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At least 19 recordsLinked to original sources
PubMed2026

A combinatorial construct library enables an expanded expression range of secreted therapeutic proteins by probiotic yeast.

Orally administered engineered probiotics, including Saccharomyces cerevisiae var. boulardii (Sb), are of emerging interest as protein therapeutic delivery platforms to treat gastrointestinal diseases. Tools to readily optimize protein output are required to optimize the therapeutic index of Sb-produced therapies. In this study, a 125-plex Sb secretion construct library was developed consisting of all possible combinations of five promoters, five secretion signals, and five terminators, which enabled a greater than 1800-fold range in Sb expression of a Gaussia luciferase (GLuc) reporter. Secretion signal and promoter identities had significant effects on secretion output. This library further enabled a 28-fold improvement of binding activity of Sb-secreted haPD-1, an established anti-tumor immunotherapeutic, and improved haPD-1 detection in mouse stool samples following oral gavage of Sb_haPD-1. Sb secretion trends of both GLuc and haPD-1 in vitro mirrored payload expression in vivo. This protein secretion library toolkit will serve as a valuable resource to rapidly optimize protein therapeutic output from engineered Sb.

Saccharomyces boulardii↗
PubMed2026

Reprogrammed Komagataella phaffii for enhanced secretory expression of human lactoferrin.

Human lactoferrin (hLF) is a multifunctional glycoprotein of the transferrin family derived from milk and mucosal secretions, which exhibits antibacterial, anti-tumor, and immunomodulatory functions, and is an important component of infant formula. Conventional methods for lactoferrin expression are often inefficient, primarily due to inadequate protein synthesis capabilities and poor stability within microbial hosts. Herein, a Komagataella phaffii yeast strain capable of high-level secretory expression of hLF was constructed by reprogramming the endoplasmic reticulum (ER) and vacuole using CRISPR/Cas9 technology. A dual-expression cassette containing the AOX1 promoter, an α-secretion signal peptide, the hLF gene, and a terminator was integrated into three different sites of the K. phaffii genome. The stepwise strategy combining expansion of the ER membrane involved in protein synthesis with knockout of vacuolar proteases further enhanced hLF production. Subsequently, 0.1 g/L FeCl₃ was added to the medium to reduce the toxicity of hLF and improve its stability. After high-density cultivation of K. phaffii through optimization of cultivation conditions in shake flasks and a 5 L bioreactor, the secretory intact hLF titer reached 2214 mg/L, representing a 76.3-fold increase achieved through these engineering strategies. In addition, antibacterial experiments demonstrated that this secretory hLF had a significant inhibitory effect on Escherichia coli, Staphylococcus aureus, and yeast. Overall, the developed K. phaffii protein expression platform enabled efficient production of lactoferrin, demonstrating its potential for expressing other lactoproteins.

Lactoferrin↗
PubMed2022

Multiplexed microfluidic chip for cell co-culture.

Paracrine signaling is challenging to study in vitro, as conventional culture tools dilute soluble factors and offer little to no spatiotemporal control over signaling. Microfluidic chips offer potential to address both of these issues. However, few solutions offer both control over onset and duration of cell-cell communication, and high throughput. We have developed a microfluidic chip designed to culture cells in adjacent chambers, separated by valves to selectively allow or prevent exchange of paracrine signals. The chip features 16 fluidic inputs and 128 individually-addressable chambers arranged in 32 sets of 4 chambers. Media can be continuously perfused or delivered by diffusion, which we model under different culture conditions to ensure normal cell viability. Immunocytochemistry assays can be performed in the chip, which we modeled and fine-tuned to reduce total assay time to 1 h. Finally, we validate the use of the chip for co-culture studies by showing that HEK293Ta cells respond to signals secreted by RAW 264.7 immune cells in adjacent chambers, only when the valve between the chambers is opened.

Microfluidics↗
PubMed2026

Comparative genomics approaches to identify genomic regions associated with the antimicrobial activity of Pseudomonas protegens PBL3.

The environmental bacterium Pseudomonas protegens PBL3 has antagonistic activity against the plant pathogenic bacterium Burkholderia glumae, an important pathogen in rice. The antimicrobial activity of P. protegens PBL3 was found in the bacteria-free secreted fraction (secretome), but the specific molecules, as well as the genetic basis of that activity, have not been identified. In this study, we integrated genomic information with antimicrobial assays on P. protegens PBL3 and additional six Pseudomonas spp. strains, to identify putative genomic regions in P. protegens PBL3 associated with antimicrobial activity. We hypothesized that Pseudomonas spp. strains with antimicrobial activity against B. glumae have conserved genes with P. protegens PBL3 that are absent in strains lacking activity. Comparative genomics analyses with anvi'o and progressiveMauve, and using P. protegens PBL3 as the reference genome, revealed 188 genes uniquely present in antimicrobial-producing strains. Seven of those genes were annotated as biosynthetic gene clusters predicted to encode secondary metabolites; additional genes were grouped into 25 contiguous clusters with functions annotated as secretion, signal transduction, regulation, transport/efflux, carbohydrate metabolism and one with an additional uncharacterized function. Altogether, this study uncovered a complex and multi-functional network of candidate genes, suggesting that the antimicrobial activity in P. protegens PBL3 is not limited to biosynthetic pathways but also involves additional regulatory, metabolic and export modules to synthesize and deploy antimicrobials.

Pseudomonas↗
PubMed1977

Signals for insulin secretion.

Glucose is an effective stimulus for the release of insulin from pancreatic beta-cells but its pre-eminence for the physiological control of insulin secretion is now challenged. The insulin response to oral glucose is much greater than the response to intravenous glucose because an intestinal factor, or factors, has a powerful stimulant effect on insulin secretion. Conversely, the hyperglycaemia which accompanies sympathetic overactivity is accompanied by reduced plasma insulin levels because adrenaline inhibits pancreatic insulin by an alpha-adrenergic mechanism. Other hormonal and chemical factors also modify pancreatic insulin release. Plasma insulin levels will be determined not only by the interplay of signals which stimulate or inhibit insulin release but also by the rate at which insulin leaves the circulation. Because insulin is secreted into the portal circulation the concentration of insulin to which hepatocytes are exposed is normally greater than that affecting peripheral tissues. This ratio will be affected by portal venous diversion and might be altered by hepatic damage. Both factors might also influence the intestinal control of insulin secretion, as the gut 'hormone' would not have to traverse the liver, which might remove some of it, before it arrived at the pancreatic islets. If insulin is the key 'hepatotrophic factor' stimulating hepatic growth and regeneration, as well as preventing atrophy, we might expect it to induce hepatic growth in otherwise normal liver and we would expect it to be secreted in larger amounts when regeneration is active.

Acetylcholine↗
PubMed1977

Signals for glucagon secretion.

The normal physiological role of glucagon is in controlling hepatic glucose output. Glucagon subserves the role of homeostasis by maintaining plasma glucose and of a stress hormone by producing hyperglycaemia. While control of glucagon release by circulating metabolites and also other hormones is clearly important, it seems likely that the nervous system exerts an over-riding influence. The parasympathetic nervous system maintains homeostasis and the sympathetic acts in stress. Glucagon levels are found to be high in cirrhosis and also after acute hepatic failure. It is likely that these changes in glucagon concentration are secondary to metabolic abnormalities. While some glucagon is cleared by the liver, a similar clearance is seen by many other tissues and it is not likely that the elevation of glucagon seen in liver failure is due solely to a gross deficiency of glucagon clearance. No liver abnormality is seen in the glucagonoma syndrome, where glucagon concentration are chronically high, or in patients who have had a total pancreatectomy, where plasma glucagon is undetectably low. It thus seems unlikely that liver mass is importantly controlled by glucagon.

Adrenalectomy↗
PubMed2026

The novel adipokine Placin regulates glucose homeostasis via insulin secretion and IGF1 receptor signaling.

While genome-wide association studies have linked the human PLAC9 gene to body mass index, its physiological function remains largely unexplored. This study identifies PLAC9 as a novel adipokine that is enriched in the stromal vascular fraction of adipose tissue. Its circulating levels correlate with key metabolic dysregulation markers in humans and mice. We utilized gain- and loss-of-function approaches in diet-induced obesity (DIO) and streptozotocin (STZ)-induced diabetic mouse models to demonstrate that PLAC9 is a critical regulator of systemic metabolism. Notably, knockdown of endogenous PLAC9 exacerbated metabolic impairments, while its overexpression significantly mitigated DIO-associated metabolic dysregulation. Additionally, recombinant PLAC9 protein administration alleviated hyperglycemia in insulin-resistant and insulin-deficient models. Mechanistically, PLAC9 potentiated calcium-dependent insulin secretion in pancreatic beta cells, promoted glucose uptake in the liver and skeletal muscle, and upregulated hepatic Ghr and Igf1 levels to facilitate glucose homeostasis. Based on these hormone-like properties, we propose renaming the protein Placin. Collectively, these findings establish Placin as a promising therapeutic target, offering translational potential for the management of both type 2 and type 1 diabetes.

Animals↗
PubMed1975

Stimulus-secretion coupling in platelets. Effects of drugs on secretion on adenosine 5'-triphosphate.

The mechanism of stimulus-secretion coupling in platelets was investigated by observing the effects of drugs on the kinetics on ATP secretion induced by either thrombin or the divalent cation ionophore A23187. The actual secretion is the same with either of these agents, since the rate constants and activation energies of secretion are the same and since drugs that affect the final, enzyme-independent steps of thrombin-induced secretion have the same effect on ionophore-induced secretion. Drugs that affect early steps of thrombin-induced secretion have no effect on ionophore-induced secretion. Drugs that act through cAMP (PGE1, theophylline, dibutyryl-cAMP) slow an early step in the mechanism of thrombin-induced secretion and completely block at higher levels, with the required concentration of inhibitor dependent on thrombin concentration. The inhibition of rate appears to be all-or-none, with no intermediate rates observed. By replacing thrombin with trypsin, which makes it possible to observe a complete change in rate-determining step from an enzyme-dependent to an enzyme-independent platelet step, it was found that these drugs slow the rate only when the enzyme-independent step is rate determining. These drugs have no effect on A23187-induced secretion. It was concluded that cAMP inhibits at a step after the enzyme step but before the final step by interfering with transmission of the stimulus-secretion coupling signal. Disruption of microfilament function by cytochalasin B (10 muM) accelerates the rate of secretion induced by either thrombin or ionophore. The microtubule agents colchicine, vinblastine, and vincristine had effects only at concentrations above those usually considered necessary for the specific inhibition of microtubule function. Drugs that inhibit prostaglandin synthesis (aspirin, indomethacin, eicosatetraynoic acid), drugs that block ATP production (antimycin A, deoxyglucose), or several other drugs previously reported to inhibit platelet function had no effect on secretion.

Adenosine Triphosphate↗
PubMed2026

Bioinformatics and Quantitative Real-Time Polymerase Chain Reaction Analysis of SUCNR1 and GPR37L1 in Schizophrenia.

Schizophrenia is a severe, complex, and multifactorial mental disorder involving numerous genetic susceptibility elements, leading to substantial disability, morbidity, and mortality. Despite significant progress in understanding its pathophysiology and etiology, specific diagnostic biomarkers for schizophrenia remain elusive. This study aimed to identify candidate molecular markers associated with schizophrenia. An integrated bioinformatics analysis was performed on the public microarray dataset GSE54913. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the most significantly enriched GO terms were related to channel activity, including passive transmembrane transporter activity, ion channel activity, gated channel activity, and substrate-specific channel activity. The top five enriched KEGG pathways were insulin secretion, cAMP signaling pathway, nucleotide excision repair, TNF signaling pathway, and glutathione metabolism. Validation was conducted using quantitative real-time polymerase chain reaction (qRT-PCR) on an independent sample set from Wuhan Rongjun Youfu Hospital. The qRT-PCR results were largely consistent with the microarray analysis (Pearson r = 0.89, 95% CI: 0.66-0.97). Protein-protein interaction (PPI) network analysis identified two hub genes, SUCNR1 and GPR37L1, which were significantly associated with the GO term 'ion channel activity' and enriched in the KEGG pathway 'insulin secretion'. Furthermore, SUCNR1 expression showed a negative correlation with verbal memory scores (r = -0.54, P = 0.015), whereas GPR37L1 expression showed a positive correlation (r = 0.59, P = 0.0034). These findings suggest that altered SUCNR1 and GPR37L1 expression may be associated with schizophrenia and may represent candidate molecular markers for further investigation.

Humans↗
PubMed1978

Nucleotide sequence of the ampicillin resistance gene of Escherichia coli plasmid pBR322.

I have determined the nucleotide sequence of the ampicillin resistance gene of pBR322, an Escherichia coli plasmid that encodes a penicillin beta-lactamase. This gene codes for a protein of 286 amino acid residues. The first 23 amino acids presumably form a signal for secretion, because they do not appear in the mature enzyme, whose partial amino acid sequence has been determined independently.

Ampicillin↗
PubMed2025

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for 1) extracellular matrix structure and metabolism (TM1 subtype), 2) secreted ligand signaling to support Schlemm's canal cells (TM2), and 3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b V265D/+ mutant mice (2,491 TM cells). In V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), to enhance mitochondrial function and metabolic resilience, significantly protected Lmx1b mutant mice from IOP elevation.

Journal Article↗
PubMed1979

Pentosephosphate shunt activity of rat pancreatic islets: its dependence on glucose concentration.

Although several attempts have been made to establish a relationship between glucose concentration and pentosephosphate shunt (PPS) activity of pancreatic islets in vitro, no such relationship has been found. Recently it has been shown that exogenous insulin, when added in vitro, inhibited islet PPS activity. Since it was possible that the failure to detect such a relationship was due to insulin released into the incubation medium, we reinvestigated the subject, introducing GPAIS (guinea pig antiinsulin serum) to bind insulin in the medium. When five islets were incubated with 16.7 mM glucose for 90 min, the absolute rate as well as the percentage of islet PPS activity were found to be significantly higher (P less than 0.05) in the presence of GPAIS than in its absence. In the presence of GPAIS, the absolute rate and the percentage of islet PPS activity increased in a dose-related manner (18, 43, and 124 pmol/five islets.90 min and 2.3%, 3.2%, 9.4%, respectively) when the glucose concentration was raised from 5.6 to 11.1 and 16.7 mM. Our data, therefore, indicate that the activity of islet PPS activity in vitro depends on the concentration of glucose, provided that insulin does not accumulate in the incubation medium. This suggests that PPS activity might play a role in glucose-induced insulin secretion. However, whether the PPS contributes to the secretory mechanism by producing a signal for insulin secretion or by forming cofactors required by the secretory mechanism remains to be established.

Animals↗
PubMed2026

SDC1+ CAFs secreting CTGF drive tumour metastasis via FGFR3 signalling in cancers.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear. OBJECTIVE: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME. DESIGN: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways. RESULTS: We identified a conserved syndecan 1 (SDC1) + CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1+ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis. CONCLUSIONS: Our study establishes SDC1+ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

Humans↗
PubMed1978

Leukocytes as secretory organs of inflammation.

Polymorphonuclear leukocytes secrete substances that defend against foreign invaders by mechanisms that bear remarkable resemblances to those of exocrine and endocrine glands. Similarly, leukocyte secretions can also damage the very host they are intended to protect. Like other secretory cells, leukocytes also bear surface receptors to detect signals that initiate secretion. Clinical implications are detailed.

Antigen-Antibody Complex↗
PubMed1977

[The role of cyclic AMP in the control of insulin secretion (author's transl)].

D-glucose stimulates the accumulation of cyclic AMP in isolated islets of Langerhans in a dose-dependent manner. This effect is present as long as the sugar remains elevated in the incubate. Under present experimental conditions the stimulation of cyclic AMP precedes insulin release. Islet or medium cyclic AMP, and insulin secretion are closely correlated at various incubation times. We conclude that the beta-cell cyclic AMP system is one of the major mediators of the glucose signal to insulin secretion. Tolbutamide and glibenclamide have similar effects in the absence or with low concentrations of glucose. These results may indicate that these sulfonylurea derivates act at sites where glucose exerts its effect.

Animals↗
PubMed2026

Revealing the cytokine-mediated embryo-maternal crosstalk during extended in vitro culture in the Arabian camel (Camelus dromedarius).

This study reports, for the first time, the establishment of endometrial organoids (EOs) from the Arabian camel (Camelus dromedarius) and evaluates their suitability as an in vitro model for embryo-maternal interactions during implantation. Endometrial tissues were collected from non-pregnant she-camels and cultured in Matrigel with a defined growth medium. By Day 7, organoids displayed a spherical morphology (200-250 µm), remained viable for up to 20 days, and expanded to approximately 1 mm. They exhibited epithelial characteristics and high proliferative activity, confirmed by expression of mucin-1, pan-cytokeratin, vimentin, and Ki67. Day 7 in vitro-produced embryos co-cultured with EOs showed significant improvements in development and trophoblast outgrowth. This was accompanied by upregulation of key developmental genes (OCT4, c-MYC, KLF4, CDX2). Cytokine profiling revealed enhanced bidirectional signaling: embryos increased secretion of CCL2, CCL4, IGF-1, IFNG, IL1α, IL12b, IL-8, LIF, IL-10, and NTF3, while EOs upregulated VEGFA, IL-8, CCL2, and TIMP1. Co-culture uniquely induced additional cytokines and amplified signaling intensity. Metabolomic analysis of embryo-conditioned medium identified 108 metabolites, including steroids associated with immunomodulation. Notably, embryos cultured in EO-conditioned medium developed up to Day 21 post-cleavage, reaching a mean diameter of 2.4 mm. Overall, camel EOs provide a physiologically relevant platform that supports embryo development and enables detailed investigation of cytokine-mediated embryo-maternal communication and implantation processes in the dromedary camel.

Camel↗
PubMed2026

Transcriptomic and proteomic signatures underlying nymphal adaptation and foam production in the forage pest Mahanarva spectabilis.

The spittlebug Mahanarva spectabilis (Distant, 1909) (Hemiptera: Cercopidae) is an important pest of forage grasses in South America, where its nymphs cause pasture damage by feeding on xylem sap and producing a characteristic foam that protects them against environmental stressors. To investigate the molecular basis of this adaptation, we integrated RNA-seq analysis of nymphs with LC-MS/MS proteomics of the Batelli gland, the primary source of foam secretion. De novo assembly of 100,666 unigenes revealed broad functional diversity, with strong representation of detoxification enzymes (CYP450s, GSTs, UGTs, carboxylesterases), transporters and ion pumps, cuticle proteins, and stress- and immunity-related genes. Nearly 16% of loci exhibited alternative splicing, particularly within detoxification, chemosensory and osmoregulatory gene families, highlighting evidence of transcriptomic variability. Signal peptide and secreted protein predictions identified 168 high-confidence candidate secreted proteins, including detoxification enzymes, proteases, structural proteins and immune-related factors, several of which are consistent with antimicrobial and surfactant-related functions. Proteomic profiling of the Batelli gland confirmed 500 proteins, enriched in chaperones, metabolic enzymes, detoxification pathways and osmoregulatory components, with the most abundant proteins corresponding to Hsp70 chaperones, ATP synthases, cuticle proteins and carbonic anhydrases. Together, these results provide an integrative transcriptomic and proteomic overview for M. spectabilis nymphs, highlighting genes and proteins associated with xylem feeding, foam production and responses potentially related to environmental stress tolerance. This comprehensive dataset not only advances the understanding of spittlebug biology but also identifies candidate molecular targets that may inform innovative strategies for controlling nymphal stages and mitigating spittlebug damage in forage systems.

Animals↗