Gabriele De Rubis

Lung cancer (LC) remains the leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. While conventional treatments such as chemotherapy and radiotherapy are highly established, adverse effects and therapy resistance necessitate the exploration of novel therapeutic strategies. This study investigates the in vitro anti-cancer potential of the flavonoid fisetin and its nanoemulsion formulation (FNE) in NSCLC, alongside fecal microbiome extract (FME) as a potential adjunct therapy. In vitro functional assays demonstrated that while pure fisetin powder did not significantly inhibit NSCLC cell proliferation, colony formation nor cell migration, FNE and FME exhibited notable cytotoxic effects. Protein array analysis identified significant downregulation of 22 key oncogenic proteins implicated in lung cancer tumour development, epithelial-mesenchymal transition, tumour microenvironment, immunomodulation, therapy resistance, and metastasis. Importantly, the computational analysis supported these results by identifying fisetin-associated genes that correspond to the experimentally downregulated proteins. Computational in silico analysis of fisetin-associated genes identified multiple lung cancer targets including IL6, SERPINE1, PDGFA, MMP3, MST1, MET, and ENPP2. These findings highlight the enhanced therapeutic efficacy achieved through a phytoceutical-loaded nanoemulsion and microbiome-modulated anti-cancer mechanisms, with improved outcomes when combining FNE and FME treatments. The integration of phytoceuticals and microbiome research represents a promising avenue for advancing NSCLC treatment strategies and overcoming current therapeutic limitations. Graphical Abstract

Nonsmall cell lung cancer (NSCLC) is one of the most prevalent cancers and leading causes of cancer‐related mortality worldwide. Despite advancements in medical treatment, current therapeutic strategies are often hindered by late‐stage diagnosis, high recurrence rates and resistance to therapies. These challenges highlight the urgent need for novel, less toxic and more effective treatment options. Phytoceuticals, bioactive plant‐derived compounds, have gained increasing attention for their potential to complement or enhance conventional cancer therapies. Among these, nobiletin, a polymethoxylated flavonoid found in citrus peels, has promising anti‐inflammatory, antioxidant and anticancer properties. This review explores the therapeutic potential of nobiletin in NSCLC, focusing on its ability to modulate key cancer hallmarks such as uncontrolled proliferation, metastasis, immune evasion and multidrug resistance. Preclinical studies suggest that nobiletin inhibits tumour growth, enhances chemosensitivity and suppresses metastasis through multiple pathways. However, its clinical application is currently limited by poor bioavailability, prompting the need for innovative delivery strategies. Therefore, this review also discusses emerging approaches to improve nobiletin′s biological activity, supporting further investigations into its role in NSCLC therapy.

Caffeine consumption is regarded as a widespread phenomenon, and its usage has continued to increase. In addition, the growing usage of antidepressants worldwide and increase in mental health disorders were shown in recent statistical analyses conducted by the World Health Organisation. The coadministration of caffeine and antidepressants remains a concern due to potential interactions that can alter a patient’s response to therapy. This review investigates the pharmacokinetic and pharmacodynamic interactions between caffeine and the five main classes of antidepressants: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and other antidepressants not categorised by class, which we have categorised as 'miscellaneous'. The interaction between fluvoxamine and caffeine resulted in increased concentrations of caffeine in the body and lowered the renal clearance of fluvoxamine. Other SSRIs such as fluoxetine and escitalopram had augmented antidepressant effects by decreasing their renal clearance and prolonging their effects in the body when coadministered with caffeine. Caffeine may also increase the concentration of paroxetine, potentially affecting its pharmacodynamic effects. TCAs such as clomipramine, imipramine, desipramine, and sertraline, were found to reduce the metabolism of caffeine. However, studies suggest caffeine had no significant effect on the concentration of these medications in blood or brain tissue. The inhibition of caffeine at high doses when used with MAOIs such as tranylcypromine and phenelzine was found to lead to a higher likelihood of experiencing hypertension. Coadministration of caffeine with venlafaxine (SNRIs) suggests minimal interactions between the two substances and the pharmacodynamic effects of venlafaxine were unlikely to be impacted by caffeine consumption. Miscellaneous antidepressants (reboxetine, mianserin, agomelatine, maprotiline, and mirtazapine) displayed varying pharmacodynamic interactions with caffeine, resulting in increased antidepressant effects where vortioxetine, maprotiline, and mirtazapine failed to demonstrate any interactions. In conclusion, caffeine demonstrated varying effects on the pharmacokinetic and pharmacodynamic properties of each class of antidepressants, with several classes of antidepressants demonstrating a similar effect on caffeine.

Lung cancer is the leading cause of cancer death globally, with non‐small cell lung cancer accounting for the majority (85%) of cases. Standard treatments including chemotherapy and radiotherapy present multiple adverse effects. Medicinal plants, used for centuries, are traditionally processed by methods such as boiling and oral ingestion, However, water solubility, absorption, and hepatic metabolism reduce phytoceutical bioavailability. More recently, isolated molecular compounds from these plants can be extracted with these phytoceuticals administered either individually or as an adjunct with standard therapy. Phytoceuticals have been shown to alleviate symptoms, may reduce dosage of chemotherapy and, in some cases, enhance pharmaceutical mechanisms. Research has identified many phytoceuticals' actions on cancer‐associated pathways, such as oncogenesis, the tumour microenvironment, tumour cell proliferation, metastasis, and apoptosis. The development of novel nanoparticle delivery systems such as solid lipid nanoparticles, liquid crystalline nanoparticles, and liposomes has enhanced the bioavailability and targeted delivery of pharmaceuticals and phytoceuticals. This review explores the biological pathways associated with non‐small cell lung cancer, a diverse range of phytoceuticals, the cancer pathways they act upon, and the pros and cons of several nanoparticle delivery systems.

Pulmonary infections have a profound influence on global mortality rates. Medicinal plants offer a promising approach to address this challenge, providing nontoxic alternatives with higher levels of public acceptance and compliance, particularly in regions where access to conventional medications or diagnostic resources may be limited. Understanding the pathophysiology of viruses and bacteria enables researchers to identify biomarkers essential for triggering diseases. This knowledge allows the discovery of biological molecules capable of either preventing or alleviating symptoms associated with these infections. In this review, medicinal plants that have an effect on COVID‐19, influenza A, bacterial and viral pneumonia, and tuberculosis are discussed. Drug delivery has been briefly discussed as well. It examines the effect of bioactive constituents of these plants and synthesizes findings from in vitro, in vivo, and clinical studies conducted over the past decade. In conclusion, many medicinal plants can be used to treat pulmonary infections, but further in‐depth studies are needed as most of the current studies are only at preliminary stages. Extensive investigation and clinical studies are warranted to fully elucidate their mechanisms of action and optimize their use in clinical practice.