Ontosight^® Newsletter Issue 21

Ontosight^® – Newsletter
February 24^th – March 09^th, 2025 – Issue 21

Welcome to the 21^th edition of Ontosight^® Newsletter! This issue features groundbreaking oncology research, including novel immunotherapy targets and resistance mechanisms, alongside key insights into neurodegenerative diseases like Alzheimer's and Parkinson’s. Explore the impact of gut microbiota on health, advancements in cardiovascular and inflammatory disorders, and emerging therapies in regenerative medicine. Plus, stay updated on the latest regulatory approvals shaping the future of healthcare.

Featured Articles

1. Oncology & Cancer Immunotherapy

• Alterations in PD-L1 succinylation shape anti-tumor immune responses in melanoma

This study links succinyl-CoA metabolism to tumor immunity and anti-PD-1 therapy efficacy in melanoma. Succinylation of PD-L1 at lysine 129 promotes its degradation, enhancing T cell-mediated tumor elimination. The CPT1A enzyme facilitates this process, and bezafibrate boosts CPT1A, suggesting new therapeutic and biomarker strategies. [Article]

• Hypoxia inducible factor-1α drives cancer resistance to cuproptosis

This study identifies HIF-1α as a key driver of cuproptosis resistance in solid tumors by regulating PDK1/3, DLAT, and metallothionein, limiting copper-induced cell death under hypoxia. High copper levels stabilize HIF-1α, further enhancing resistance. Targeting HIF-1α may sensitize tumors to cuproptosis, offering a potential therapeutic strategy. [Article]

• Harnessing Macrophages in Cancer Therapy: from Immune Modulators to Therapeutic Targets

Tumor-associated macrophages (TAMs) promote angiogenesis, metastasis, and immune suppression in cancer but can also be activated to attack tumors. Targeting TAMs is a promising immunotherapy strategy, including blocking recruitment, reprogramming, and using CAR-macrophages. This review explores TAM functions and therapeutic approaches in cancer treatment. [Article]

• Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer

The novel HSP90 inhibitor C210 overcomes doxorubicin resistance in quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics. C210 disrupts OXPHOS-associated proteins, leading to mitochondrial apoptosis and selective cancer cell elimination. In vivo, C210 shows promising anticancer efficacy by inhibiting OXPHOS metabolism. [Article]

2. Neurological & Neurodegenerative Disorders

• Opposite causal effects of type 2 diabetes and metformin on Alzheimer's disease

This study finds opposing effects of type 2 diabetes (T2D) and metformin on Alzheimer's disease (AD) risk. T2D is linked to a decreased AD risk, while metformin use shows a potential increase in AD risk. These findings emphasize the need to assess AD risk in metformin users. [Article]

• Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease

This study uses spatial transcriptomics to explore how Aβ immunization clears amyloid-β in Alzheimer's disease (AD). It identifies microglial states linked to Aβ removal, highlighting the roles of TREM2, APOE, and complement signaling in immune responses. Findings offer insights into enhancing Aβ-targeted immunotherapies for AD treatment. [Article]

• Decoding Alzheimer's Disease With Depression: Molecular Insights and Therapeutic Target

This study identified ITGB5 and SPCS1 as predictive biomarkers for Alzheimer's disease (AD) with depression using machine learning and WGCNA analysis. A positive correlation between AD and depression was confirmed, with 84 shared genes identified. Four potential drugs targeting ITGB5 were found, offering promising therapeutic avenues. [Article]

• Probiotic-fermented ginger-processed Gastrodia elata BI. ameliorates AlCl(3)-induced cognitive dysfunction in an Alzheimer's disease rat model by regulating the gut microbiota and CREB/BDNF pathway

Fermented Gastrodia elata BI. (FGGE) improves cognition, neural function, and gut microbiota balance in an AlCl₃-induced Alzheimer's disease (AD) rat model. FGGE reduces oxidative stress, restores cholinergic function, and activates the cAMP/BDNF pathway for neural regulation. It also enhances beneficial gut bacteria, suggesting a gut-brain axis mechanism for AD relief. [Article]

3. Gut Microbiota & Immunometabolism

• Probiotic-fermented ginger-processed Gastrodia elata BI. ameliorates AlCl(3)-induced cognitive dysfunction in an Alzheimer's disease rat model by regulating the gut microbiota and CREB/BDNF pathway

This study explores fermented Gastrodia elata BI. (FGGE) and its effects on Alzheimer’s disease (AD) in rats. FGGE improves cognitive function, reduces brain oxidative stress, restores cholinergic function, and balances the gut microbiota. Its therapeutic effects may act through the gut-brain axis, offering potential as a functional food for AD management. [Article]

• The Detrimental Impact of Ultra-Processed Foods on the Human Gut Microbiome and Gut Barrier

This review highlights the negative impact of ultra-processed foods (UPFs) on gut health, leading to dysbiosis, increased permeability, and inflammation. UPFs reduce beneficial bacteria and are linked to chronic diseases and gut-brain axis dysfunction. Dietary changes and stricter regulations are needed to mitigate their harmful effects. [Article]

• Combined traditional Chinese medicine and probiotics (TCMP) alleviates lipid accumulation and improves metabolism in high-fat diet mice via the microbiota-gut-liver axis

This study evaluates a TCMP formula (lotus leaf, hawthorn, Chinese holly, and Bifidobacterium lactis BPL-1) in high-fat diet (HFD)-fed mice. TCMP reduces fat accumulation, improves lipid metabolism, and enhances gut microbiota by increasing beneficial bacteria and short-chain fatty acids. Multi-omics analysis confirms its role in inhibiting lipid biosynthesis, making it a promising anti-obesity therapy. [Article]

4. Cardiovascular & Inflammatory Disorders

• Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis

This study identifies CYSLTR2 and P2RY6 as receptors mediating ceramide-induced atherosclerosis via Gq and inflammasome signaling. Blocking these pathways reduces atherosclerosis severity, independent of cholesterol levels, offering new therapeutic targets. Structural analysis reveals how long-chain ceramides bind and activate CYSLTR2, highlighting a novel mechanism in cardiovascular disease progression. [Article]

• Vitamin E ameliorates blood cholesterol level and alters gut microbiota composition

This study highlights vitamin E’s (VE) role in reducing LDL-C levels and its impact on the gut microbiota, particularly increasing SCFA-producing and bile acid-metabolizing bacteria like Lachnospira sp. and Faecalibacterium spp.. The findings suggest that VE’s health benefits may be partially mediated through gut microbiota modulation, with variations in response linked to individual microbial compositions. [Article]

• Role of oxidative balance score in staging and mortality risk of cardiovascular-kidney-metabolic syndrome: Insights from traditional and machine learning approaches

Oxidative Balance Score (OBS) is associated with cardiovascular-kidney-metabolic (CKM) syndrome severity and mortality risk, with lower OBS quartiles linked to higher mortality rates. OBS mediates the effects of inflammation, lifestyle, and frailty on outcomes, and machine learning models effectively predict CKM progression and mortality. This study supports OBS as a risk stratification tool for CKM management. [Article]

• Draconis Sanguis (DS) from the fruit of Daemonorops draco Bl. ameliorates cardiac function through optimizing myocardial energy metabolism by promoting angiogenesis in ischemic heart failure

Draconis Sanguis (DS) improves ischemic heart failure (IHF) by enhancing angiogenesis and optimizing energy metabolism via the HIF-1α/VEGF pathway. DS increased survival rates, cardiac function, and ATP production, while reducing pathological damage in ischemic myocardium. These findings highlight DS as a potential therapeutic for heart failure. [Article]

5. Regenerative Medicine, Precision Therapies & Biomarker Discovery

• Mucosal macrophages govern intestinal regeneration in response to injury

Macrophages play a crucial role in intestinal regeneration following radiation-induced enteritis by promoting fetal-like reprogramming and proliferation of intestinal epithelial cells. Ablation of macrophages compromised regeneration, while key secreted molecules NRG1 and SPP1 were identified as drivers of this process. Therapeutic targeting of macrophages may enhance intestinal healing and improve cancer patients' quality of life. [Article]

• Tumor gene expression signatures associated with outcome in large B-cell lymphoma treated with CD19-directed CAR T-cell therapy (axicabtagene ciloleucel)

Researchers analyzed tumor transcriptomics from the ZUMA-7 trial to identify gene expression signatures (GES) predicting outcomes in CAR T-cell therapy for large B-cell lymphoma. A 6-gene signature (6-GES) correlated with improved survival, while a 17-gene signature (17-GES) was linked to disease progression and resistance. These findings provide predictive biomarkers for risk stratification and optimizing next-generation CAR T therapies. [Article]

• Identification and Validation of Four Serum Biomarkers With Optimal Diagnostic and Prognostic Potential for Gastric Cancer Based on Machine Learning Algorithms

Researchers integrated multi-omics data from TCGA and GEO databases to identify four promising biomarkers (CHI3L1, FCGBP, VSIG2, TFF2) for gastric cancer (GC). These biomarkers, validated through RT-PCR, ELISA, and bioinformatics, demonstrated strong diagnostic and prognostic potential. Their correlation with immune cell infiltration suggests a role in GC pathogenesis, paving the way for further clinical applications. [Article]

• Ferroptosis-Related Genes Are Effective Markers for Diagnostic Targets of Crohn's Disease

Researchers identified ferroptosis-related genes as potential diagnostic biomarkers for Crohn’s disease (CD), correlating with iron deficiency and immune responses. Bioinformatics and immunohistochemical analysis revealed key genes (e.g., STAT3, MT1G, LCN2) linked to macrophage infiltration and neutrophil recruitment in CD patients. These findings suggest that ferroptosis-associated gene panels could improve CD diagnosis and prognosis. [Article]

Additional Highlights

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

• Melatonin protects retinal pigment epithelium cells against ferroptosis in AMD via the PI3K/AKT/MDM2/P53 pathway [Article]
• Antidrug antibodies to adalimumab do not associate with immunologically related adverse events[Article]
• Glutamine binds HSC70 to transduce signals inhibiting IFN-β-mediated immunogenic cell death[Article]
• FDA approvals decline but drug innovation remains strong even among small sponsors[News]
• Entrada Therapeutics Announces FDA Removal of Clinical Hold on ENTR-601-44[News]
• Bavarian Nordic Announces Acceptance of Marketing Authorization Application for Chikungunya Vaccine in the UK for Persons Aged 12 and Older[News]
• FDA Accepts Supplemental Biologics License Application for Genentech’s Gazyva for the Treatment of Lupus Nephritis [News]
• Odronextamab BLA Accepted for FDA Review for the Treatment of Relapsed/Refractory Follicular Lymphoma [News]
• Vertex Receives CHMP Positive Opinion for Expanded Label for KAFTRIO® in Combination With Ivacaftor for People With Cystic Fibrosis to Include Rare Mutations [News]
• European Medicines Agency Validates Gilead’s Marketing Authorization Application and EU-Medicines for All Application for Twice-Yearly Lenacapavir for HIV Prevention [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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