Volume 40, Issue 2

Individual variations in the response to thiopurine-based anticancer drugs are influenced by genetic and environmental factors, making it challenging to optimize dosing and minimize toxicity. Among the key genes involved, genetic variations in the nudix hydrolase 15 ( NUDT15 ) gene affect on thiopurine metabolism, thus influencing drug efficacy and the risk of severe adverse effects, such as myelosuppression, These variations also contribute to inter-individual differences in drug tolerance and clinical outcomes. Despite the recognized impact of NUDT15 variations, there has been limited comprehensive exploration of these variants and their clinical significance in thiopurine therapy. This review provides a thorough analysis of NUDT15 genetic variants by synthesizing findings from prior clinical studies and employing in silico analyses to predict the functional effects of variants with uncertain significance. Comprehensive analysis of NUDT15 variants and their interactions with other metabolic pathways could offer valuable insights for advancing personalized medicine in cancer treatment. This review aims to establish a foundation for integrating NUDT15 genetic information into the clinical practice, reducing toxicity, and improved therapeutic outcomes in patients undergoing thiopurine-based chemotherapy.

The review article, “Navigating the Crossroads of Cell Death: Interplay and Intersections Among Ferroptosis, Apoptosis, and Autophagy,” delves into the complex interactions between these three key cell death pathways. Understanding how ferroptosis, apoptosis, and autophagy intersect is crucial for maintaining cellular homeostasis. Each pathway represents a unique mechanism of cell death, and recent research highlights their intricate interconnections and mutual influences. Exploring these relationships is vital for comprehending how cells make fate decisions and how these processes are implicated in various diseases. The review’s significance lies in elucidating the molecular details of cell death and providing insight into how cells balance survival and death. The interplay among ferroptosis, apoptosis, and autophagy has important implications for developing therapeutic interventions, particularly in diseases where cell death regulation is disrupted. By examining the molecular crosstalk between these pathways, researchers can identify new drug targets and devise strategies to modulate cell fate effectively. This review aims to enhance our understanding of cell biology by offering a detailed perspective on the dynamic and interconnected nature of these cell death mechanisms.

Objectives Hepatocellular carcinoma (HCC) is a common type of liver cancer that progresses quickly and has limited treatment options. Nutraceutical anacardic acid (AA), a bioactive compound derived from cashew nut shell, has emerged as a potential candidate for HCC treatment owing to its reported anti-inflammatory, anticancer and diverse pharmacological properties. In the present study, we investigate the potential of AA as an HCC inhibitor using molecular docking, gene ontology, and network pharmacology. Methods The pharmacokinetic and physicochemical properties of AA were assessed using Swiss ADME. SuperPred, Similarity Ensemble Approach, ChEMBL and Swiss Target Prediction online tools were used for determining molecular targets of AA. In addition, GeneCards, NCBI, DisGeNET and UniProt ID were used to search the targets of HCC and the top 25 hub genes were determined using Cytohubba plugin. A protein protein interaction (PPI) network was constructed through the STRING database. Gene Ontology (GO) biological process and Kyoto Encyclopaedia of Genes and Genes (KEGG) pathway enrichment analysis were performed through FunRich and ShinyGO 0.77. Moreover, molecular docking studies were performed on NF-κB and GSK-3β. The expression levels of the hub genes were also validated by western blotting. Results Comprehensive data analysis identified 375 targets for AA and 11,333 for HCC, with 264 targets in common. Network analysis determined 25 key HCC targets, including caspase-3, and NF-κB. Gene ontology and topology analysis highlighted essential pathways implicated in HCC progression such as the renin-angiotensin system, VEGF signalling, and apoptosis. Molecular docking analysis revealed strong binding affinity of HCC proteins with NF-κB and GSK-3β. Upregulation of p-NRF2 and p-GSK-3β, and downregulation of p-NF-κB and caspase-1 expression were validated using western blotting. Conclusions Taken together, our study highlights the potential of AA as a promising chemopreventive agent for HCC because of its significant modulatory effects on important regulatory proteins linked to cell division, inflammation, apoptosis, and antioxidant response.

Objectives Primary hypothyroidism is a prevalent endocrine disorder, typically treated with levothyroxine (LT). However, prolonged use of LT may result in complications and suboptimal outcomes for some patients. Majoone Sarkhas (MS), is a polyherbal formulation comprises four plants: Commiphora mukul , Operculina turpethum , Embelia tseriam-cottam , and Dryopteris filix-mas . It is traditionally used in Unani medicine for managing hypothyroidism associated conditions. The aim of this study was to assess the synergistic effect of Majoone Sarkhas in combination with LT for the treatment of primary hypothyroidism. Methods This randomized, single blind, standard clinical trial involved 100 subjects allocated into two groups: an adjuvant treatment group (n=50) and a standard control group (n=50). The adjuvant group received 10 g of MS twice daily in addition LT once daily, while the control group was treated with LT alone once daily. Both groups underwent treatment for 60 days. Changes in thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), and free-thyroxine (FT4) levels from baseline to the 60th day were recorded and analyzed statistically to evaluate the outcomes. Results The study showed adjuvant group (MS + LT) had more reduction (4.99 vs. 3.93) in serum TSH level in comparison to control group (LT), which was statistically significant (p<0.001), it also showed increase in serum FT3 (2.88 ± 0.31 vs. 2.97 ± 0.44) and FT4 (1.06 ± 0.17 vs. 1.20 ± 0.27) levels, when compared with baseline values and after completion of trial. Conclusions The change in thyroid function profiles among adjuvant group, receiving MS with LT in primary hypothyroidism was both clinically and statistically significant. The safety parameters those were followed by serum level of ALT, AST, blood urea and serum creatinine were within the range, indicating the MS is safe medication to be used as an adjuvant therapy with LT (Clinical Trial Registration Code: CTRI/2018/02/011962).

Objectives Phosphorus, an essential mineral with diverse biological functions, has recently garnered attention for its potential role in modulating the immune system. However, no study is present regarding the effect of homoepthic preparation of Phosphorus on immune system. Thus, this study aims to investigate the immunomodulatory effects of Phosphorus, shedding light on its impact on Normal and Immunosuppressive conditions in mice. Methods The immunomodulatory effect of Phosphorus 6C, 30C, and 200C was tested using Sheep red blood cells on humoral antibody titer and delayed-type hypersensitivity assays. The effect of Phosphorus was investigated in cyclophosphamide induced immune-compromised mice by assessing hematology, organ index, phagocytic index, histology, cytokine level, and their mRNA expression in the spleen. Results Phosphorus 6C produced a significant increase in the primary and secondary humoral immune response. While Phosphorus treatment at 6C, 30C, and 200C did not significantly alter hematological and organ index parameters, it considerably enhance the phagocytic index at 30C and 200C, and raise the levels of TNF-α and IL-2 in mice against immunosuppression induced by CPM after the pretreatment with Phosphorus-30C. Conclusions The present study shows that Phosphorus 6C potency augment the humoral immunity. In case of immunosuppression, Phosphorus at high dilution might play a significant role but more research is needed to find out the possible effect of Phosphorus preparation.