Current Molecular Medicine - Volume 24, Issue 11, 2024

Several signaling pathways are involved in the process of angiogenesis, which is one of the most important hallmarks of glioblastoma multiforme (GBM). Identifying related gene variants can help researchers work out what causes anti-angiogenesis drug resistance.

The goal of this systematic analysis was to identify all mutations and polymorphisms involved in angiogenesis pathways in GBM and their impact on clinical outcomes.

The keywords include glioblastoma, angiogenesis, signaling pathway, mutation, polymorphism, and related terms used to search ISI, PubMed, and Scopus for relevant articles published up to January 2022. The PRISMA protocol was used to conduct our systematic review. The related articles were taken into consideration. The risk of bias in the associated articles was surveyed, as well as the article scoring. Two authors collaborated on data extraction.

The inclusion criteria were included in 32 articles out of a total of 787 articles. VEGF, HIF1a, EGFR, PI3K, and MAPK are the pathways that have been studied the most. IDH1, VEGF, VEGFR, EGFR, and HIF1a are the genes with the highest frequency of mutations or polymorphisms.

In conclusion, this study found that angiogenesis in primary or recurrent GBM is linked to gene changes in eleven signaling pathways. However, some of these gene mutations have been researched numerous times in relation to angiogenesis, while others have only been studied once. Understanding these changes will help us employ combination therapies more effectively for GBM patients' survival and personal medicine.

Aminoglycosides are among the first-choice antibiotics for routine clinical use. However, dose-limiting factors such as ototoxicity and nephrotoxicity are considered as serious complications of aminoglycosides.

In this systematic review, the main goal was to investigate the efficacy and incidence of nephrotoxicity and ototoxicity of once-daily dosing (ODD) and multiple daily dosing (MDD) regimens of aminoglycosides through available randomized controlled trials (RCTs).

We performed a literature-based research in relevant databases, including EMBASE, MEDLINE, and SCOPUS published between 1987 and 2023 using the keywords “aminoglycosides”, “pharmacokinetics”, “ODD”, “MDD”, “once daily”, “multiple daily”, “dosing regimen”, “nephrotoxicity”, “ototoxicity”, “efficacy”, “safety”, and “toxicity”. As so told, the results of this article were limited to papers available in English. Our initial search yielded 1124 results. After a review of the titles and abstracts of the articles, 803 articles were excluded from this study because they did not address the toxicity and effectiveness of ODD versus MDD of aminoglycosides. A total number of 20 studies on gentamicin, tobramycin, netilmicin, and amikacin met the inclusion criteria for the efficacy of aminoglycosides and their role in ototoxicity and nephrotoxicity were included in this review. Studies recruited different age classes, and the age of relevant cohorts varied from only a few days to more than 70 years. Results: The most common clinical condition in the included studies was cystic fibrosis.

In most studies, there were no significant differences between the two regimens regarding ototoxicity. In addition, the ODD regimens were safer than MDD concerning nephrotoxicity.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide. NAFLD is often associated with features of Metabolic Syndrome such as obesity and insulin resistance.

The current comprehensive meta-analysis was performed to evaluate the association between circulating Omentin levels and NAFLD. A systematic search in Scopus, Web of Science, PubMed, and Google Scholar databases was conducted to identify relevant studies up until 5th May 2022. The standard mean difference (SMD) values and 95% confidence intervals (CIs) were computed for the association of Omentin levels with NAFLD risk in a random effect model.

The meta-analysis involved 6 case-control studies with a total of 371 cases and 269 controls. Pooled SMD showed no significant difference in serum Omentin between NAFLD and healthy groups (SMD= -0.047 and 95% CI -0.957_0.862 P=0.91). Subgroup analysis based on sample size showed that the average Omentin levels were significantly higher in NAFLD patients in studies with sample size ≥70 (SMD=0.356 CI 0.056_0.655 P=0.02).

Additional well-designed studies with more sample sizes are essential to clarify the potential role of Omentin as a risk marker of NAFLD.

Osteoarthritis (OA) is a chronic inflammatory condition that affects the articular cartilage. Astragaloside IV (AS-IV) constitutes the primary active component of the Chinese herbal medicine Huangqi (Radix Astragali Mongolici). AS-IV demonstrates anti-inflammatory and anti-apoptotic attributes, exhibiting therapeutic potential across various inflammatory and apoptosis-related disorders. Nevertheless, its pharmaceutical effects in OA are yet to be fully defined.

This study aimed to investigate the protective impact of AS-IV on rat chondrocytes treated with IL-1β and ascertain whether autophagy plays a role in this effect.

Chondrocytes were isolated and cultivated from the knee joints of neonatal SD mice. The study included the blank control group, the model group, and the AS-IV concentration gradient group (50, 100, 200 µmol/L) to intervene with chondrocytes. The MTT assay was employed to assess cell viability at varying culture periods, enabling the determination of suitable concentration and duration. Subsequently, chondrocytes were treated with the optimal AS-IV concentration and divided into three groups: the model group replicated IL-1β-induced inflammatory chondrocyte injury, the AS-IV group received a co-culture of AS-IV and IL-1β, and a blank control group was established. Changes in cell morphology and structure were observed using ghost pen cyclic peptide staining. ELISA was used to measure TNF-α and GAG levels in cell supernatants. RT-qPCR assessed p62 and LC3 mRNA expression, while Western Blot evaluated p62 and LC3II/I protein expression.

AS-IV promoted chondrocyte proliferation and concurrently inhibited cell apoptosis. An optimal AS-IV dose of 200 µmol/L and a suitable reaction time of 48 h were identified. Ghost pen cyclic peptide staining indicated that the model group's cytoskeleton exhibited fusiform changes with reduced immunofluorescence intensity, as opposed to the blank control group. The AS-IV group displayed more polygonal cytoskeletal morphology with increased immunofluorescence intensity. AS-IV reduced TNF-α levels and elevated GAG levels in the culture supernatant. Additionally, AS-IV lowered p62 mRNA and protein expression while increasing LC3 mRNA expression in cultured chondrocytes.

Our findings suggest that AS-IV mitigates inflammatory chondrocyte injury, safeguarding chondrocytes through a potential autophagy suppression mechanism. These results imply that AS-IV could offer preventive advantages for OA.

The purpose of this study was to investigate the role of miR-148b in liver injury in rats with traumatic hemorrhagic shock (THS) and to elucidate its potential mechanism.

The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of rats were detected by enzyme-linked immune sorbent assay (ELISA), and the injury of rat liver was analyzed by hematoxylin-eosin (H&E) staining. Apoptosis of rat hepatocytes and normal rat liver cell line (BRL3A) was identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and flow cytometry, respectively. MiR-148b and sirtuin 6 (SIRT6) expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. Lactate dehydrogenase (LDH) content and cell viability were measured by commercial kits and cell counting kit-8 (CCK-8) assay, respectively. The binding sites of miR-148b and SIRT6 were predicted by the Starbase database and verified by dual luciferase reporter assay.

MiR-148b expression in THS rats or ischemia-reperfusion (I/R)-treated cells was higher than in the control group. Overexpression of miR-148b further promoted the effects of I/R, which enhanced the levels of ALT, AST and LDH, cell apoptosis of liver tissue or BRL3A cells and decreased the expression of SITR6. Besides, miR-148b negatively correlated with SIRT6, and upregulated the expression of SIRT6 could partly reverse the effect of miR-148b.

Hepatocyte injury induced by I/R was achieved by regulating miR-148b /SIRT6 axis.

Airway remodeling is one of the reasons for severe steroid-resistant asthma related to HMGB1/RAGE signaling or Th17 immunity.

Our study aims to investigate the relationship between the HMGB1/RAGE signaling and the Th17/IL-17 signaling in epithelial-mesenchymal transformation (EMT) of airway remodeling.

CD4⁺ T lymphocytes were collected from C57 mice. CD4⁺ T cell and Th17 cell ratio was analyzed by flow cytometry. IL-17 level was detected by ELISA. The E-cadherin and α-SMA were analyzed by RT-qPCR and immunohistochemistry. The E-cadherin, α-SMA, and p-Smad3 expression were analyzed by western blot.

The HMGB1/RAGE signaling promoted the differentiation and maturation of Th17 cells in a dose-dependent manner in vitro. The HMGB1/RAGE signaling also promoted the occurrence of bronchial EMT. The EMT of bronchial epithelial cells was promoted by Th17/IL-17 and the HMGB1 treatment in a synergic manner. Silencing of RAGE reduced the signaling transduction of HMGB1 and progression of bronchial EMT.

HMGB1/RAGE signaling synergistically enhanced TGF-β1-induced bronchial EMT by promoting the differentiation of Th17 cells and the secretion of IL-17.

Some tumors have a poor prognosis regarding TPD52 (tumor protein D52). This study aims to explore TPD52's role in the cancer process from a pan-cancer perspective.

A pan-cancer analysis was conducted to investigate how TPD52 may be involved in cancer as well as its association with prognosis.

A variety of human cancers express TPD52 abnormally and correlate with clinical stage. There was a significant association between low expression of TPD52 and poor survival in BRCA, KIRP, LAML, LIHC, UCEC, and UVM. TPD52 alterations were most frequently amplified in pan-cancer. The co-occurrence of 10 genes alterations was found in the TPD52 altered group. There was a significant association between TPD52 expression and MSI in four cancer types and TMB in twelve cancer types. There was a significant correlation between TPD52 expression and immune-related cell infiltration. A significant correlation was found between TPD52 expression in many tumor types and 8 immune checkpoint genes. There were signaling pathways involved in pan-cancer caused by TPD52, including endocytosis, Fc gamma R-mediated phagocytosis, and so on. TPD52 may be involved in chemotherapy and chemoresistance.

The TPD52 gene may be important for human cancer treatment.

Scinderin (SCIN) is a calcium-dependent protein implicated in cell growth and apoptosis by regulating actin cleavage and capping. In this study, we investigated the role of SCIN in hydrogen peroxide-induced lens epithelial cell (LEC) injury related to age-related cataract (ARC).

Anterior lens capsules from ARC patients were collected to examine SCIN expression levels. Immortalized human LEC cell line SRA01/04 and lens capsules freshly isolated from mice were induced by H2O2 to mimic the oxidative stress in ARC. The role of SCIN was investigated by gain-of-function (overexpression) and loss-of-function (knockdown) experiments. Flow cytometry (FCM) and Western-blot (WB) assays were performed to investigate the effect of SCIN on apoptosis. The oxidative stress (OS) was examined by detecting malondialdehyde (MDA) level, superoxide dismutase (SOD) and catalase (CAT) activity. The interaction between SCIN mRNA and miR-489-3p was predicted by StarBase and miRDB databases and validated by luciferase reporter activity assay.

SCIN was significantly elevated in cataract samples, and the expression levels were positively correlated with the nuclear sclerosis grades. SCIN overexpression promoted OS and apoptosis in H2O2-induced SRA01/04 cells, while SCIN silencing showed the opposite effect. We further showed that miR-489-3p was a negative regulator of SCIN. miR-489-3p overexpression suppressed apoptosis and OS in H2O2-induced SRA01/04 cells by targeting SCIN.

Our study identified SCIN as an upregulated gene in ARC, which is negatively regulated by miR-489-3p. Targeting miR-489-3p/SCIN axis could attenuate OS-induced apoptosis in LECs.

Silver nanoparticles (Ag-NPs) have garnered significant attention in recent years due to their therapeutic effects. Curcumin (CUR) has been utilized as a coating agent for synthesizing Ag-NPs, intended to act as a potential drug.

This study was designed to evaluate the safety and efficacy of curcumin-synthesized silver nanoparticles on rats exposed to chlorpyrifos (CPF) during their pubertal development.

Forty-two male Wistar rats, 23 days old, were selected and randomly divided into 7 groups (n=6) as follows: positive control, negative control, CPF (5 mg/kg), silver nanoparticles synthesized using curcumin at 40 µg/kg (CUR-Ag-NPs 40), CUR-Ag-NPs 80, CPF+ CUR-Ag-NPs 40, CPF+ CUR-AgNPs 80. All treatments were administered via gavage for 30 days. At the end of the study, rats were anesthetized using ketamine (50 mg/kg), and xylazine, (10 mg/kg) and blood was collected from the heart for serum analysis of liver enzymes, urea, and creatinine.

Liver and kidney tissues were isolated for histopathological analysis. No significant differences were observed in serum levels of AST, ALT, and ALP enzymes as well as urea and creatinine levels among the different groups. Light microscopy observation revealed multifocal inflammatory mononuclear cell subsets in liver tissue associated with mild inflammatory mononuclear cell infiltration in the portal region in CPF, CUR-Ag-NPs 40, CUR-Ag-NPs 80, CPF+CUR-Ag-NPs 40, and CPF+CUR-Ag-NPs 80 groups. Histological examination of kidney tissue showed degenerative changes in the tubular epithelium, congestion, and mild infiltration of mononuclear inflammatory cells in the renal interstitial tissue in the CPF group, CUR-Ag-NPs 40, CUR-Ag-NPs 80, CPF+CUR-Ag-NPs 40 and CPF+CUR-Ag-NPs 80 groups.

This study failed to establish the safety and efficacy of CUR-Ag-NP at 40 and 80 µg/kg in prepubertal rats exposed to CPF. However, further studies should be conducted to thoroughly characterize the efficacy of CUR-Ag-NP in developmental animal models.