Ontosight^® Newsletter Issue 7

Ontosight^® – Newsletter
August 12^th – August 25^th, 2024 – Issue 7

Welcome to the 7^th edition of Ontosight^® Newsletter! This issue we spotlight pioneering research in cancer therapeutics, uncovering novel targets and resistance mechanisms, along with transformative approaches in neurodegenerative disease treatment. We delve into the latest findings in metabolic disorders and obesity, and explore groundbreaking immunological therapies. Additionally, we highlight innovative advancements in mitochondrial metabolism, offering new perspectives on cancer, fertility preservation, and mental health.

Featured Articles

1. Cancer Research and Therapeutics

• The periosteum provides a stromal defense against cancer invasion into the bone

The periosteum, a cellular layer covering bones, undergoes a protective thickening—known as the periosteal reaction—when facing cancer invasion, particularly in head and neck squamous cell carcinomas (HNSCCs). This thickening is driven by the upregulation of the TIMP1 gene, which inhibits matrix-degrading proteases, thus preventing cancer from invading the bone. Disruption of this protective response in mouse models accelerates bone invasion and decreases survival, suggesting that the periosteal reaction serves as a stromal defense mechanism against tumor progression. [Article]

• CRISPR screening identifies PRMT1 as a key pro-ferroptotic gene via a two-layer regulatory mechanism

This study identifies protein arginine methyltransferase 1 (PRMT1) as a crucial regulator of ferroptosis, a form of iron-dependent cell death. PRMT1 promotes ferroptosis by reducing intracellular glutathione levels and inhibiting the activity of ferroptosis suppressor protein 1 (FSP1). Inhibiting PRMT1 in mice prevents ferroptosis in the liver and enhances survival, suggesting PRMT1 as a potential target for anti-ferroptosis therapies. [Article]

• Targeting CD13/aminopeptidase N as a novel therapeutic approach for scleroderma fibrosis

This study identifies the soluble CD13 (sCD13)-bradykinin receptor B1 (B1R) signaling axis as a key driver of skin fibrosis in systemic sclerosis (SSc). Elevated levels of CD13, B1R, and MMP14 in SSc skin promote fibrotic processes, which can be inhibited by targeting B1R. The findings suggest that blocking the sCD13-B1R pathway could be a promising therapeutic strategy for SSc. [Article]

• BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression

This study highlights the potential of BRD4-specific proteolysis-targeting chimeras (PROTACs) in treating basal-like breast cancer (BLBC). The PROTAC 6b effectively targets BRD4 for degradation, reducing the levels of the oncogenic transcription factor KLF5 and inhibiting tumor growth in xenograft models. The combination of 6b with KLF5 inhibitors showed enhanced efficacy, suggesting that 6b could be a promising new treatment for BLBC. [Article]

• Comparative time-series multi-omics analyses suggest H1.2 involvement in anoxic adaptation and cancer resistance

The study investigates the naked mole rat’s (NMR) exceptional resistance to hypoxia and cancer by comparing embryonic fibroblasts from NMRs and mice. It identifies that higher levels of histone H1.2 in NMR cells, due to lower PARP1 inhibition, enhance HIF-1α activity and promote autophagy. This mechanism contributes to greater survival under low oxygen and reduced tumor formation. These findings suggest that H1.2 plays a key role in both anoxic adaptation and cancer resistance in NMRs. [Article]

2. Neuroscience and Neurodegenerative Diseases

• Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson’s disease

The study investigates how neuroinflammation contributes to dopaminergic neuron loss in Parkinson’s disease and explores a novel therapeutic approach using viral delivery of interleukin 10 (IL-10) specifically to microglia. This method reduces inflammation and neuron loss by inducing a distinct microglial cell state with enhanced phagocytotic activity and promoting the development of regulatory T cells. The findings suggest that IL-10 gene therapy could be a promising strategy to protect neurons and modulate immune responses in Parkinson’s disease. [Article]

• Structural insights into Frizzled3 through nanobody modulators

The study provides detailed structures of the Wnt receptor Frizzled3 (FZD3) bound to nanobodies. The crystal structure reveals how Nb8 binds to FZD3’s cysteine-rich domain, competing with Wnt5a and activating β-catenin signaling. Additionally, the cryo-EM structure of FZD3 with Nb9 shows binding to the cytoplasmic region, inhibiting interactions with Dishevelled (DVL) and GαS. These findings enhance understanding of FZD3’s functional interactions and offer potential therapeutic insights. [Article]

• Repurposing antidiabetic drugs for Alzheimer’s disease: A review of preclinical and clinical evidence and overcoming challenges

Repurposing antidiabetic drugs for Alzheimer’s disease (AD) treatment is gaining attention. This review highlights preclinical evidence showing that drugs like GLP-1 analogs, DPP4 inhibitors, metformin, thiazolidinediones, and SGLT2 inhibitors have neuroprotective effects in AD models by reducing amyloid plaques, tau hyperphosphorylation, and cognitive impairment. It also emphasizes the need for well-designed clinical trials to address patient selection, outcome measures, and potential risks. While some antidiabetic drugs show promise, challenges such as disease heterogeneity and risk evaluation must be addressed through ongoing trials. [Article]

• Post-translational Modifications of α-Synuclein, their Therapeutic Potential and Crosstalk in Health and Neurodegenerative Diseases

α-Synuclein aggregation is central to Parkinson’s disease and related disorders, with various post-translational modifications (PTMs) influencing its misfolding and aggregation. This review explores the diverse PTMs of α-Synuclein, including phosphorylation, ubiquitination, and acetylation, and their interplay (PTMs crosstalk) that affects disease pathology. It also discusses how these PTMs impact α-Synuclein’s function, their potential as biomarkers, and therapeutic targets for synucleinopathies. [Article]

• Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

This study investigated the dynamics of nuclear mitochondrial DNA (Numts) in humans by analyzing postmortem brain and blood samples. It found that brain tissue, particularly the dorsolateral prefrontal cortex, contains more Numts than blood and that increased Numts are linked to earlier mortality. Longitudinal studies in human fibroblasts showed a gradual accumulation of Numts, with faster rates in cells with mitochondrial DNA instability. These findings suggest that spontaneous Numts formation in postmitotic tissues could impact lifespan and may have functional significance. [Article]

3. Metabolic Disorders and Obesity

• Obesity intensifies sex-specific interferon signaling to selectively worsen central nervous system autoimmunity in females

Obesity increases autoimmunity in women by inducing a serum protein signature linked to Th1 and IL-17 pathways and exacerbating multiple sclerosis (MS) signaling. Female mice with diet-induced obesity show worsened MS symptoms and increased Th1 cell expansion. This effect is associated with higher IFN-α levels and enhanced T cell activation, driven by increased adiposity and modifiable by ovarian removal or type I IFN receptor knockdown. [Article]

• Novel metabolic and lipidomic biomarkers of sarcopenia

This study investigated the impact of resistance training and nutritional support (RTNS) on biomarkers of sarcopenia in older adults. Through a 12-week trial, differences in plasma metabolomic and lipidomic profiles between sarcopenic patients and controls were identified. Key findings included altered levels of metabolites such as carnitine and PI 32:1, with PI 32:1 showing high diagnostic accuracy for sarcopenia. RTNS effectively normalized some metabolite levels, suggesting potential therapeutic benefits and providing new insights into sarcopenia’s mechanisms and treatment options. [Article]

• Acetate enables metabolic fitness and cognitive performance during sleep disruption

This study explores how chronic sleep fragmentation (SF) affects metabolism and cognition using a mouse model. SF mice showed impaired cognitive function, glucose metabolism, and insulin sensitivity. Increased acetate levels in hypothalamic astrocytes were identified as a protective response. Elevating acetate through infusion or specific gene deletion improved these impairments by restoring key metabolic pathways. The study also found elevated acetate in patients with obstructive sleep apnea and type 2 diabetes, highlighting acetate’s potential protective role against sleep-related metabolic and cognitive issues. [Article]

• Regulated and adaptive in vivo insulin secretion from islets only containing β-cells

This study found that mice with islets composed solely of β-cells, and human pseudoislets with only β-cells, maintained effective blood glucose regulation and insulin secretion. Despite the absence of non-β-cells, these models exhibited normal glucose tolerance and insulin sensitivity. These results suggest that non-β-cells are not essential for glucose homeostasis or β-cell function, supporting the development of diabetes treatments using β-cell-only clusters. [Article]

4. Immunology and Infectious Diseases

• Less Deformable Erythrocyte Subpopulations Biomechanically Induce Endothelial Inflammation in Sickle Cell Disease

This study reveals that poorly deformable sickle red blood cells (RBCs) cause endothelial dysfunction directly through mechanotransduction, rather than solely through microvascular obstruction. By using microfluidic models and computational simulations, the research shows that these sickle RBCs and pharmacologically-dehydrated normal RBCs induce inflammatory responses in endothelial cells via abnormal physical interactions and increased shear stress. This highlights a new aspect of sickle cell disease vasculopathy where reduced RBC deformability leads to endothelial inflammation. [Article]

• The emerging role of the gut microbiota and its application in inflammatory bowel disease

This review examines the role of gut microbiome dysbiosis in inflammatory bowel disease (IBD) and its potential as a biomarker and therapeutic target. It highlights how current treatments targeting inflammation are often ineffective and explores emerging therapies aimed at correcting microbiome imbalances. These advancements include nanoparticle delivery, fecal microbiota transplantation, nutritional therapies, probiotic engineering, phage therapy, stem cells, and herbal formulas. [Article]

• Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation

This study identifies gelsolin (GSN) as a key regulator of NLRP3 inflammasome activation in macrophages, which is reduced in rheumatoid arthritis (RA) patients. GSN interacts with NLRP3, affecting its activation and maintaining mitochondrial stability and calcium equilibrium. GSN-deficient mice showed worsened inflammatory symptoms in RA and other models, highlighting its potential as both a diagnostic biomarker and therapeutic target for RA and other inflammatory diseases. [Article]

• Intestinal helminth infection impairs vaccine-induced T cell responses and protection against SARS-CoV-2 in mice

In mice, infection with the intestinal helminth Heligmosomoides polygyrus bakeri (Hpb) impairs the efficacy of an mRNA COVID-19 vaccine by reducing polyfunctional CD4+ and CD8+ T cell responses. Although vaccine-induced B cell responses remain unchanged, Hpb infection diminishes protection against SARS-CoV-2 variants, particularly Omicron. The suppression of CD8+ T cell responses is mediated through an IL-10 pathway, with blockade of IL-10 restoring some of the vaccine-induced immune response. [Article]

5. Mitochondrial and Cellular Metabolism

• Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice

In a mouse model of depression, disrupted circadian rhythms in the medial prefrontal cortex (mPFC) are linked to mood regulation. Ketamine counteracts these disruptions, with the mPFC clock’s functionality being crucial for depression and treatment response. Silencing Per2 or enhancing clock modulators like ROR shows potential antidepressant effects by improving synaptic plasticity in the mPFC, highlighting the clock’s role in depression and therapeutic strategies. [Article]

• Engineered mitochondria exert potent antitumor immunity as a cancer vaccine platform

Engineered mitochondria, enriched with cancer antigens like OVA and TRP2, show promise as effective vaccines. These mitochondria activate dendritic cells via the TLR2 pathway, enhancing antitumor immunity in murine models. The study presents a platform for developing versatile vaccines using antigen-loaded mitochondria, potentially beneficial for cancer and other diseases. [Article]

• Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson’s Disease

Ginsenoside Rg3 (Rg3) enhances cardiolipin levels, promoting mitochondrial homeostasis and improving motor function in Parkinson’s disease (PD) models. Rg3 boosts mitochondrial health by increasing cardiolipin synthesis through its interaction with GRB2 and TRKA, and by enhancing mitochondrial oxidative phosphorylation. Tenofovir Disoproxil Fumarate (TDF) also supports this mechanism. These findings suggest Rg3 and TDF as promising candidates for PD prevention through cardiolipin regulation. [Article]

• Fertility protection during chemotherapy treatment by boosting the NAD(P)+ metabolome

Boosting NAD+ levels can protect ovarian function and mitigate chemotherapy-induced infertility in mice, as shown by improved oocyte yield and follicle health. Nicotinamide mononucleotide (NMN) treatment also reduced tumor growth without affecting chemotherapy efficacy. These findings suggest that NAD+ precursors could be a promising non-invasive approach to preserve ovarian function in cancer patients and enhance cancer therapy. [Article]

Additional Highlights

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

• Lactate helps cancer cells resist chemotherapy [Article]
• The surprising cause of fasting’s regenerative powers [News]
• AbbVie’s SKYRIZI® (risankizumab) Recommended by NICE for Moderately to Severely Active Ulcerative Colitis [News]
• As Mpox Cases Surge in Africa, WHO Declares a Global Emergency-Here’s What to Know [News]

Company	Drug Name	Regulatory Body	Approval/Type	Disease	NewsLink
IASO Bio	Equecabtagene Autoleucel	U.S. FDA	Investigational NDA	Non-renal Systemic Lupus Erythematosus & Lupus Nephritis	Link
Sandoz	Enzeevu™ (aflibercept-abzv)	U.S. FDA	Marketing Approval	Neovascular Age-related Macular Degeneration	Link
Ascendis Pharma	YORVIPATH® (Palopegteriparatide)	U.S. FDA	Marketing Approval	Hypoparathyroidism	Link
Galderma	Nemluvio® (nemolizumab)	U.S. FDA	Marketing Approval	Prurigo Nodularis	Link
AstraZeneca	Enhertu	China NMPA	Marketing Approval	Advanced or Metastatic HER2-positive Gastric or GEJ Adenocarcinoma	Link
AstraZeneca	Lynparza & Imfinzi	European Commission	Marketing Approval	Advanced/Recurrent Endometrial Cancer	Link
AstraZeneca	Imfinzi	U.S. FDA	Priority Review and Breakthrough Therapy Designation	Limited-stage Small Cell Lung Cancer	Link
AstraZeneca	Imfinzi	U.S. FDA	Marketing Approval	Resectable Non-small Cell Lung Cancer	Link
AstraZeneca	Fasenra	China NMPA	Marketing Approval	Severe Eosinophilic Asthma	Link
Gilead	Livdelzi (Seladelpar)	U.S. FDA	Accelerated Approval	Primary Biliary Cholangitis	Link
Incyte & Syndax	Niktimvo™ (axatilimab-csfr)	U.S. FDA	Marketing Approval	Chronic GVHD	Link
Deciphera	Vimseltinib	U.S. FDA	Priority Review	Tenosynovial Giant Cell Tumor (TGCT)	Link
Bavarian Nordic	Chikungunya Vaccine	U.S. FDA	Priority Review for BLA	Chikungunya	Link
Pfizer & BioNTech	Omicron KP.2-adapted COVID-19 Vaccine	U.S. FDA	Approval & Authorization	COVID-19	Link
Liquidia	YUTREPIA™ (treprostinil) Inhalation Powder	U.S. FDA	Tentative Approval	PAH, PH Associated with Interstitial Lung Disease	Link
Astellas	PADCEVTM™ (enfortumab vedotin)	China NMPA	Marketing Approval	Locally Advanced or Metastatic Urothelial Cancer	Link
Phanes Therapeutics	PT217	U.S. FDA	Orphan Drug Designation	Neuroendocrine Carcinoma	Link
Johnson & Johnson	BALVERSA® (erdafitinib)	European Commission	Marketing Approval	Unresectable or Metastatic Urothelial Carcinoma	Link
Johnson & Johnson	RYBREVANT® (amivantamab-vmjw) & LAZCLUZE™ (lazertinib)	U.S. FDA	Marketing Approval	EGFR-mutated Advanced Lung Cancer	Link
ReAlta Life Sciences	RLS-0071	U.S. FDA	Orphan Drug & Fast Track Designation	Steroid-Refractory Acute GVHD	Link
Regeneron	Linvoseltamab	U.S. FDA	BLA Update	Relapsed/Refractory Multiple Myeloma	Link
Moderna	mRESVIA(R)	European Commission	Marketing Approval	Respiratory Syncytial Virus (RSV)	Link
Moderna	COVID-19 mRNA Vaccine (Targeting Variant JN.1)	Japan MHLW	Partial Change Application Approval	COVID-19	Link
Moderna	Updated COVID-19 Vaccine (Targeting KP.2 Variant)	U.S. FDA	sBLA Approval	COVID-19	Link
Innovent	Dupert®（Fulzerasib)	China NMPA	Marketing Approval	Advanced NSCLC with KRAS G12C mutation	Link

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