Ontosight^® Newsletter Issue 16

Ontosight^® – Newsletter
December 16^th – December 29^th, 2024 – Issue 16

Welcome to the 16^th edition of Ontosight^® Newsletter! This issue highlights breakthroughs in cancer research, neuroscience, autoimmune therapies, gut microbiota, and pharmacology, with a focus on novel therapeutic strategies and natural products. We also cover key regulatory updates shaping the healthcare industry. Stay informed on the latest scientific innovations and trends.

Featured Articles

1. Cancer Biology and Therapy

• Infiltrating plasma cells maintain glioblastoma stem cells through IgG-Tumor binding

Glioblastoma stem cells (GSCs) interact with aberrantly enriched plasma cells (PCs), which promote GSC proliferation via the IgG-FcγRIIA-AKT-mTOR axis, contributing to poor prognosis. PCs are recruited to GSC niches through the CCL2-CCR2 chemokine program and influenced by immune checkpoint inhibitors. This study provides a framework for targeting both tumor-intrinsic and microenvironmental dependencies in glioblastoma. [Article]

• Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-α breast cancer risk

Endocrine-targeting therapies like tamoxifen reshape the breast microbiome, increasing Firmicutes such as Lactobacillus spp., and influencing tissue metabolism to reduce tumorigenesis. Probiotic interventions in mice decreased tumor proliferation, altered metabolic gene expression, and selectively reduced ER+ breast cancer cell viability. These findings suggest that microbiome modulation by endocrine therapies may lower ER+ breast cancer risk by regulating tumor-associated microbiota and metabolism. [Article]

• Pan-cancer analysis shows that BCAP31 is a potential prognostic and immunotherapeutic biomarker for multiple cancer types

BCAP31 is an ER-associated protein overexpressed in various cancers, linked to poor prognosis and immune microenvironment alterations. High BCAP31 levels correlate with immune cell infiltration, immune-related pathways, and resistance to therapies, impacting patient outcomes. Functional assays showed BCAP31 knockdown reduces cancer cell migration, invasion, and proliferation. These findings suggest BCAP31 as a potential biomarker and therapeutic target in cancer immunology. [Article]

• The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells

Proteolysis targeting chimeras (PROTACs) enable selective protein degradation but face resistance due to cellular transporters. The ATP-binding cassette transporter ABCC1/MRP1 was identified as a key efflux pump reducing PROTAC bioavailability in cancers. Genetic screens also revealed pathways like ubiquitination and mTOR signaling as contributors to PROTAC resistance, highlighting strategies to overcome this challenge. [Article]

• Gut microbiota protect against colorectal tumorigenesis through lncRNA Snhg9

The intestinal microbiota protects against colorectal cancer (CRC) in mice by suppressing the long non-coding RNA Snhg9, which inhibits the tumor suppressor p53. Snhg9 disrupts p53 activity by dissociating SIRT1 from CCAR2, promoting tumor growth. Antibiotic-induced microbiota depletion upregulates Snhg9, accelerating CRC progression, with similar mechanisms observed in humans. [Article]

2. Neuroscience and Neurological Disorders

• Anti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer's disease

Alzheimer's disease (AD) may be linked to herpes simplex virus 1 (HSV-1), with HSV-1 proteins, especially ICP27, colocalizing with p-tau in brain samples. HSV-1 infection increases tau phosphorylation, which reduces ICP27 expression and neuronal death. The cGAS-STING-TBK1 pathway drives this immune response, suggesting a role for tau phosphorylation in AD's innate immunity. [Article]

• Vascular endothelial growth factor receptor-1 (FLT1) interactions with amyloid-beta in Alzheimer's disease: A putative biomarker of amyloid-induced vascular damage

FLT1 levels are elevated in Alzheimer's disease (AD) and correlate with increased amyloid, tau, and cognitive decline. Higher FLT1 in CSF and brain tissue is linked to increased tau, especially in amyloid-positive individuals. These findings suggest FLT1 as a potential biomarker for early-stage AD and its vascular-immune role in neurodegeneration. [Article]

• Calcineurin: An essential regulator of sleep revealed by biochemical, chemical biological, and genetic approaches

A biochemical and chemical biology approach identified a critical role for calcineurin (CaN) in sleep regulation. Mice with a mutation in salt-inducible kinase 3 (SIK3) showed increased sleep, and CaN dephosphorylated SIK3, promoting sleep. Knocking down CaN significantly reduced sleep, highlighting its importance in sleep regulation and advancing sleep research methodologies. [Article]

3. Autoimmune Advances and T-cell Therapies

• CD19 CAR-T cell therapy: a new dawn for autoimmune rheumatic diseases?

Autoimmune rheumatic diseases (ARDs) are characterized by dysregulated immune responses and persistent autoreactive B cells, limiting the effectiveness of current treatments. CD19 CAR-T cell therapy has shown promise in depleting B cells and achieving clinical remission in ARDs. This review explores the potential of CD19 CAR-T cells in ARDs, discussing key considerations like target cell populations, CAR design, and safety. Successful adoption of CAR-T in autoimmune treatments may lead to lasting immune resets. [Article]

• Gut microbiota mediated T cells regulation and autoimmune diseases

Gut microbiota plays a critical role in regulating immune responses and the progression of autoimmune diseases (AIDs), with specific bacterial strains either maintaining immune homeostasis or promoting immuno-pathogenesis. Dysbiosis, characterized by altered microbial diversity, is linked to AIDs like rheumatoid arthritis, diabetes, and inflammatory bowel disease. This review highlights the potential of microbiota-based interventions as adjunctive therapies for AIDs, emphasizing the need for further research into the precise role of individual bacterial strains. [Article]

• Early Onset Active Inflammatory Bowel Disease Is Associated With Psychiatric Comorbidities: A Multi-Network Propensity-Matched Cohort Study

A population-based study revealed that active Inflammatory Bowel Disease (IBD) shortly after diagnosis is linked to higher rates of psychiatric comorbidities. Patients with active IBD had significantly higher odds of developing disorders like depression, anxiety, and substance use disorders. They also had increased use of psychotropic medications such as antidepressants, antipsychotics, and mood stabilizers. These findings emphasize the importance of addressing behavioral health in IBD patients for effective management. [Article]

4. Gut Microbiota and Disease Interactions

• Houttuynia cordata-Derived Exosome-Like Nanoparticles Mitigate Colitis in Mice via Inhibition of the NLRP3 Signaling Pathway and Modulation of the Gut Microbiota

This study investigates the therapeutic potential of Houttuynia cordata-derived exosome-like nanoparticles (HELNs) in treating ulcerative colitis (UC) in mice. HELNs alleviated colitis symptoms by targeting inflamed colon tissue, regulating the immune environment, and inhibiting the NLRP3/NOD-like receptor signaling pathway. They also balanced the gut microbiota, reducing harmful bacteria and promoting beneficial ones. These findings suggest that HELNs may offer a promising treatment for UC. [Article]

• The direct and indirect inhibition of proinflammatory adipose tissue macrophages by acarbose in diet-induced obesity

This study explores the effects of acarbose on adipose tissue macrophage (ATM)-mediated inflammation in obesity and obesity-induced insulin resistance (IR). Acarbose enhances the abundance of propionic acid-producing Parasutterella, inhibiting proinflammatory M1-like ATMs through GPR43, and directly inhibits M1-like ATM inflammation via GPR120. In both mouse and human macrophages, acarbose reduces inflammation, improving obesity and IR. These findings suggest that acarbose could have broader therapeutic applications due to its immune-regulatory effects. [Article]

• Rice extracellular vesicles send defense proteins into fungus Rhizoctonia solani to reduce disease

This study reveals that rice plants use extracellular vesicles (EVs) to transfer defense proteins into the fungal pathogen Rhizoctonia solani. These EVs are internalized by the fungal cells, and reducing their transfer increases disease susceptibility. Overexpression of defense proteins in either the plants or fungi reduces infection, highlighting a new form of protein exchange that helps combat crop diseases. [Article]

5. Pharmacology and Therapeutics

• Natural products as Nrf2 modulators for ferroptosis inhibition in renal disease therapy: Recent progress and future prospects

This study examines the role of Nrf2 in regulating ferroptosis and its implications for various renal diseases. It highlights over twenty natural products that modulate Nrf2 to inhibit ferroptosis and exert renoprotective effects in conditions like acute kidney injury, diabetic nephropathy, and renal fibrosis. The study underscores the potential of these natural products in developing therapeutic strategies for renal diseases by targeting Nrf2-related ferroptosis. [Article]

• A pharmacovigilance study of the association between proton pump inhibitors and tumor adverse events based on the FDA adverse event reporting system database

This study analyzes the relationship between proton pump inhibitors (PPIs) and tumor adverse events (TAEs) using the FDA Adverse Event Reporting System (FAERS). It identifies ten significant TAEs associated with PPIs, including gastric cancer and renal cell carcinoma, and highlights that these events make up 2.36% of all PPI-related adverse events. The findings emphasize the need for cautious long-term use of PPIs and further research into the underlying mechanisms and risk factors. [Article]

• Mechanism of Fangji Huangqi decoction against acute kidney injury based on network pharmacology and experimental validation

This study used a network pharmacology approach to explore how Fangji Huangqi Decoction (FJHQD) combats acute renal injury (AKI). The results identified 20 bioactive ingredients and 274 overlapping targets, with the PI3K-AKT signaling pathway playing a key role in FJHQD's protective effects. Further in vitro and in vivo experiments validated that FJHQD alleviates renal injury by activating the PI3K-AKT pathway, with Liquiritigenin being a key bioactive ingredient. [Article]

Additional Highlights

Explore more groundbreaking research and regulatory updates in our biweekly newsletter:

• High-alcohol-producing Klebsiella pneumoniae aggravates lung injury by affecting neutrophils and the airway epithelium [Article]
• Adipocyte-derived ferroptotic signaling mitigates obesity[Article]
• FDA targets more online vendors selling unapproved GLP-1RA products[News]
• Datopotamab deruxtecan application in the EU for patients with advanced nonsquamous non-small cell lung cancer voluntarily withdrawn[News]

Stay informed about the latest in medical research and innovation. Join us in two weeks for more insights into the dynamic world of healthcare and life sciences advancements.

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