Vol 31, No 33 (2024)

:Human papillomavirus (HPV) infections are the cause of warts, lesions and cancer, with different types of HPV causing different symptoms. HPV infections are the primary cause of cervical cancer. There are over 220 different types of HPV, and only nine of these can currently be vaccinated. There is a need to treat these viral infections without just treating the symptoms of the infection, as is currently the main method. There is a wide range of small molecules that have been used to inhibit various stages of the HPV infectious cycle. This review examined 132 small molecules from 121 studies that specifically target aspects of HPV infections. HPV DNA encodes for six early genes (E1 to E7, skipping E3) and two late genes (L1 and L2). According to the results, these targets for small molecule inhibitors fall into three categories: those targeting E1 and E2, targeting E6 and E7 and, finally, targeting L1 and L2. Inhibitors of E6 and E7 are the most widely studied targets, with the majority of HPV inhibition in this area. While compounds targeting both E1/E2 and E6/E7 have made it to clinical trials, there has been no significant advancement on the topic.

:The immune system is the key player in a wide range of responses in normal tissues and tumors to anticancer therapy. Inflammatory and fibrotic responses in normal tissues are the main limitations of chemotherapy, radiotherapy, and also some newer anticancer drugs such as immune checkpoint inhibitors (ICIs). Immune system responses within solid tumors including anti-tumor and tumor- promoting responses can suppress or help tumor growth. Thus, modulation of immune cells and their secretions such as cytokines, growth factors and epigenetic modulators, pro-apoptosis molecules, and some other molecules can be suggested to alleviate side effects in normal tissues and drug-resistance mechanisms in the tumor. Metformin as an anti-diabetes drug has shown intriguing properties such as anti-inflammation, anti-fibrosis, and anticancer effects. Some investigations have uncovered that metformin can ameliorate radiation/chemotherapy toxicity in normal cells and tissues through the modulation of several targets in cells and tissues. These effects of metformin may ameliorate severe inflammatory responses and fibrosis after exposure to ionizing radiation or following treatment with highly toxic chemotherapy drugs. Metformin can suppress the activity of immunosuppressive cells in the tumor through the phosphorylation of AMP-activated protein kinase (AMPK). In addition, metformin may stimulate antigen presentation and maturation of anticancer immune cells, which lead to the induction of anticancer immunity in the tumor. This review aims to explain the detailed mechanisms of normal tissue sparing and tumor suppression during cancer therapy using adjuvant metformin with an emphasis on immune system responses.

Background:Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies.

Aims:This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM.

Methods:The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs).

Result:Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features.

Conclusion:In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

Background:Acute lung injury (ALI) is a serious complication that may accompany severe pneumonia in children. Derived from exosomes of human umbilical cord mesenchymal stem cell exosome (HucMSC-Exo) can contribute to the regeneration of damaged lung tissue. This study aims to investigate the impact of HucMSC-Exo on ALI and its potential mechanisms.

Methods:Firstly, RT-qPCR was performed to assess the expression of miR-335-5p. Subsequently, Pearson correlation analysis was performed to examine the correlation between METTL14 and miR-335-5p, as well as the correlation between METTL14 and ITGB4., while RNA immunoprecipitation (RIP) was used to determine the m6A modification level of ITGβ4. Additionally, molecular biology techniques were employed to evaluate the expression of glycolysis-related factors. Definitively, an LPS-induced ALI model was established to investigate the effect of miR-335-5p on mice lung tissue.

Results:miR-335-5p was found to be highly expressed in HucMSC-Exo. Transfection with miR-335-5p mimics resulted in increased glucose uptake. Pearson correlation analysis revealed a negative correlation between METTL14 and miR-335-5p, as well as between METTL14 and ITGβ4. The m6A level of ITGβ4 was elevated in ALI. Overexpression of METTL14 was found to reduce the expression and glucose uptake of ITGβ4, while overexpression of ITGβ4 reversed the effects of METTL14 overexpression. in vivo, results demonstrated that miR-335-5p can improve the extent of lung tissue lesions and reduce glycolytic levels.

method:HucMSC-Exos were successfully cultured and identified. The LPS-induced ALI model was established using A549 cells and BALB/c mice. Pearson correlation coefficient analyzed the association between METTL14 and miR-335-5p or ITGβ4 in clinical specimens. The modification level of m6A was detected using RNA m6A colorimetry and RNA immunoprecipitation. The cell damage, apoptosis, expression of inflammatory factors, and glycolytic-related factors were determined molecularly and immunohistochemically in various groups.

Conclusion:This study reveals the mechanism by which miR-335-5p derived from HucMSC-Exo could alleviate LPS-induced ALI by regulating the m6A modification of ITGβ4, providing a new direction for the treatment of ALI.

:This patent describes the novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors. The patent includes the synthesis of compounds, compositions containing them and their use in the treatment of or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).