Current Medicinal Chemistry - Online First

Centromere protein M (CENPM), a member of the CENP family, is correlated with several malignancies, but its role in colon adenocarcinoma (COAD) is unclear. This study aims to explore the expression, prognostic significance, and biological role of CENPM in COAD.

The association of CENPM with the occurrence and progression of COAD was thoroughly analyzed via several bioinformatics databases. Furthermore, the correlation between CENPM expression and clinicopathological features and prognostic value was validated via immunohistochemistry (IHC) of tissue microarrays (TMAs) from 80 patients.

CENPM mRNA expression was significantly elevated in COAD samples compared with healthy tissues. As COAD progressed, CENPM expression decreased, and patients with lower CENPM transcript levels had a worse prognosis. IHC results further confirmed the overexpression of CENPM in COAD patients, identifying this gene as an independent prognostic factor. Additionally, high CENPM expression was linked to methylation in COAD patients, and the primary function of CENPM and its neighboring genes was determined to be cell cycle regulation. Immunological analysis demonstrated that CENPM expression was positively correlated with activated CD8+ T cells, CD4+ T cells, and dendritic cells (DCs) but negatively correlated with regulatory T cells (Tregs). CENPM expression was positively correlated with that of the immune checkpoint genes LAG3, CD244, LGALS9, PDCD1 (PD1), and PVRL2 but negatively correlated with the expression of BTLA, CSF1R, KDR, IL10RB, PDCD1LG2, and TGFBR1.

These findings collectively highlight a multifaceted role of CENPM in COAD, linking its overexpression to improved patient outcomes through mechanisms involving cell cycle control and immunomodulation. Its significant correlation with key immune infiltrates and checkpoint markers implies potential utility as a novel predictor for immunotherapy responsiveness.

CENPM is an independent prognostic factor for COAD, with its overexpression associated with improved survival. It regulates the cell cycle and tumor microenvironment, making it a promising potential predictive biomarker for immune therapy response.

Sodium Selenite (NaSe) is a molecule with various biological activities. Bone fractures and osteoporotic diseases are increasingly common health issues, prompting the search for alternative treatments. Therefore, the purpose of this study was to examine the antioxidant and osteogenic properties of NaSe.

The experiments were conducted using the hFOB1.19 osteoblast cell line. The MTT assay was used to assess the effects of NaSe on cell viability, while cytotoxicity was evaluated with Lactate Dehydrogenase (LDH) assays. Osteogenic differentiation was assessed by alizarin red staining, and Alkaline Phosphatase (ALP) activity and intracellular Reactive Oxygen Species (ROS) levels were also analyzed.

The results showed that NaSe significantly enhanced cell viability in a dose-dependent manner at low doses (0.01-1μM), with the most effective dose being 1μM (p<0.05). LDH activity remained similar to the control within the 0.01-1μM range but increased significantly at higher concentrations (5-50 μM) in both 24- and 48-hour experiments (p<0.05). NaSe reduced intracellular ROS levels significantly between 0.01-1 μM, with 1 μM being the most effective concentration (p<0.05). The highest ALP activity was observed at 0.1 μM NaSe (p < 0.05), and calcium deposition increased in a concentration-dependent manner (p<0.05). The most effective dose for enhancing mineralization was 0.1 μM (p<0.05).

This study demonstrates that NaSe has antioxidant and osteogenic effects at low doses in hFOB cells. These positive effects suggest that NaSe could be a promising candidate for in-vitro, in-vivo, and clinical trials, providing hope for new treatments for bone diseases.

One of the most effective osteoanabolic drugs for treating osteoporosis is romosozumab, which was developed as a consequence of growing knowledge of the Wnt signaling system. This review explored how romosozumab affects the bone mineral density (BMD) in osteoporotic patients.

Up until January 2024, PubMed, Web of Science, and Scopus were reviewed for any randomized controlled trials (RCTs) evaluating the impact of osteoporotic treatment with romosozumab on BMD changes and bone metabolism markers in primary osteoporosis patients. Pooled Hedges’ g indices, which were consistently used across all included studies to measure standardized mean differences, were computed along with their corresponding 95% confidence intervals using either a random-effects or fixed-effects model.

Out of the 1855 papers, 24 RCTs met the inclusion criteria. Patients with osteoporosis who received romosozumab for a period of time demonstrated an augmentation in their lumbar spine BMD. The study findings indicated that the total hip and femoral neck BMD demonstrated significant enhancement in 22 (out of 23) and 19 (out of 21) studies, respectively.

In patients with osteoporosis, romosozumab could markedly increase the total hip, lumbar spine, and femoral neck BMD. This finding could be verified by measuring bone turnover indicators such as PINP, TRACP-5b, and CTX.

Low back pain (LBP) and sciatica are among the most prevalent musculoskeletal disorders, leading to significant disability and an economic burden. Neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), play critical roles in pain modulation and neuronal function. While NGF-targeting monoclonal antibodies have shown potential in treating chronic pain, their efficacy and safety remain under debate. This study employs Mendelian Randomization (MR) to assess the causal relationships between NGF, BDNF, GDNF, and the risk of LBP and sciatica.

We conducted a two-sample MR analysis using genetic instruments for NGF, BDNF, and GDNF. LBP and sciatica data were obtained from FinnGen. The inverse variance weighted (IVW) method was applied as the primary causal estimation, with the weighted median (WM) and MR-Egger regression used for sensitivity analyses. Reverse MR was performed to evaluate bidirectional causality. Furthermore, we used expression quantitative trait loci (eQTLs) within 50 kb of each gene locus as genetic instruments for NGF regulation, ensuring that the genetic variants used directly influence neurotrophic factor expression.

MR analysis revealed a significant causal association between NGF and an increased risk of LBP (OR = 1.121, 95% CI 1.021-1.230, p = 0.016) and sciatica (OR = 1.158, 95% CI 1.034-1.296, p = 0.010), while BDNF and GDNF showed no significant associations with pain outcomes. Sensitivity analyses confirmed the robustness of the NGF findings, with no evidence of horizontal pleiotropy or heterogeneity. Reverse MR analysis showed no significant causal effect of LBP or sciatica on NGF levels (p > 0.05), ruling out reverse causality. Additionally, we investigated the NGF-eQTL, which captures genetically regulated NGF expression, and found a significant association between the NGF-eQTL and LBP (OR = 1.040, 95% CI 1.010-1.070, p = 0.007). Unlike external NGF measurements, the NGF-eQTL minimizes environmental confounding and reverse causation, providing stronger genetic evidence supporting NGF as a therapeutic target for LBP.

Our findings provide strong genetic evidence that nerve growth factor (NGF) plays a causal role in the development of low back pain and sciatica, supporting NGF inhibition as a promising therapeutic strategy. These results align with clinical observations where anti-NGF monoclonal antibodies demonstrated pain-relieving effects, though safety concerns remain. In contrast, no causal associations were observed for BDNF or GDNF, underscoring the specificity of NGF in peripheral pain sensitization. The study demonstrates the value of Mendelian Randomization in minimizing confounding and reverse causation, thereby strengthening causal inference. Future work should focus on pharmacogenomic predictors to identify patients most likely to benefit from NGF-targeted interventions while minimizing adverse effects.

This study provides genetic evidence that NGF plays a causal role in LBP and sciatica, reinforcing its potential as a therapeutic target. However, BDNF and GDNF were not significantly associated with pain outcomes, suggesting distinct mechanisms of pain modulation. While clinical trials of anti-NGF monoclonal antibodies have demonstrated efficacy in pain reduction, concerns about adverse effects, such as joint degeneration, habe limited their widespread clinical use. Future research should explore genetic predictors of anti-NGF therapy response to optimize treatment strategies for LBP and related musculoskeletal pain disorders.

Many medications associated with an increased risk of dementia do not have adequate warning labels, leading to a significant underestimation of their potential dangers. This study aims to leverage the FAERS database to identify drugs strongly linked to dementia and to examine the relationship between these drugs using Mendelian randomization techniques. The ultimate goal is to mitigate the risk of developing dementia.

We utilized the FAERS database to identify medications significantly associated with dementia cases. The DrugBank, OpenTargets, and STITCH databases were employed to pinpoint the target genes of these drugs. We then conducted Mendelian randomization analysis to explore the correlation between the expression of drug target genes and the incidence of dementia. Additionally, a time-to-onset analysis assessed the temporal relationships of drug ingestions. Furthermore, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction Network (PPI) analyses were performed to investigate the molecular pathways linked to target genes related to drugs associated with dementia.

A total of 28,139 dementia events were recorded in the FAERS database. Our Mendelian randomization analysis revealed a significant association between the expression of all identified drug target genes and dementia in both blood and brain tissues. Specifically, we identified nine drug target genes with significant correlations, implicating quetiapine, clozapine, valproic acid, alendronate, and digoxin as being strongly associated with dementia, which could provide insight into areas of clinical concern regarding dementia occurrence.

The adverse event data sourced from the FAERS database indicate that certain medications are associated with an increased risk of developing dementia, a finding corroborated by our Mendelian randomization analysis. Establishing a comprehensive monitoring and risk assessment program is crucial for identifying high-risk individuals and facilitating informed medication choices, thereby potentially reducing the incidence of dementia.

Tyrosinase, a copper-containing enzyme, is responsible for melanin production, and its overactivity can lead to hyperpigmentation.

This study aimed to evaluate triazolothiadiazoles (3a-h, 4a-f) and triazolothiadiazines (5a-h) against human and mushroom tyrosinase isozymes.

Several derivatives, such as 3a-3b, 3d, 4c-4f, 5d, and 5e, were identified as potent and selective inhibitors of mushroom tyrosinase, with IC50 values ranging from 1.9 to 15.2 µM. Similarly, compounds 3f, 4b, 5a, and 5b effectively inhibited human tyrosinase, with IC50 values between 12.6 and 18.5 µM. Mechanism-based studies revealed that these active compounds exhibited competitive inhibition against both isozymes without any cytotoxic effects. In-silico analysis further demonstrated that these compounds fit well into the active site of both tyrosinase isozymes.

Additionally, the pharmacokinetic profile of these compounds highlighted promising drug-like properties, making them potential candidates for the development of effective therapeutics for skin disorders.