Mandana AmeliMojarad

The adaptive immune response depends on T cell receptor (TCR) diversity to counter cancers, autoimmunity, and infections. This diversity is encoded within CDR3, which serves as a unique barcode for each T cell clone. Characterizing CDR3 sequences is essential for tracking clonal dynamics, identifying neoantigen-reactive T cells, and designing personalized immunotherapy. While TCR-seq remains the benchmark, existing RNA-seq datasets offer a cost-effective retrospective alternative. However, tools like MiXCR and TRUST4, optimized for TCR-enriched samples, are limited in bulk and single-cell RNA-seq due to low transcript abundance and sparse coverage. In this review, we synthesize quantitative evidence from published head-to-head benchmarking studies that performed matched RNA-seq and TCR-seq on the same biological samples. These studies demonstrate that standard RNA-seq typically recovers only 3–5% of unique clonotypes identified by TCR-seq, with substantial underrepresentation of low-frequency clones; however, in T cell-rich tissues and when high sequencing depth is combined with optimized computational pipelines, RNA-seq can capture the majority of high-frequency clonotypes, albeit with limited accuracy in clonotype frequency estimation and poor α/β pairing recovery. We review computational efforts to recover CDR3 sequences from RNA-seq data, highlighting recurrent obstacles: transcript scarcity, fragmentation, short reads, and assembly errors. We critically assess whether artificial intelligence can overcome these barriers . We also examine emerging wet-lab strategies including probe-based enrichment, FUME-TCRseq, and rhTCRseq. We conclude that RNA-seq cannot replace TCR-seq, but AI-enhanced tools with targeted library improvements could expand the utility of existing datasets and degraded specimens.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited therapies. Reprogrammed lipid metabolism, driven by upregulated de novo lipogenesis, is a key tumorigenic mechanism. The enzyme ACSL3 is strongly correlated with poor HCC prognosis, positioning it as a potential therapeutic target. Material and Methods: ACSL3 expression was assessed in vivo and ex vivo using comparative analysis. Bioinformatic investigations, including gene set enrichment analysis (GSEA) and KEGG pathway analysis, were employed to identify signaling pathways and biological processes associated with ACSL3 overexpression. Results: ACSL3 expression was consistently elevated in HCC models. Enrichment analyses revealed that high ACSL3 levels are associated with activation of the STAT3 signaling pathway and upregulation of key lipogenic enzymes, suggesting a feedforward oncogenic loop. Predictive data also indicate a correlation between ACSL3 expression and the immune checkpoint regulator PD‐L1. Conclusion: These findings underscore ACSL3 as a significant biomarker and candidate therapeutic target in HCC. Its role bridges dysregulated lipid metabolism with oncogenic signaling and immune evasion, warranting further investigation into ACSL3‐targeted strategies.

Angiotensin-converting enzyme 2 (ACE2), a key regulator of the renin-angiotensin system (RAS), maintains central nervous system (CNS) homeostasis by metabolizing neuroinflammatory peptides like angiotensin II (Ang II) and apelin-13, thereby exerting neuroprotective effects. Recent evidence underscores ACE2’s paradoxical roles in neurodegeneration: its loss of function due to SARS-CoV-2 spike protein binding exacerbates neuroinflammation and cognitive decline, while its upregulation may mitigate AD pathology by reducing amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The COVID-19 pandemic has further highlighted ACE2 axis dysregulation as a potential accelerator of AD progression, with studies reporting elevated biomarkers of neurodegeneration in post-COVID patients. Therefore, in this review, we highlight the emerging insights into ACE2’s dual role in AD and other neurodegenerative diseases, emphasizing its interactions with microglial activation, blood-brain barrier integrity, and mitochondrial dysfunction. We also critically evaluate novel therapeutic strategies, including recombinant ACE2, ACE2-derived peptides, and gene therapy approaches designed to restore RAS balance without compromising viral defense mechanisms. By integrating mechanistic and clinical insights, this work highlights ACE2 as a promising target for neurodegenerative disease interventions.

A pan-cancer analysis summarizing the overall changes in mRNA and protein stability of ADM9, as well as its oncogenic function on immune cell line modulation and checkpoints within the tumor microenvironment (TME), is lacking, despite the fact that ADM9 up-regulation is correlated with the progression of many cancers. Therefore, in this study, we comprehensively analyzed the role of ADAM9 expression and its prognostic value in different cancers to fill this gap. Multiple bioinformatics databases such as Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were used to evaluate the ADAM9 genetic alternation, phosphorylation, and methylation, and indicated highly positive correlated genes that might play a critical interaction with ADAM9 and their molecular function with GO analysis. We also evaluate the effect of higher ADAM9 with prominent immune modulatory genes and immune infiltration especially in liver cancer pathogenesis stimulates lower NK cell effector functions based on its role in MICA shedding and increasing the Tregs infiltration. Immunohistochemistry (IHC) staining from 90 pathologically verified samples proved the positive correlation between ADAM9 and tumor stages and proved the higher expression of ADAM9 correlated genes (SNX9, APP, TNF, CDH1, ITGAV, MAD2L2) in HCC pathogenesis. In conclusion, this pan-cancer study provides a comprehensive understanding of the prognostic value of ADAM9 in various tumors emphasizing its importance to be considered as an innovative treatment approach, especially in tumor immunity shortly.

Cuproptosis is a recently discovered form of regulated cell death triggered by excess copper (Cu) strongly influenced by the import, export, and intracellular utilization of Cu known as Cu homeostasis. Cinobufagin (CB) is a well-known Chinese medicine for its apoptosis-inducing role; however, its function on cuproptosis is poorly understood. To evaluate the effect of CB on inducing cell death through cuproptosis, we used RNA-seq data of HepG2-treated cells with CB to understand Cuproptosis genes. By using CCK-8 assay, Ross assay, GSH assay, and qRT-PCR, we found that CB could enhance cuproptosis in primary liver cancer cell lines, especially by increasing copper transporters CTR1, CTR2, and LIAS and downregulation of copper efflux transporters ATP7A and ATP7B resulted in increased reactive oxygen species (ROS) production, copper ionophores while reduced intracellular copper chelator glutathione (GSH) synthesis. In conclusion, our findings indicated that CB by increasing cuproptosis-related genes can mediate higher cell cytotoxicity against HepG2 and HUH7 and could provide a new insight into mechanisms of CB as an anti-tumor agent for targeting liver cancer.

Introduction: Alzheimer's disease (AD), the main cause of dementia, is characterized by synaptic loss and neurodegeneration. Amyloid‐β (Aβ) accumulation, hyperphosphorylation of tau protein, and neurofibrillary tangles (NFTs) in the brain are considered to be the initiating factors of AD. However, this hypothesis falls short of explaining many aspects of AD pathogenesis. Recently, there has been mounting evidence that neuroinflammation plays a key role in the pathophysiology of AD and causes neurodegeneration by over‐activating microglia and releasing inflammatory mediators.Methods: PubMed, Web of Science, EMBASE, and MEDLINE were used for searching and summarizing all the recent publications related to inflammation and its association with Alzheimer's disease.Results: Our review shows how inflammatory dysregulation influences AD pathology as well as the roles of microglia in neuroinflammation, the possible microglia‐associated therapeutic targets, top neuroinflammatory biomarkers, and anti‐inflammatory drugs that combat inflammation.Conclusion: In conclusion, microglial inflammatory reactions are important factors in AD pathogenesis and need to be discussed in more detail for promising therapeutic strategies.

Coronavirus Disease 2019 (COVID‐19) has become a global pandemic in 2020 with high patient mortality due to acute respiratory distress syndrome which is possibly induced by a Cytokine release syndrome and more specifically through an interleukin‐6 (IL‐6) booster. Currently, IL‐6/IL‐6R inhibitors indicated an effective function in reducing the inflammatory markers in severe COVID‐19 patients. In this comprehensively narrative review, we searched online academic databases including (Google Scholar, Web of Science, and Pub Med), the relevant literature was extracted from the databases by using search terms of COVID‐19, IL‐6, and IL6 inhibitor as free‐text words and also with the combination with OR/AND to summarise the latest discoveries on the inhibitors of IL‐6 and its receptor's especially focussing on the role of natural product, Naringin (NAR) as a flavonoid found in citrus fruits, with considerable anti‐inflammatory and antiviral properties in COVID‐19 treatments. Our data Therefore in comparison with other synthetic monoclonal antibodies NAR may provide a good qualification for the development of novel anti‐inflammatory agents, especially against Covid 19 based on recent studies.

Corona virus disease 2019 (COVID-19) has become a deadly infectious disease, especially for those with co-morbidities such as diabetes. People with diabetes developing a viral infection, seem to have harder treatments due to fluctuations in blood glucose levels therefore, effective therapeutic approaches need to be considered for them. Statins are well-known lipid-lowering drugs; they also have anti-inflammatory and immunomodulatory effects and can impact on expression of microRNAs (miRNAs). In this study we investigate the effects of simvastatin on the expression of miR-150-5p as a famous regulator of inflammation and its association with multiple cancers in 30 patients with Type 2 diabetes mellitus (T2DM) and COVID-19 compared to the COVID-19 hospitalized patients before and after treatment with simvastatin with real-time-PCR after 2month, and evaluate its targets gens and functions with the help of bioinformatics and GO enrichment analysis respectively. Our results showed that simvastatin can increase miR-150-5p and therefore down regulate expression of its target genes involving in immune stimulation and decrease lipid profile including LDL-C, total cholesterol, and ApoB, especially in the group with type 2 diabetes mellitus (T2DM) and COVID-19 compared to the patients with only COVID-19. Simvastatin as an anti-inflammatory agent can modulate miRNAs expression; it can be suggested as an adjunct therapy especially for T2DM patients with COVID-19. Further studies may help us for developing better treatments about therapeutic manipulation of miRNAs in vivo.