Cancer is one of the leading causes of mortality worldwide and is recognized as a complex, multifactorial disease with no clearly defined etiology for its onset and progression. Long non-coding RNAs (lncRNAs) are widely distributed across the human body and play varied roles in regulating cellular processes. In recent years, they have gained the attention of the scientific community as key regulators of cancer due to their diverse functional roles and complex regulatory mechanisms. Aberrant expression of lncRNAs contributes to tumor progression, functioning as oncogenes that modulate various pathways through different mechanisms. Early technologies could not study lncRNAs effectively and considered it as “junk” RNA. Studies using gene-expression analyses, functional experiments, and animal-based models have shown that dysregulated lncRNAs are implicated in the maintenance of cancer stem cells (CSCs) and in driving therapeutic resistance. Additionally, lncRNAs have shown promise as valuable biomarkers for cancer diagnosis, prognosis, predicting patient outcomes, and guiding treatment strategies. Moreover, therapeutic strategies targeting lncRNAs, such as antisense oligonucleotides (ASOs), RNA interference (RNAi), exosome-based delivery systems, nanomedicine, virus-mediated therapy, and CRISPR-Cas technologies, have opened new avenues for cancer treatment. This review highlights the diverse roles of lncRNAs in therapeutic resistance and emphasizes their clinical potential as diagnostic and prognostic tools and emerging therapeutic strategies.

Alzheimer's disease (AD) is a common neurological disorder marked by progressive cognitive decline and memory loss, and it remains a major global health concern due to the limited effectiveness of current symptomatic treatments. This study used SSZ, a novel, chemically synthesized compound featuring pyrrolopyridine and N-cyclohexyl groups, designed as a multi-targeted inhibitor with anti-AD pharmacophore properties. We investigated the therapeutic potential of SSZs using an experimental rat model of AD produced by amyloidbeta (A(3). SSZ demonstrated substantial pharmacological activity by targeting key enzymes implicated in AD pathogenesis, including BACE-1, gamma-secretase, MAO-B, and acetylcholinesterase. In addition, SSZ therapy demonstrated neuroprotective benefits by significantly reducing apoptotic markers (Bax, caspase-3) and upregulating the anti-apoptotic protein Bcl-2. This compound also restored myelin basic protein (MBP) levels and reduced pathological markers such as neurofilament light chain (NEFL) and microtubule-associated protein (MAP). Moreover, SSZ increased antioxidant defences, such as glutathione (GSH) and superoxide dismutase (SOD), decreased oxidative stress markers, such as lactate dehydrogenase (LDH), nitric oxide (NO), and malondialdehyde (MDA), and regulated inflammatory cytokines, such as TNF-alpha and IL-1(3. Notably, SSZ restored neurotransmitter levels, dopamine, acetylcholine, and glutamate, essential for cognitive function. Histopathological analyses revealed that SSZ mitigated neuronal and myelin damage across critical brain regions, including the midbrain, hippocampus, and cortex. When combined with standard treatments such as donepezil and memantine, SSZ demonstrated synergistic effects, further enhancing its therapeutic efficacy. These results highlight SSZ's potential as a multi-targeted therapeutic option to combat AD pathogenesis and improve therapy approaches.

High cholesterol is a major risk factor for cardiovascular diseases (CVDs), which remain one of the leading causes of mortality worldwide. Statins, including atorvastatin, are commonly prescribed to lower cholesterol levels, but their long-term use often leads to undesirable side effects. This study investigated natural seaweed-derived compounds as potential alternatives to statins by targeting PCSK9, a key protein involved in cholesterol regulation. Advanced in silico techniques were applied to screen 1,191 seaweed metabolites to identify potential PCSK9 inhibitors. These compounds were narrowed down to 3 leads (CID 10067100, 11413290, and 11640528) based on their binding affinities, pharmacokinetic behavior, and predicted toxicity. These selected compounds have shown excellent profiles in subsequent analyses: post-docking MM-GBSA, HOMO-LUMO, and QSAR. Finally, molecular dynamics simulations provided valuable insights into the further stability assessment of these compounds over a 200 ns period. These compounds also reflected superior results in post-simulation MM-GBSA analysis, PCA clustering behavior, and DCCM patterning. Among these three lead compounds, CID 11,413,290 (RL003) from Laurencia microcladia consistently outperformed the control (atorvastatin) and all other lead compounds across the majority of the assessments. It exhibited a higher binding score (-6.58 kcal/mol), optimal ADME characteristics, lower toxicity, and a consistently superior MD simulation profile. This seaweed-derived compound showed strong potential to inhibit PCSK9 activity and could serve as a promising, safer alternative to statins. Nevertheless, further experimental validation through wet lab studies is required to justify its clinical applicability.

Alzheimer's Disease (AD) is a multifactorial neurodegenerative disorder characterized by dysregulated kinase signaling, neuroinflammation, immune remodeling, and Blood-Brain Barrier (BBB) dysfunction. In this study, we applied an integrated systems pharmacology approach to investigate the therapeutic potential of resveratrol-derived phytochemicals in AD. Initially, nine structurally related stilbene derivatives were screened for Central Nervous System (CNS), drug-likeness, and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Pterostilbene and desoxyrhapontigenin demonstrated superior lipophilicity, intestinal absorption, and predicted BBB permeability, prioritizing them for downstream analyses. Differential Gene Expression (DEG) analysis of the GSE85426 dataset identified 818 AD-associated genes, which were further explored using Weighted Gene Co-expression Network Analysis (WGCNA). Fourteen co-expression modules were constructed, with nine modules significantly correlated with the AD phenotype. Integrated overlap analysis combining compound targets, DEGs, curated AD databases, and WGCNA modules identified high-confidence therapeutic targets, highlighting Mitogen-Activated Protein Kinase (MAPK1) and MAPK3 as central hub genes. Functional enrichment analysis revealed dominant involvement of MAPK signaling, neurotrophin signaling, Toll-like receptor pathways, and synaptic vesicle regulation. Immune infiltration profiling demonstrated increased myeloid-associated signatures and subtle adaptive immune alterations in AD samples. Machine learning approaches, Support Vector Machine-Recursive Feature Elimination (SVM-RFE), Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest (RF), consistently identified Thymidine Phosphorylase (TYMP) as a robust peripheral biomarker candidate. Moreover, molecular docking demonstrated stable binding of resveratrol derivatives within a conserved hydrophobic pocket, with pterostilbene exhibiting the strongest binding affinity (-6.80 kcal/mol). Collectively, this multi-layered analysis suggests that resveratrol derivatives may exert therapeutic effects through coordinated modulation of kinase-driven signaling networks and neuroinflammatory pathways, supporting their potential as multi-target.

This study explored the potential of green-synthesized alginate encapsulated silver nanoparticles (AgNPs) for anticancer, antibacterial, and antifungal therapeutic applications. The physicochemical characterization of the biosynthesized nanoparticles was performed using various established techniques. The synthesis of alginate encapsulated AgNPs was confirmed by UV-visible spectroscopy, which showed a peak at ∼450 nm. The SEM images showed an agglomerated structure with an average particle size of 43 nm. Moreover, FTIR analysis displayed a characteristic peaks around 500–700 cm−1, which are typically associated with Ag–O stretching vibrations, confirming the presence of silver oxide bonds. Furthermore, clear distinct peaks of C, O, Ag and Na were observed in the EDS and corresponding peaks of silver and alginate in X-ray diffraction spectra as well as X-ray photon spectroscopy indicates the purity and crystallinity of the alginate encapsulated AgNPs. The cytotoxicity assay demonstrated a dose-dependent reduction in cell viability of HCT-116 cells with an IC50 concentration of 28 μg/mL The alginate encapsulated AgNPs was able to induce reactive oxygen species (ROS) production by 22 % and triggered apoptosis by 18 %. Additionally, our biosynthesized AgNPs exhibited significant antimicrobial activity against Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Candida albicans with zone of inhibition (ZOI) of 19.5 mm, 14.5 mm, 17.5 mm, and 16.5 mm, respectively. These findings suggest the potential of our alginate-encapsulated AgNPs, which should be further validated and exploited as multitargeted therapeutics against colon cancer and microbial diseases.

Toxoplasmosis is a zoonotic infectious disease caused by the intracellular apicomplexan parasite Toxoplasma gondii and primarily affects warm-blooded animals. Despite its global spread, the disease has limited therapeutic interventions. Chemotherapy can be used as a treatment, but there are potential side effects and contraindications. Despite several epitope-based in-silico vaccine studies, no mRNA-based vaccine has yet been explored. This study aims to design an mRNA vaccine using reverse vaccinology and immunoinformatics based on MIC1, MIC3, ROP29, and SAG1 proteins, which contribute to the attachment and activation processes of T. gondii. The selected epitopes achieved 100 % combined coverage worldwide. The favorable biophysical properties of the vaccine indicated its solubility and potential functional stability in the human body. The secondary and tertiary structural predictions of the refined vaccine revealed its well-stabilized configuration with a Ramachandran score of 80.9 % and a Z-score of -7.55. Docking analysis revealed a predicted high binding affinity toward TLR-2 and TLR-4 receptors. However, the lowest energy scores of -1000.5 kJ/mol and -1008.6 kJ/mol for TLR-2 and TLR-4, respectively, reflected highly favorable intermolecular interactions, which were further supported by MM-GBSA and molecular dynamics simulations. The vaccine showed cloning efficiency in Escherichia coli strains, and immune simulation predicted strong induction of B and T cells. Finally, the optimal and centroid structures of the designed mRNA vaccine were modelled. The vaccine developed in this study may serve as a probable future candidate against this parasite, reinforcing the need for additional in-vitro and in-vivo analyses.

INTRODUCTION:Ovarian cancer (OC) is a malignancy of the female reproductive system for which cisplatin chemotherapy is one of the first-line treatments. Despite the initial response to chemotherapy, such patients eventually develop resistance, which poses a major obstacle to treatment, along with potential side effects. Phytochemicals function as chemosensitizers, offering novel therapies in OC patients by targeting drug resistance, and are perceived to be less toxic. Plumbagin has emerged as an anticancer compound, with some findings suggesting its anti-ovarian cancer activity. However, there is no study on the potential of plumbagin to target cisplatin resistance in non-high-grade OC. The current study aimed to determine the antitumor activity of plumbagin for cisplatin resistance in OC cells in vitro, and to identify its potential molecular target for therapeutic benefit using in silico studies. METHODS:Plumbagin was used for in vitro cytotoxic effects on cisplatin-resistant (A2780-CR) and sensitive (A2780-CS) isogenic cell lines using a crystal violet cell viability assay. The binding of plumbagin to the nine selected molecular targets was estimated by molecular docking and their binding energies were compared. The stabilities of the selected docked complexes were confirmed by molecular dynamics simulation (MDS) and molecular mechanics generalized born surface area (MM-GBSA) calculations, and conclusions were drawn to predict the inhibition potential of plumbagin to its best targets. RESULTS:Plumbagin demonstrated the potential to kill A2780-CR cells, and, expectedly, the cell death effect on A2780-CS ovarian cancer cells demonstrated its anti-tumor activity in vitro. It was found to be noneffective in killing normal non-tumorigenic RPE cells, even at higher doses. Docking analysis suggested that it potentially inhibits through various pharmacological targets with high affinity for binding to Chk1 (PDB ID=1ia8) and Aurora Kinase (PDB ID=5ORL). Molecular dynamic simulation data revealed strong and stable protein-ligand complex formation, which was measured in terms of root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg). On the other hand, the MM-GBSA study revealed that the binding free energy of the CT1019-1ia8 complex (-84.26 ± 2.99 Kcal/mol) and CT1019-5ORL (-67.04 ± 2.63 Kcal/mol) was better when compared to other complexes. DISCUSSION:Plumbagin showed anti-ovarian cancer benefits in cisplatin-resistant ovarian cells, and the potential pharmacological targets identified were Chk1 and Aurora kinase. CONCLUSION:Our study offers promising insights into plumbagin, particularly in combating cisplatin-resistance OC. However, further in vivo and mechanistic studies are required to validate plumbagin's potential as a therapeutic candidate for OC treatment.

Cancer encompasses a diverse range of disease conditions marked by the uncontrolled growth of abnormal cells and is often associated with high recurrence rates. The development and progression of cancer are closely linked to the disruption of key molecular pathways that regulate cellular and tissue homeostasis. Among the various molecular players involved, circular RNAs (circRNAs) have gained increasing attention from the scientific community because of their aberrant expression in various cancer types, leading to its progression and development. CircRNAs represent a distinct class of covalently closed RNA with distinct tissue- and cell-specific expression profiles and are essential for controlling key cellular processes. It has emerged as a crucial regulatory molecule that contributes to numerous hallmarks of cancer, such as enhanced cell proliferation, growth suppression evasion, resistance to cell death, induction of angiogenesis, invasion and metastasis, maintenance of cancer stem cells, immune evasion, metabolic reprogramming, promotion of inflammation, impairment of DNA damage, genomic instability, non-mutational epigenetic reprogramming, and therapeutic resistance. This review aims to enhance our understanding on the role of circRNAs on several cancer hallmarks and promote further research into their underlying mechanism of action, to identify and utilize them as potential therapeutic strategies.

Declining testosterone levels in aging men represent a growing clinical concern, with late-onset hypogonadism (LOH) affecting an estimated 20–30

Glioblastoma is a malignant and invasive brain cancer that is difficult to treat and has a short survival rate. This work aims to identify the efficiency of alkaloids from Solanaceae family as anti-glioblastoma drugs employing network pharmacology, molecular docking and molecular dynamics studies. Initially, key alkaloids were identified and screened for drug-likeness, oral bioavailability and molecular weight, resulting in the selection of seven promising compounds: Scopolamine, Atropine, Norhyoscyamine, Solanidine, Vindoline, Duboisine and Homatropine. By analyzing the microarray data, DEGs were obtained related to glioblastoma, and combined with the identified alkaloid targets to establish the compound-target-pathway network. Gene ontology and KEGG pathway analyses identified important biological processes and signaling pathways that contribute to glioblastoma development. Molecular docking analysis indicated the potential of the identified alkaloids to bind effectively with receptors including EGFR, MDM2 and AURKA which are fundamental in glioblastoma development. Molecular dynamics simulations at 100 ns supported the stabilities and interactions of these protein-ligand complexes as well. This thorough review indicates that Solanaceae alkaloids could serve as multifunctional drug candidates for glioblastoma treatment and provide a new direction for the pharmacotherapy of glioblastoma based on natural resources.

Cynanchum acutum L. is a traditional medicinal plant known for its diverse pharmacological activities, such as anti-inflammatory, antibacterial, and antioxidant effects. This study aimed to evaluate the antiproliferative and apoptotic potential of the ethanolic extract of C. acutum L. fruits on liver cancer cells (HepG2), while assessing its safety in a normal human lung fibroblast cells (PCS-201-013). Comprehensive phytochemical profiling using HPLC-UV and LC-Ion trap-ESI-MS revealed, isovitexin (1407.5 mcg/g) and epicatechin (1175.3 mcg/g) as the dominant flavonoids, alongside substantial amounts of O-caffeic acid (170.4 mcg/g), orientin (162.6 mcg/g). In addition, vitexin (29.8 mcg/g), rutin (17.7 mcg/g), iso-orientin (21.2 mcg/g), and chlorogenic acid (15.6 mcg/g) were found in modest concentrations in dried fruit powder. The MTT assay exhibited a dose-dependent cytotoxicity with an IC50 value of 40 mu g/mL, while showing minimal toxicity toward normal fibroblast cells. It significantly suppressed cell migration and colony formation ability, indicating both anti-metastatic and antiproliferative effects. Moreover, the fruit extract resulted in mitochondrial membrane depolarization and increased ROS production in a dose-dependent manner. We also observed simultaneous cell cycle arrest at G1/S and G2/M phases and a significant increase in apoptotic cell populations (5.23 %-42.2 %). Collectively, these results highlight C. acutum fruit extract potential against the studied liver cancer cells. The presence of compounds, such as isovitexin and related flavonoids may have contributed to the observed effects. Future work will focus on isolating these compounds and conducting more detailed mechanistic and in vivo studies.

Circular RNAs (circRNAs) is a type of non-coding RNAs abundantly found in eukaryotic cells, have gained increasing attention in cancer research lately. They act as mediators in several signaling pathways by facilitating communication between different cell types. Aberrant expression of circRNAs has been observed in numerous cancer types, where they contribute to tumor initiation and progression. They can also influence the tumor microenvironment (TME) by regulating the function of various immune cells, such as T-cells, B-cells, natural killer (NK) cells, and macrophages, as well as other crucial components that include cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and extracellular matrix (ECM). Furthermore, circRNAs are also implicated in regulating the epithelial-mesenchymal transition (EMT) through their interactions with the zinc finger E-box binding (ZEB), Twist, Snail, Slug proteins, and transforming growth factor-beta (TGF-β), including the development of resistance to cancer therapies. They can also modulate immune checkpoints and reduce the effectiveness of immune checkpoint inhibitors (ICIs). In this review, we focused on the pivotal roles of circRNAs in cancer biology with special emphasis on their involvement in the TME, EMT, and therapeutic resistance. We have also explored translational potential of circRNAs, identified the current challenges and limitations they encounter, and potential strategies to overcome these obstacles. This article underscores the significant potential of circRNAs in the realm of cancer biology; however, further studies are required to exploit different circRNAs as prognostic, diagnostic, and therapeutic markers against various cancer types.

Leishmaniasis, caused by the protozoan parasites of the genus Leishmania, poses a significant global health challenge, particularly in the resource-limited regions where it causes high mortality. Regardless in the progress of treatment strategies, the emergence of drug resistance and limited efficacy requires the search of novel therapy and therapeutic targets. MicroRNAs, the crucial post-transcriptional regulators of gene expression, play critical roles in host–pathogen interactions. Here, we screened the miRNAs dysregulated during Leishmania donovani infection through literature search. hsa-miR-330-5p, one of the miRNAs which through human KEGG 2021 and Human Cyc 2016 analysis was found to be involved in multiple pathways including sphingolipid signaling pathway. Sphingolipids are important class of lipids involved in different cellular processes and therefore are the targets of many pathogens including Leishmania. hsa-miR-330-5p was found downregulated after 24 h of Leishmania donovani infection in THP-1 derived human macrophages. Target prediction of sphingolipid biosynthetic genes through in silico prediction tools showed 3/ UTR of serine palmitoyltransferase long chain base subunit 1 to be a target of hsa-miR-330-5p. The in silico target prediction of hsa-miR-330-5p was validated by cloning the 3/ UTR target sequence of gene, transfecting and performing luciferase assay in HEK 293 T cell line. Transfection of mimic of hsa-miR-330-5p reduced the luciferase activity which validated the in silico target prediction. Further, mimic of hsa-miR-330-5p inhibited the expression of the target gene, serine palmitoyltransferase long chain base subunit 1 and augmented the expression of pro-inflammatory cytokines in L. donovani infected THP-1 derived macrophages. Mimic of hsa-miR-330-5p also led to a significant reduction in the intracellular parasite burden in both THP-1 derived as well as primary human macrophages. This study has not only identified the sphingolipid biosynthesis regulatory miRNA but will also help in the development of novel and effective treatment strategy against leishmaniasis in future.

MicroRNAs (miRNAs) or small noncoding RNA molecules, 18-22 nucleotides long, are evolutionarily conserved and may have an impact on the behavior and progression of tumors. Cancer initiation, proliferation, invasion, and metastasis are all related to the specific deregulation of miRNAs. It also affects the genes involved in metabolism, apoptosis, cellular differentiation, and proliferation. Understanding the functional roles of miRNAs could shed light on the intricate molecular mechanism that underlie cancer growth. The purpose of this review is to investigate the presence of tumor-suppressive, oncogenic, and metastatic miRNAs in cancer cells, specifically breast cancer (BC) and how these miRNAs affect the development of BC and its subtypes. In addition, the miRNA-based therapeutic strategies and utilization of different delivery system to enhance the efficacy has also been covered. Based on our article, miRNAs appear to be cutting-edge prognostic, therapeutic, and diagnostic tools for the treatment of BC. However, several barriers, such as, delivery systems, side effects, demographic variabilities, and lengthy clinical studies needs to be optimized before these miRNAs could be routinely used in clinical settings.

Leishmania donovani is an intracellular protozoan parasite that has successfully evolved to manipulate host macrophages. The exact mechanism by which Leishmania spp evades macrophage function is not fully understood. Recently, several studies have shown that pathogens target host-microRNA to alter cellular pathways for their persistence. Here, we explored the alterations in host sphingolipid biosynthetic pathway regulatory microRNAs during Leishmania donovani infection. Here, the sphingolipid biosynthetic pathway genes serine palmitoyltransferase long chain base subunit 1 (SPTLC1), 3-ketodihydrosphingosine reductase (KDSR), ceramide synthase 1(CERS1) and dihydroceramide desaturase 1 (DEGS1) were found to be upregulated while N-Acylsphingosine Amidohydrolase 1 (ASAH1) was downregulated but no significant changes were observed in sphingomyelin synthase 1 (SGMS1) and sphingosine kinase 1 (SPHK1) in Leishmania donovani infected THP-1 derived macrophages (TDM) at 24 h. Bioinformatic analysis using miRWalk 2.0 predicted SPTLC1 to be a target of hsa-miR-15a-5p and hsa-miR-330-5p, CERS1 to be targeted by hsa-miR-10396a-3p, and ASAH1 by hsa-miR-513a-5p; all of these miRNAs have been previously reported to be dysregulated during infection. Since hsa-miR-15a-5p was found common to target SPTLC1 in all three databases, namely Targetscan, miRDB, and miRTarBase therefore the expression of hsa-miR-15a-5p was selected for further studies. We found a downregulated expression of hsa-miR-15a-5p during Leishmania donovani infection. In silico target prediction followed by in vitro target validation of hsa-miR-15a-5p showed SPTLC1 as one of the targets. Additionally, mimics of hsa-miR-15a-5p reduced the expression of SPTLC1, upregulated mainly the proinflammatory cytokines, and reduced the parasites in TDM as well as Peripheral Blood Mononuclear Cell (PBMC) derived human macrophages.

Cancer stem cells (CSCs) are implicated in tumor initiation, therapeutic resistance and disease recurrence, making them critical targets for cancer treatment. In this study, a comprehensive network pharmacology-based framework was employed to identify natural phytochemicals that may inhibit CSC pathways across multiple cancer types. A curated set of 82 anticancer phytochemicals was screened for drug-likeness using absorption, distribution, metabolism, excretion and toxicity profiling and physicochemical properties, which led to the selection of 10 promising candidates. These compounds were subjected to target prediction analysis, resulting in 916 potential targets, of which 493 overlapped with known cancer-related genes. Gene ontology (GO) enrichment analysis revealed that these overlapping genes were significantly involved in biological processes such as cellular metabolism, stress response and catabolic regulation, all of which are crucial to CSC maintenance. The cellular component and molecular function analyses supported their role in exosome signaling, protein interaction and transcriptional regulation. KEGG pathway analysis highlighted enrichment in critical CSC-associated signaling cascades, including PI3K-Akt, MAPK, cytokine interactions and NF-kappa B pathways. Moreover, protein-protein interaction (PPI) network analysis identified 10 hub genes, seven of which (TNF, IL6, STAT3, SRC, EGFR, CASP3, PTGS2) showed significant association with poor survival outcomes based on Kaplan-Meier analysis. Molecular docking and dynamic simulation further validated strong and specific binding of phytochemicals, especially Rosmarinic acid, Catechin and Shikonin, against key targets (IL6, STAT3 and EGFR), suggesting their role in CSC inhibition. Overall, this integrative study highlights the potential of selected phytochemicals as multi-target therapeutic candidates capable of modulating CSC-associated networks and pathways.

Cancer is a major contributor to global morbidity and mortality. Among the different forms of cancer, colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second most common cancer type in women globally. We aimed to explore the possible synergistic anticancer potential of curcumin (Cur) and plumbagin (PL) in the human colon cancer cell line (HCT-116). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)/cytotoxicity assay revealed IC50 values of 7.7 and 7.5 μM for Cur and PL, respectively, as a separate entity. However, the combined treatment of Cur + PL significantly enhanced the cancer cell growth inhibitory potential compared with solitary treatments with an IC50 value of 6.8 μM. The combined treatment also led to the induction of apoptosis by 41%, cell cycle arrest at the G2/M phase, while Bax and p53 genes were found to be upregulated and the Bcl-2 gene was downregulated compared to the untreated/solvent control. Furthermore, combined treatment elevated reactive oxygen species (ROS) production by 59% and resulted a decline in the mitochondrial membrane potential (MMP) compared to the control. Catalase and superoxide dismutase (SOD) activities were significantly reduced, leading to enhanced lipid peroxidation (LPO) and compromised membrane integrity, which were also confirmed by 4',6-diamidino-2-phenylindole (DAPI) + propoidium iodide (PI) staining were also noted. Our in vitro data were further supported by molecular docking, which showed a higher binding energy of the proteins (Bax, Bcl-2, and p53) with Cur + PL. Overall, our findings highlight the potent synergistic effects of the Cur and PL combination, which can be exploited as a combination therapy for CRC.

Chronic inflammatory diseases are leading causes of morbidity and mortality, necessitating the development of targeted therapeutics with improved safety. Many drugs have been withdrawn from the market because of their off-target effects, particularly hERG inhibition, which leads to severe cardiotoxicity. The NF-κB pathway plays a critical role in inflammation and immune response, making IKKβ an attractive therapeutic target. Thioridazine, a known inhibitor of IKKβ, has demonstrated potential anti-inflammatory effects. However, its clinical utility is severely limited by the strong inhibition of the hERG potassium channel, which increases the risk of cardiac arrhythmias. Therefore, it is necessary to develop safer IKKβ inhibitors using rational drug design approaches. By leveraging a similar compound library and in silico techniques, we aimed to retain the original therapeutic potential of thioridazine, while minimising its drawbacks. A library of thioridazine derivatives was computationally designed and screened by molecular docking and simulations. The selected compounds were subjected to patch-clamp analysis, confocal microscopy, western blotting, and qRT-PCR to evaluate their anti-inflammatory potential and hERG affinity, respectively. TDZ-D2{10-(2-oxo-2-pyrrolidin-1-ylethyl)acridin-9-one}, a thioridazine derivative, displayed significantly lower hERG binding while maintaining strong IKKβ inhibition, preserving IκBα stability, reducing NF-κB p65 translocation, and suppressing pro-inflammatory cytokine expression. This study highlights the potential of ligand-based lead optimisation techniques for mitigating off-target effects, thereby offering a safer anti-inflammatory therapeutic candidate. By overcoming the cardiotoxicity associated with thioridazine, TDZ-D2 presents a promising avenue for drug development for inflammatory diseases.

Liver cancer, particularly Hepatocellular Carcinoma (HCC), remains a significant global health challenge owing to its high incidence and position as the fourth leading cause of cancer-related mortality. HCC represents 75-85% of all liver cancer cases and ranks as the sixth most prevalent cancer globally. Several factors, including late-stage diagnosis, limited treatment effectiveness, resistance to conventional therapies, and adverse side effects, hinder the delivery of life-prolonging care to patients with HCC. Current treatment options such as chemotherapy, immunotherapy, and adjuvant therapy are often associated with severe side effects. Consequently, there is an urgent need for improved diagnostic methods and alternative therapeutic approaches to extend life expectancy and reduce HCC-related mortalities. Artificial Intelligence (AI) is an emerging technology that offers promising advances for the early detection of HCC. In terms of alternative treatments, natural compounds have garnered significant attention because of their diverse biological activities, such as antitumor, antiviral, antimicrobial, antioxidant, anti-inflammatory, hepatoprotective, antimutagenic, and cardioprotective effects, and their relatively lower side effect profiles. These compounds exhibit hepatoprotective properties by modulating key molecular pathways involved in HCC development and progression. This article provides an overview of recent advances in the understanding of liver cancer etiology, therapeutic targets in HCC pathogenesis, the role of AI in its detection, and the potential of natural products, particularly flavonoids, as preventive and therapeutic agents against HCC, highlighting their underlying mechanisms of action.

Breast cancer (BC) is the most prevalent cancer in women and remains the leading cause of cancer-related mortality globally. Its development is influenced by multiple factors, including genetics, environmental, aging, and modulation of various signaling pathways. The heterogeneity of BC together with the emergence of treatment resistance and recurrence have prompted researchers to explore and develop new therapeutic approaches. Recently, oncology research has primarily focused on the development of targeted therapies against molecular abnormalities in BC. These therapies include monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates, PI3K/Akt/mTOR pathway inhibitors, CDK 4/6 inhibitors, PARP inhibitors, antiangiogenic agents, and various other targeted drugs. Immunomodulatory strategies, including immune checkpoint inhibitors (anti-PD-1/PD-L1), CTLA-4 blockers, adoptive T-cell therapy, and cancer vaccines, stimulate immune response against cancer cells. Epigenetic therapies like DNMT and HDAC inhibitors have also shown promise in BC treatment. This review highlights how innovative approaches like targeting intratumoral heterogeneity, liquid biopsy for resistance mutation detection, bypass mechanisms (FGFR1 activation following CDK4/6 inhibition), artificial intelligence-based drug discovery, patient-derived organoids, and adaptive trial designs are shaping BC treatment. By combining molecular insights with precision therapeutics, these advancements offer significant potential to address resistance, improve efficacy, and enhance patient outcomes.