxygen consumption, and extracellular acidification under hypoxia and inflammatory conditions. These findings suggest that PGRN deficiency causes cardiotoxicity via secretory components of macrophages that exhibit metabolic abnormalities under hypoxia.

Cardiac fibroblasts-mtExosomes-macrophages axis aggravates ventricular remodeling after acute myocardial infarction

Abstract Background Intercellular communication between cardiac fibroblasts (CFs) and macrophages plays an important role in the progression of ventricular remodeling after acute myocardial infarction (AMI). Following intense oxidative stress, activation of mitochondrial quality control (MQC) systems is necessary to eliminate damaged components. Recent studies have highlighted the emergence of a new form of MQC called mitochondrial-derived vesicles (MDVs), which can be released into the extracellular space via exosomes. Our previous research has revealed that exosomes derived from fibroblasts treated with oxygen-glucose deprivation (OGD) contained mitochondrial damage components, which we named "mtExosomes". The uptake of mtExosomes by macrophages can significantly promote inflammatory response. Purpose To explore the specific effects of CFs-mtExosomes-macrophages communication axis on ventricular remodeling after AMI. Methods Male C57 mice underwent left anterior descending coronary artery-ligation surgery for orthotopic myocardial injection of CFs derived exosomes. Primary neonatal mouse CFs were isolated and cultured for 24h in sugar-free medium with 1% O2 (OGD) to mimic ischemic injury in vitro. Conditioned medium was separated to obtain exosomes by ultracentrifugation. Label-free quantitative proteomics was used to identify differentially expressed proteins in exosomes. The damaged mitochondrial components in the exosomes were identified using mito-tracker and nanoflowmetry. After co-culture with OGD-CFs derived exosomes for 24h, RNA-seq was performed to analyze the activated inflammatory signaling pathways in bone marrow-derived macrophages. Results OGD-CFs derived exosomes significantly reduced cardiac function post-surgery day 3 in model mice, and fibrotic remodeling was observed at 28 days. In vitro co-culture experiments revealed that the conditioned medium from OGD-CFs increased the expression and secretion of IL-1β and IL-6 in macrophages. Separation of secretory components by differential centrifugation suggested that exosomes had the most significant pro-inflammatory effect on macrophages. Exosome proteomics showed that fibroblast-derived exosomes were rich in mitochondrial proteins. A significant fluorescence signal was detected by nanoflowmetry after incubation of OGD-CFs-derived exosomes with Mito-tracker. OGD-CFs derived exosomes also had higher mtDNA, mtROS, and ATP levels. RNA-seq enrichment analysis revealed significant activation of Toll-like receptor and NOD-like receptor signaling pathways in macrophages. Western blot analysis further confirmed the up-regulation of NLRP3/Caspase-1/IL-1β and TLR9/NF-κB/IL-6 signaling pathways. Conclusion Following ischemic injury, CFs in infarction area release exosomes rich in damaged mitochondria (mtExosomes). The uptake of mtExosomes by macrophages promotes the secretion of IL-6 and IL-1β via NLRP3/Caspase-1/IL-1β and TLR9/NF-κB/IL-6 signaling pathways, leading to ventricular remodeling after AMI.Graphical Abstract

Identification and characterization of putative biomarkers and therapeutic axis in Glioblastoma multiforme microenvironment.

Non-cellular secretory components, including chemokines, cytokines, and growth factors in the tumor microenvironment, are often dysregulated, impacting tumorigenesis in Glioblastoma multiforme (GBM) microenvironment, where the prognostic significance of the current treatment remains unsatisfactory. Recent studies have demonstrated the potential of post-translational modifications (PTM) and their respective enzymes, such as acetylation and ubiquitination in GBM etiology through modulating signaling events. However, the relationship between non-cellular secretory components and post-translational modifications will create a research void in GBM therapeutics. Therefore, we aim to bridge the gap between non-cellular secretory components and PTM modifications through machine learning and computational biology approaches. Herein, we highlighted the importance of BMP1, CTSB, LOX, LOXL1, PLOD1, MMP9, SERPINE1, and SERPING1 in GBM etiology. Further, we demonstrated the positive relationship between the E2 conjugating enzymes (Ube2E1, Ube2H, Ube2J2, Ube2C, Ube2J2, and Ube2S), E3 ligases (VHL and GNB2L1) and substrate (HIF1A). Additionally, we reported the novel HAT1-induced acetylation sites of Ube2S (K211) and Ube2H (K8, K52). Structural and functional characterization of Ube2S (8) and Ube2H (1) have identified their association with protein kinases. Lastly, our results found a putative therapeutic axis HAT1-Ube2S(K211)-GNB2L1-HIF1A and potential predictive biomarkers (CTSB, HAT1, Ube2H, VHL, and GNB2L1) that play a critical role in GBM pathogenesis.

SNARE Protein Snc1 Is Essential for Vesicle Trafficking, Membrane Fusion and Protein Secretion in Fungi.

Fungi are an important group of microorganisms that play crucial roles in a variety of ecological and biotechnological processes. Fungi depend on intracellular protein trafficking, which involves moving proteins from their site of synthesis to the final destination within or outside the cell. The soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) proteins are vital components of vesicle trafficking and membrane fusion, ultimately leading to the release of cargos to the target destination. The v-SNARE (vesicle-associated SNARE) Snc1 is responsible for anterograde and retrograde vesicle trafficking between the plasma membrane (PM) and Golgi. It allows for the fusion of exocytic vesicles to the PM and the subsequent recycling of Golgi-localized proteins back to the Golgi via three distinct and parallel recycling pathways. This recycling process requires several components, including a phospholipid flippase (Drs2-Cdc50), an F-box protein (Rcy1), a sorting nexin (Snx4-Atg20), a retromer submit, and the COPI coat complex. Snc1 interacts with exocytic SNAREs (Sso1/2, Sec9) and the exocytic complex to complete the process of exocytosis. It also interacts with endocytic SNAREs (Tlg1 and Tlg2) during endocytic trafficking. Snc1 has been extensively investigated in fungi and has been found to play crucial roles in various aspects of intracellular protein trafficking. When Snc1 is overexpressed alone or in combination with some key secretory components, it results in enhanced protein production. This article will cover the role of Snc1 in the anterograde and retrograde trafficking of fungi and its interactions with other proteins for efficient cellular transportation.

Abstract 425: Characterization of TKI-induced drug-tolerant persister cells from a patient-derived cell line

Abstract Introduction: Targeted therapies provide clinical benefits in patients harboring oncogene-driven cancers, but relapses invariably occur. Studies on resistance mechanisms are essential to guide the development of next-generation inhibitors. An increasing number of studies focus on an earlier stage of disease evolution. Resistance may develop from the selection of preexisting resistant cells or by adaptation of drug-tolerant persister (DTP) cells. In this context, our study depicts DTP cells able to survive the initial tyrosine kinase inhibitor (TKI) exposure without harboring genetic changes, in order to identify the vulnerabilities existing in this cell state. Materials and Methods: This project focuses on a patient-derived cell line from the prospective MATCH-R clinical trial (NCT0251782). The model is a non-small cell lung cancer harboring EML4-ALK fusion and ALK C1156Y/G1269A mutation, sensitive to the 3rd generation ALK TKI lorlatinib. In vitro, fully resistant cells were generated by long-term lorlatinib exposure and the acquired resistance mechanism resulted from an epithelial-mesenchymal transition (EMT). DTP cells were generated under shorter drug exposures that eradicate sensitive carcinoma cells. Results and Discussion: Carcinoma cell plasticity drives cell transformation towards a phenotypic state, rendering them more tolerant to drugs. To better characterize this phenotype, we first focused on EMT and observed that DTP cells co-harbored epithelial and mesenchymal markers. We noticed that DTP cells exhibited an intracellular reactive oxygen species (ROS) rate making them dependent on protective oxidation-reduction mechanisms against oxidative stress-related damage. We revealed the overexpression of p21 and p27, known to bind to cyclin-CDK complexes and induce cell-cycle arrest. This dormant phenotype of DTP cells was underlined by a global repressive chromatin state evidenced by enrichment in H3K27me3, H3K36me3 and H3K9me3 marks; the latter mark also being a component of senescence-associated heterochromatin foci. In agreement, a high level of SA-β-gal and senescence-associated secretory phenotype components (CXCL10, PAI-1), evidenced that our DTP model displayed a senescence-like phenotype. We quantified an increase in γH2AX DNA damage foci in DTP cells compared to sensitive cells, in line with the concept that TKI treatment may have a role in DNA repair modulation that ultimately promotes new mutations. Together, our data depicted DTP features that might be relevant to identify drug candidates overcoming resistance (HDAC inhibitors, senolytic drugs and DNA repair inhibitors). Conclusion: We demonstrated potential targetable features of DTP cells. A combination of targeted therapies with DTP drug candidates could represent a therapeutic opportunity to improve the depth of response and delay the emergence of resistance in patients. Citation Format: Floriane Brayé, Francesco Facchinetti, Helena Gerber, Juliette Juigné, Giorgia Guaitoli, Jean-Paul Thiery, Santiago Ponce, Benjamin Besse, Ken A. Olaussen, Luc Friboulet. Characterization of TKI-induced drug-tolerant persister cells from a patient-derived cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 425.

3,4-Dihydroxybenzalacetone Inhibits the Propagation of Hydrogen Peroxide-Induced Oxidative Effect via Secretory Components from SH-SY5Y Cells.

The polyphenol derivative 3,4-dihydroxybenzalacetone (DBL) is the primary antioxidative component of the medicinal folk mushroom Chaga (Inonotus obliquus (persoon) Pilat). In this study, we investigated whether the antioxidative effect of DBL could propagate to recipient cells via secreted components, including extracellular vesicles (EVs), after pre-exposing SH-SY5Y human neuroblastoma cells to DBL. First, we prepared EV-enriched fractions via sucrose density gradient ultracentrifugation using conditioned medium from SH-SY5Y cells exposed to 100 µM hydrogen peroxide (H2O2) for 24 h, with and without 1 h of 5 µM DBL pre-treatment. CD63 immuno-dot blot analysis demonstrated that fractions with density of 1.06-1.09 g/cm3 had CD63-like immuno-reactivities. Furthermore, the 2,2-diphenyl-1-picrylhydrazyl assay revealed that the radical scavenging activity of fraction 11 (density of 1.06 g/cm3), prepared after 24-h H2O2 treatment, was significantly increased compared to that in the control group (no H2O2 treatment). Notably, 1 h of 5 µM DBL pre-treatment or 5 min of heat treatment (100 °C) diminished this effect, although concentrating the fraction by 100 kDa ultrafiltration enhanced it. Overall, the effect was not specific to the recipient cell types. In addition, the uptake of fluorescent Paul Karl Horan-labeled EVs in concentrated fraction 11 was detected in all treatment groups, particularly in the H2O2-treated group. The results suggest that cell-to-cell communication via bioactive substances, such as EVs, in conditioned SH-SY5Y cell medium, propagates the H2O2-induced radical scavenging effect, whereas pre-conditioning with DBL inhibits it.

Molecular mechanisms regulating extracellular matrix-mediated remodeling in the ductus arteriosus

Progressive remodeling throughout the fetal and postnatal period is essential for anatomical closure of the ductus arteriosus (DA). Internal elastic lamina interruption and subendothelial region widening, elastic fiber formation impairment in the tunica media, and intimal thickening are distinctive features of the fetal DA. After birth, the DA undergoes further extracellular matrix-mediated remodeling. Based on the knowledge obtained from mouse models and human disease, recent studies revealed a molecular mechanism of DA remodeling. In this review, we focus on matrix remodeling and regulation of cell migration/proliferation associated with DA anatomical closure and discuss the role of prostaglandin E receptor 4 (EP4) signaling and jagged1–Notch signaling as well as myocardin, vimentin, and secretory components including tissue plasminogen activator, versican, lysyl oxidase, and bone morphogenetic proteins 9 and 10.

The (Sialyl) Tn antigen: Contributions to immunosuppression in gastrointestinal cancers.

Cellular signaling pathways are intricately regulated to maintain homeostasis. During cancer progression, these mechanisms are manipulated to become harmful. O-glycosylation, a crucial post-translational modification, is one such pathway that can lead to multiple isoforms of glycoproteins. The Tn (GalNAc-O-Ser/Thr) and Sialyl Tn (STn; Neu5Ac-GalNAc-O-Ser/Thr) antigens resulting from the incomplete synthesis of fully branched O-glycan chains on proteins contribute to disease progression in the pancreas and other gastrointestinal cancers. The tumor microenvironment (TME) is a major constituent of tumors and a key modulator of their behavior. Multiple cellular and secretory components of the TME dictate the development and metastasis of tumors. Immune cells like macrophages, natural killer (NK) cells, dendritic cells, B and T lymphocytes are a part of the tumor "immune" microenvironment (TIME). The expression of the Tn and STn antigens on tumors has been found to regulate the function of these immune cells and alter their normal antitumor cytotoxic role. This is possible through multiple cell intrinsic and extrinsic signaling pathways, elaborated in this review. Studying the interaction between Tn/STn antigens and the TIME of gastrointestinal cancers can help develop better and more robust therapies that can counteract immunosuppressive mechanisms to sensitize these tumors to anticancer therapies.

Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.

Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models. We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline. Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs. Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.

Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?

A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC's form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC's form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.

Histomorphology and Chemical Constituents of Interdigital Gland of Vembur Sheep, Ovis aries.

The interdigital gland is a specialized skin gland located between the digits of Artiodactyla (i.e., even-toed ungulates). Its secretion participates in semiochemical communication, and protects from ultraviolet radiation as well as fungal and bacterial infections of the feet. The present study aimed at finding if there are male-female differences in the anatomy, morphology, and volatile compounds of the interdigital gland of the South Indian breed of Vembur sheep. A total of 24 sheep (12 each of male and female) were spotted at the slaughterhouse and the interdigital gland was removed for examination. The anatomical examination revealed it to resemble a tobacco pipe and to consist of a body, flexure, and excretory duct with an external orifice located at the cleft of the digits. Morphometrically, the interdigital glands differed between males and females. The gland possesses a distinct fibrous capsule, epidermis, and dermis. The fibrous capsule contains several parallel bundles of collagen fibers, nerve fibers, and blood vessels, etc. The epidermis consists of keratinized squamous epithelium formed of stratum basale, stratum granulosum and stratum spinosum. The dermis consists of hair follicles, nerve plexuses, arrector pili muscles, and apocrine and sebaceous glandular lobules. The latter, lined by a simple cuboidal epithelium, are arranged in clusters of acini in the upper portion of the dermis. The apocrine secretory lobules, made up of parenchymal cells, are found in the lower portion of the dermis. The density and diameter of the apocrine and sebaceous secretory lobules were significantly higher in the males than females. Scanning electron microscopic (SEM) analysis confirmed the apocrine and sebaceous secretory components. Twenty-three major compounds were identified in the interdigital gland postings of male and female sheep, among which butanoic acid, 2-methylpropanoic acid, 1-heptanol and octadecanoic acid were present only in the male glandular post, whereas octane, 7-hexyl-tridecane, tetradecane, heptadecane and decanoic acid were present only in the female glandular post. Tetradecanol, tetradecanoic acid and hexadecanol peaks, reportedly antibacterial compounds in pronghorn antelopes, were highly prominent in both male and female sheep. Thus, the interdigital gland of Vembur sheep has two major secretory lobules, namely, sebaceous and apocrine, larger in males than females, which secrete a variety chemical compounds that may serve as chemical communication systems and protect the sheep from foot-borne diseases.

DLC1 inhibits colon adenocarcinoma cell migration by promoting secretion of the neurotrophic factor MANF.

DLC1 (deleted in liver cancer-1) is downregulated or deleted in colorectal cancer (CRC) tissues and functions as a potent tumor suppressor, but the underlying molecular mechanism remains elusive. We found that the conditioned medium (CM) collected from DLC1-overexpressed SW1116 cells inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but had no effect on proliferation, which suggested DLC1-mediated secretory components containing a specific inhibitor for colon adenocarcinoma cell migration. Analysis by mass spectrometry identified mesencephalic astrocyte-derived neurotrophic factor (MANF) as a candidate. More importantly, exogenous MANF significantly inhibited the migration of colon adenocarcinoma cells HCT116 and SW1116, but did not affect proliferation. Mechanistically, DLC1 reduced the retention of MANF in ER by competing the interaction between MANF and GRP78. Taken together, these data provided new insights into the suppressive effects of DLC1 on CRC, and revealed the potential of MANF in the treatment of CRC.

Morphological and functional relationship between the orbital gland and olfaction in Upupa epops (hoopoe) and Bubulcus ibis (cattle egret).

This study used both anatomical and histological techniques to investigate the orbital gland's topographic relationship with the surrounding system, using the hoopoe and cattle egret as biological models. Hoopoe has a spindle-shaped lacrimal gland that is suspended on the lateral edge of the frontal bone, whereas cattle egret has a tiny lacrimal gland that is embedded posteriorly within the periorbital fascia. The hoopoe's lacrimal gland has a single duct that runs parallel to the nasolacrimal duct and opens into the posterior nostril hole. In the cattle egret, the tubule-alveolar secretory components comprise neutral and acid glycosaminoglycan. In addition, the Harderian gland is found in both these species, but their draining ducts differ; the Harderian gland of the hoopoe opens into the anterodorsal to the conjunctival fornix, whereas the Harderian gland of the egret opens anteriorly. In both hoopoe and egret, the secretions of Harderian gland include neutral and acid glycosaminoglycan. The Harderian gland is categorized as type II in hoopoe and type I in cattle egrets. The present results concluded that both orbital glands of two bird species studied play an essential role in eye health, where cleaning and lubrication of the cornea surface. Furthermore, the lacrimal gland's location and secretory features may strengthen the olfactory sensitivity of hoopoe, which relies heavily on scent to locate their food, whereas egret relies heavily on visual cues.