Current Pharmacogenomics and Personalized Medicine - Volume 22, Issue 1, 2025

Triple-negative breast cancer (TNBC), an aggressive and difficult-to-treat subtype with a grim outlook, relies heavily on chemotherapy due to the lack of molecular targets. In this study, we sought to uncover potential therapeutic targets by analysing differential gene expression between TNBC and normal breast tissue.

Microarray data from the Gene Expression Omnibus (GEO) database was analysed to identify differentially expressed genes. It revealed 514 upregulated and 336 downregulated genes between TNBC and normal breast tissue. A subsequent protein-protein interaction (PPI) network, visualized through Cytoscape, highlighted critical hub genes linked to the progression of TNBC. Survival analysis linked their overexpression to poor patient outcomes, underscoring it as a key driver of TNBC progression. Following the identification of genes, virtual screening and MMGBSA (Molecular Mechanics Generalized Born Surface Area) studies were conducted, which led to the identification of potential molecules that can target the protein.

Critical hub genes associated with TNBC progression were identified, and their overexpression was linked to poor survival outcomes. Virtual screening and MMGBSA studies led to the discovery of potential molecules targeting the identified protein.

The findings of this study pave the way for further exploration for improving TNBC outcomes by targeting the key genes involved in TNBC progression and providing potential molecular targets for therapeutic intervention.

This case report presents a 26-year-old male with complaints of obesity, hepatomegaly, and early-stage neuropsychiatric symptoms, including obsessive-compulsive disorder (OCD) and obsessive imagination. The investigation aimed to identify major gene mutations contributing to both neuropsychiatric disorders and abnormalities in lipid metabolism.

The subject had marked dyslipidemia with an increased LDL-C (163 mg/dL), total cholesterol (236 mg/dL), and borderline triglycerides (172 mg/dL) levels. Moreover, the patient had Grade 1 fatty liver and splenomegaly. Neurological symptoms like panic attacks, obsessive-compulsive disorder, and obsessive imagination have been associated with mutations in LRP8, FLG, and MT-CYB, which points to a possible disruption in neuronal signalling pathways.

Obesity is the primary cause of hepatomegaly and is also suggested to be inversely involved in mental health. Our results show a complex interplay between lipid metabolism, liver dysfunction, and neuropsychiatric disorders. Personalised therapeutic strategies, focusing on both the diagnosis and the interactions between the results, are a necessary factor for future medical care and treatment.

Colorectal cancer (CRC) remains a pervasive and lethal cancer type worldwide, significantly impinging on patients' lives and burdening society economically. Current treatments like surgery, chemotherapy, and radiotherapy have significant limitations, including high rates of recurrence after surgery and drug resistance. This underscores the urgent need for new biomarkers and therapeutic targets. This study aims to explore the expression levels of REEP2 (Receptor Expression-Enhancing Protein 2) and its potential association with CRC.

Utilizing public datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), we conducted a comprehensive analysis including differential expression assessment, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, as well as Kaplan-Meier survival analysis.

Our findings reveal a significant decrease in REEP2 expression levels in CRC tissues compared to normal tissues (p < 0.001). The receiver operating characteristic (ROC) curve analysis further underscores this observation with an area under the curve (AUC) of 0.889 (CI=0.855–0.923), highlighting its potential as a diagnostic biomarker. Furthermore, our differential expression analysis identified 1,131 differentially expressed genes (DEGs) linked to REEP2, predominantly enriched in nucleosome and calcium signaling pathways. Kaplan-Meier analysis indicates that lower REEP2 expression is linked to improved overall survival, with a hazard ratio (HR) of 1.48 (p=0.029). Additionally, we observed a correlation between REEP2 expression and the infiltration of immune cells, as well as several clinical characteristics, such as patient age and TNM staging.

In conclusion, our research suggests that REEP2 could serve as a valuable biomarker for the diagnosis and potential treatment of CRC, which warrants further investigation into its potential application in treatment.

Parkinson’s disease is increasingly prevalent among the elderly. This study aimed to explore the potential of Zinda Tilismath, a traditional Unani medicine, in mitigating Parkinson's disease symptoms.

Male Sprague-Dawley rats were used to evaluate the effectiveness of Zinda Tilismath in paraquat-induced Parkinsonism. The rats were divided into six groups: a negative control group, a positive control group, a group treated with the standard drug Selegiline, and three groups receiving different doses of Zinda Tilismath (high, medium, and low). To assess motor function and locomotion, the rats were subjected to behavioral tests, including the Rotarod, Actophotometer, and bar tests. Additionally, biochemical analyses measured dopamine levels and acetylcholinesterase (AChE) activity, while histopathological examinations were performed to substantiate neuroprotective effects. The study also included in silico docking analyses to explore the interactions between the active components of Zinda Tilismath and the proteins MAO-B and PINK1 which are implicated in Parkinson's disease.

Docking studies revealed significant binding affinities of Zinda Tilismath components such as camphor (Binding energy kcal/mol -6.9, -5.9), L-limonene (-6.8, -5.9), Tetradecane (-5.9, -4.4) Decane (-5.2, -3.8), Isoborneol (-6.4, -6.3), Alpha pinene (-6.6, -6.2) with MAO-B and PINK1 genes, indicating potential therapeutic effects. Acute toxicity studies showed no adverse effects at 2000 mg/kg, establishing the safety of Zinda Tilismath. In vivo studies demonstrated that Zinda Tilismath at mid-dose improved motor function and locomotion in the Rotarod (105.0 ± 3.60s), Actophotometer (261 ± 21.33) and Bar test (15.67 ± 0.88) where lower dose also displayed an improved motor and locomotion in the Rotarod (98.00 ± 2.30), Actophotometer (231 ± 19.06) and Bar test (12.33 ± 1.20) in comparison to Positive control [Rotarod (28.00 ± 49.2), Actophotometer (88.67 ± 17.42), Bartest (2.33 ± 0.33)]. The results of the test drug are comparable to the standard drug Selegiline. Biochemical assays confirmed increased dopamine levels with Zinda Tilismath as compared to disease-induced group and reduced AChE activity as compared to positive control. Histopathological analysis indicated neuroprotective effects in the substantia nigra region of the brain.

Zinda Tilismath exhibits promising neuroprotective effects in a paraquat-induced Parkinsonism model, comparable to Selegiline. These findings suggest its potential as a safe and effective alternative treatment for Parkinson's disease, warranting further investigation. Zinda Tilismath exhibits possible neuroprotective advantages, however, certain limitations must be acknowledged. This encompasses dependence on in silico docking studies lacking experimental validation, insufficient exploration of long-term toxicity, and unclear modes of action. Furthermore, obstacles in applying findings to clinical settings, like interspecies variations and pharmacokinetics, must be addressed. Comprehensive research is vital to determine its effectiveness, safety, and therapeutic potential.

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, with emerging evidence highlighting neuroinflammation as a critical driver of disease progression. Activated microglia and astrocytes exacerbate neuronal damage, necessitating innovative therapeutic approaches beyond traditional amyloid- and tau-targeted strategies. Gene therapy has recently gained attention for its potential to modulate neuroinflammatory pathways and improve treatment efficacy.

This review synthesizes current literature on gene therapy applications for neuroinflammation in AD. Key methodologies include an analysis of CRISPR-Cas9, RNA interference, and viral vector-based delivery systems. Studies focusing on the modulation of pro-inflammatory mediators such as cytokines, chemokines, and immune receptors were assessed to determine therapeutic feasibility and efficacy.

Gene therapy interventions demonstrate promising capabilities in regulating neuroinflammatory responses, with several strategies successfully targeting inflammatory mediators implicated in AD pathogenesis. Additionally, experimental approaches indicate that gene therapy may enhance amyloid-beta clearance through immune modulation, offering a dual therapeutic benefit. However, challenges remain in optimizing delivery mechanisms, ensuring treatment safety, and validating long-term efficacy.

The growing interest in gene therapy for AD underscores its potential to address neuroinflammation a previously underexplored therapeutic target. While technological advancements continue to refine delivery systems, further research is necessary to enhance translational feasibility. Ethical and safety considerations surrounding gene editing warrant comprehensive evaluation before clinical implementation. Future research should prioritize optimizing CNS delivery and long-term monitoring of gene-modified cells to ensure treatment stability.

Gene therapy presents a novel approach for modulating neuroinflammation in AD, offering potential benefits beyond conventional treatments. Continued advancements in gene-editing techniques and targeted delivery systems will be critical in overcoming existing barriers and maximizing therapeutic outcomes in neurodegenerative disease management.

Cancer is a dreadful illness caused by uncontrolled cell growth. Several studies have demonstrated that the overexpression of growth factors and receptors, the triggering of oncogenes, and the deactivation of tumor suppressor genes are the primary reasons for aggressive and resistant forms of cancer. The epidermal growth factor receptor (EGFR) is one such receptor that is targeted by medications to treat cancer. In this work, we attempted to create novel compounds that will function as EGFR inhibitors by using the molecular structure of 4-amino-7-methoxy quinazoline as a template.

A covalent molecular docking investigation was carried out by introducing several functional groups to the template of 4-amino-7-methoxy quinazoline, and evaluating the binding capacity of all ligands to the target domains. Using ADME analysis and DFT study, the potential of proposed compounds for additional in vitro and in vivo experiments was assessed.

Based on the generated results, the addition of N- (pyrimidin-4-yl) acrylamide at C-4 and the addition of (E)-N-methyl-4-(piperidin-1-yl) but-2-enamide at C-6 of 4-amino-7-methoxy quinazoline enhanced the binding affinity of the designed compound to the targeted protein efficiently.

The findings we reported demonstrated that the virtually designed S10 could block EGFR; hence, this S10 molecule is a noteworthy inhibitor of EGFR TK.

Thus, the proposed compound S10 quinazoline derivative has the potential to be a lead compound for future preclinical development, providing a viable therapeutic approach for targeting EGFR-driven cancer with overcoming resistance mechanisms.

The CACNA1C gene is a voltage-gated calcium channel involved in regulating calcium entry into the cells. The gene is associated with various types of diseases like cancer, schizophrenia, bipolar disease, anxiety, phantom tooth pain, and diabetic peripheral neuropathy.

This study aimed to investigate the missense single nucleotide polymorphism associated with the human CACNA1C gene using bioinformatics tools.

The study focused on understanding the structural and functional distribution of high-risk nsSNPs of the CACNA1C gene using several bioinformatics tools.

Retrieval of missense SNP of CACNA1C gene from NCBI and Uniprot database. Recognition of deleterious nsSNPs using SIFT, Polyphen v2, PROVEAN, Panther, PhD-SNP, and SNPs & GO. Structural stability was detected with the help of I-Mutant and MUPro. GeneMANIA and STRING gave details regarding the gene-gene and protein-protein interactions. Another functional characterization was predicted using SOPMA, AlphaFold, and NetPhos 3.1.

The functional analysis identified 14 nsSNPs to be deleterious from 1824 non-synonymous missense SNP. The identified nsSNPs, namely, rs34534613, rs79891110, rs80315385, rs199473391, rs199586997, rs200935321, rs368861681, rs369421219, rs370634418, rs376872233, rs377564636, rs200325545, rs267603426, and rs372495864 were subjected to various structural and functional characterization using I-Mutant 2.0, MUPro, GeneMANIA, STRING, SOPMA, AlphaFold and NetPhos 3.1.

Our study recognized 14 nsSNPs to be detrimental to the structure and function of the CACNA1C gene. The identified nsSNPs may aid in serving as a potential therapeutic target for disease diagnosis.

Mycobacterium tuberculosis (Mtb) is the primary cause of infectious tuberculosis (TB) and is primarily spread through respiratory droplets. TB is an ancient disease discovered a century ago, and still despite all the advances in the medical sciences, this disease continues to be one of the top 10 diseases. WHO reported that in 2024, 10.6 million people were infected with TB, and 1.6 million fatalities were linked to the disease. The conventional TB treatment encompasses the use of antimicrobial drugs, but due to shortcomings like the emergence of antimicrobial resistance, lengthy treatment protocols, side effects, and drug tolerance, antimicrobial therapies are not yielding successful outcomes in TB treatment. Therefore, an alternate approach to the conventional TB treatment protocol is warranted.

A meticulous evaluation of scientific, qualitative, and quantitative research from the most prominent scientific databases was carried out. We searched Embase, Scopus, Web of Science, Google Scholar, and PubMed literature on TB management up to date. The present study discusses immunotherapy and drug repurposing as emerging potential alternate treatment options for combating TB. This study examines TB resistance, the immunotherapy approach, and the mechanism of action of all repurposing drugs for effective multidrug-resistant TB (MDR-TB) management.

Many studies have been conducted globally for effective drug repurposing and immunotherapy for multidrug-resistant TB (MDR-TB) management. The success of immunotherapy in treating fatal diseases in the previous years has been in the limelight, and treating infectious diseases like TB with immunotherapeutic approaches holds great promise.

Conventional TB treatments face challenges like resistance and long durations. Immunotherapy and drug repurposing offer promising alternatives by enhancing immune response and using existing drugs with new applications. These strategies could improve outcomes in MDR-TB and warrant further clinical investigation.

In this review, we have summarised the immunomodulatory drugs that have been repurposed for tuberculosis treatment. Drug repurposing is a cost-effective and time-efficient method of developing new drugs by repurposing an existing drug for a new therapeutic use.

Haemophilus influenzae, a gram-negative, facultative anaerobic coccobacillus, is a member of the Pasteurellaceae family. It causes a variety of invasive and non-invasive bacterial infections known as H. influenzae infections. The increasing prevalence of antibiotic resistance highlights the need to identify novel therapeutic targets for treating H. influenzae infections. The emerging trends in the field of Pharmacoinformatics have aided in the prediction of novel putative therapeutic targets.

This study aims to identify novel putative therapeutic targets in H. influenzae using a subtractive genomic approach.

Subtractive Genomics, a simple yet powerful approach for the identification of novel therapeutic targets for bacterial pathogens, was employed in this study. The core proteome of 72 strains of H. influenzae was analysed through a multi-step filtration process to exclude the non-essential proteins and those homologous to the human proteome. Metabolic pathway analysis was conducted to identify pathogen-specific proteins, followed by druggability analysis and three-dimensional structure prediction.

On analysing the core proteome, 115 proteins were found to be unique and non-homologous to the human proteome. Further screening of these proteins led to the identification of 25 proteins involved in the 29 unique metabolic pathways of bacteria. Subsequent analysis finally resulted in the identification of five novel therapeutic targets for H. influenzae that are unique, non-homologous to the human proteome, essential for bacterial survival, and involved in unique metabolic pathways of bacteria.

This study successfully identified five novel therapeutic targets through subtractive genomics, contributing to the efforts against antimicrobial resistance in H. influenzae. Further experimental validation is necessary to strengthen these findings and advance therapeutic development.

To investigate the pharmacological implications of the ligand cis-4-Benzyl-2,6-diphenyltetrahydropyran, focusing on its pathways, potential disease associations, and therapeutic applications in Type 2 Diabetes Mellitus (T2DM).

Cis-4-Benzyl-2,6-diphenyltetrahydropyran has been previously identified for its heightened binding affinity to T2DM targets. Understanding its diverse pathways and interactions with neurotransmitter signaling, neuronal receptors, and enzymes/metabolism can provide insights into its potential roles in disease modulation and therapeutic applications.

The primary objective of this study was to investigate the pharmacological effects of cis-4-Benzyl-2,6-diphenyltetrahydropyran in the context of Type 2 Diabetes Mellitus (T2DM). The study sought to understand its influence on neurotransmitter signaling, focusing on its modulation of G Protein-Coupled Receptors (GPCRs) and their role in diabetes pathogenesis. Utilizing KEGG pathway and gene ontology analyses, the study aimed to explore the ligand's involvement in neuroactive ligand-receptor interactions and the calcium signaling pathway, examining its broader impact on biological functions like inflammation, immune response, reproductive processes, and cellular metabolism associated with diabetes.

The study employed KEGG pathway and gene ontology analyses to profile cis-4-Benzyl-2,6-diphenyltetrahydropyran. The ligand's influence on neurotransmitter signaling, neuronal receptors, enzymes, and metabolic pathways was examined. Enrichment analysis was conducted to identify associated genes and pathways, focusing on the ligand's role in Neuroactive ligand-receptor interaction and the Calcium signaling pathway. Molecular docking and molecular dynamic simulations were performed to assess the ligand's interaction with the OPRK1 receptor, a G protein-coupled receptor implicated in metabolic regulation. Binding stability was analyzed using Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), and Solvent Accessible Surface Area (SASA). MMPBSA binding free energy analysis was conducted to validate the stability and strength of the ligand-receptor interaction.

The study revealed that cis-4-Benzyl-2,6-diphenyltetrahydropyran significantly impacts neurotransmitter signaling and cellular homeostasis by modulating GPCR pathways, including neuroactive ligand-receptor interaction and calcium signaling pathways. These pathways play critical roles in inflammation, immune response, reproductive processes, and cellular metabolism. Molecular docking and dynamic simulations demonstrated a strong and stable binding between the ligand and the OPRK1 receptor, a key GPCR implicated in metabolic regulation. The binding was supported by favorable binding free energy values (-255.58 kJ/mol) and consistent structural stability metrics, including minimal deviations in RMSD (0.2–0.4 nm) and stable radius of gyration (2.35–2.45 nm). Solvent Accessible Surface Area (SASA) analysis confirmed a compact ligand-receptor interaction, while hydrogen bonding reinforced binding specificity. These findings highlight the ligand's relevance in diabetes pathogenesis, particularly in regulating pathways involved in insulin sensitivity and glucose metabolism.

This study advances our understanding of the cellular effects of cis-4-Benzyl-2,6-diphenyltetrahydropyran, highlighting its multifaceted potential in diabetes research. The strong interaction with OPRK1 suggests that the ligand could influence key pathways related to insulin sensitivity and metabolic regulation. However, the findings are derived from computational methodologies, and experimental validation through in vitro and in vivo studies is essential to confirm the ligand's biological activity and therapeutic relevance. The findings establish a foundation for targeted investigations and drug development, positioning this ligand as a promising candidate for therapeutic applications in diabetes mellitus.

The research highlights the effect of phytochemical compounds on the correlation of cellular pathways of cytokines and antioxidant enzymes at the molecular levels.

This work examines the effects of phytochemical substances on the expression of (IL1β and IL6, IL10) genes present in different amounts in garlic, grape seed, and pomegranate extracts in various amounts. Within the same framework, genes (SOD1, NFE2L2, JUN) expressing themselves genetically are responsible for the cellular pathways that carry out oxidative and redox reactions in cells.

Extracts of grape seeds (1.2% or 2.4%), pomegranates (1.2% or 2.4%), and garlic (0.5% or 1.2%) were applied to human peripheral blood leukocyte cultures. Real-time polymerase chain reaction (PCR) was utilised to evaluate the expression of genes.

We found that the level transcription of the SOD1 gene negatively correlates with the level transcription of cytokines IL1β when grape seed extract (2.4%) is added to the medium for culturing human blood cells. Furthermore, with the addition of 1.2% and 2.4% grape seed extract, there is a link between the expression of the SOD1 and IL6 genes. We found a positive correlation between the expression of the NFE2L2 and IL10 genes after adding pomegranate extract (1.2%). Finally, following the addition of grape seed extract (1.2%) and garlic extract (1.2%), there is a link observed between the transcription level of the JUN and IL1b genes.

The importance of the study lies in revealing the effect of phytochemicals on the intersection of the two pathways: the inflammatory pathway and the oxidative pathway. Whereas, it gives a clearer picture of the mechanism of action of these compounds as antioxidants and anti-inflammatories, depending on the close relationship between inflammatory properties and oxidative properties.

Lung cancer (LC) is a lethal malignancy with a late diagnosis and poor prognosis. During the last decade, the identification of oncogenic driver alterations has noticeably changed the therapeutic landscape and contributed to the emergence of the “oncogene addiction” concept and precision medicine in oncology. Among these alterations, the spotlight has turned to driver mutations in the KRAS and BRAF genes, which have garnered significant attention due to the emergence of targeted therapies and the potential for personalized treatment strategies.

Hence, the present study aimed to evaluate the mutational landscape of the KRAS and BRAF genes in LC Moroccan patients along with their frequencies and their correlation with clinicopathological features.

A total of 60 fresh biopsies were collected from patients with primary LC and were subjected to PCR-DNA sequencing of exon 2 of KRAS and exon 15 of BRAF genes in order to detect the most common mutations known by their implication in response to targeted therapies.

Sequencing analysis revealed that mutations in KRAS and BRAF genes represented respectively 8.3% and 6.7% of cases; one patient had two KRAS mutations (G12A and K5E), and none had simultaneous BRAF and KRAS mutations. The vast majority of patients harboring KRAS mutations were men, formal smokers with adenocarcinomas, and at advanced stage (stage III). BRAF mutations were mainly detected in men and non-smokers with adenocarcinoma. Statistical analyses showed no significant correlation between KRAS and BRAF substitutions and clinico-pathological features (p>0.05).

The presence of these mutations will be used as a valuable molecular biomarker to select potential candidates eligible for effective personalized therapy using available agents targeting these mutations. However, much effort is needed to identify other druggable mutations to generalize personalized LC therapy for better management of this devastating disease.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of benign tumors due to mutations in the NF1 gene, which encodes the tumor suppressor neurofibromin. This study aimed to identify novel inhibitors of neurofibromin through drug repurposing of clinical trial compounds from the Zinc15 database.

Utilizing advanced in silico techniques, we conducted molecular docking via PyRx and molecular dynamics simulations with GROMACS. Among the compounds analyzed, ZINC000261527152 (Tetrodotoxin) emerged as a promising candidate due to its binding affinity to NF1. Tetrodotoxin formed stable conventional and carbon-hydrogen bonds with key residues, including GLU 981, GLY 984, GLN 985, SER 1030, SER 1561, and ASN 1563. Molecular dynamics simulations confirmed the stability of the Tetrodotoxin-NF1 complex, with favorable RMSD, RMSF, radius of gyration (Rg), and solvent-accessible surface area (SASA) values over a 100 ns simulation period.

These results suggest that Tetrodotoxin could effectively inhibit neurofibromin, presenting a novel therapeutic approach for neurofibromatosis. However, despite the promising computational findings, further experimental validation through in vitro and in vivo studies is essential to confirm the efficacy and safety of Tetrodotoxin as a treatment for NF1.

This research underscores the utility of computational drug repurposing methodologies and their role in accelerating the discovery of novel treatments for genetic disorders, particularly neurofibromatosis, thereby potentially improving patient outcomes and quality of life.

The Calcitonin receptor (CALCR) gene encodes a protein essential for bone metabolism, playing a key role in inhibiting bone resorption and promoting renal calcium excretion. Polymorphisms in CALCR have been associated with differences in bone mineral density, osteoporosis, and an increased risk of calcium stone urolithiasis.

This study aimed to investigate the non-synonymous SNPs of human genes.

This study was conducted to analyse the structural and functional impact of high-risk non-synonymous single nucleotide polymorphisms (nsSNPs) in the CALCR gene using bioinformatics tools.

We retrieved nsSNPs from the NCBI and Uniprot databases and assessed their deleterious potential using SIFT, PolyPhen v2, PROVEAN, PANTHER, PhD-SNP, and SNPs and GO. Gene-gene interactions were examined with GeneMANIA, while protein-protein interactions were analyzed via STRING. Structural and functional predictions were performed using I-Mutant, MUPro, ConSurf, SOPMA, NetSurf 2.0, AlphaFold, and NetPhos 3.1.

Our analysis found 17 deleterious nsSNPs (rs972946, rs138829125, rs146344939, rs148707949, rs149570603, rs149628324, rs200643258, rs200900623, rs201985045, rs267601640, rs368981699, rs369253212, rs369926913, rs371453754, rs374929068, rs375143115, rs375417465) that destabilize the CALCR protein. ConSurf revealed that 9 of these high-risk nsSNPs are located in conserved regions, with the variants S129Y, R321Q, D101Y, D77V, L176F, P122S, N312S, M187T, and W406R being identified as highly conserved. NetsurfP-2.0 analysis indicated that some nsSNPs are exposed while others are buried, and phosphorylation analysis highlighted variations in threonine and tyrosine residues.

These findings indicate that the identified nsSNPs may substantially affect the functionality of CALCR and could potentially be used as biomarkers for disease diagnosis and targets for therapy.