Search Results (1,363)

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood–brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets—including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites—that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody–drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases. Full article

Human colorectal cancer (CRC) encompasses tumors affecting a segment of the large intestine (colon) and rectum. It is the third most commonly diagnosed malignancy and the second leading cause of cancer deaths worldwide. It is a multifactorial disease, whose carcinogenesis process involves genetic and epigenetic alterations in oncogenes and tumor suppressor genes, including genes related to DNA repair. The pathogenic mechanisms are described based on the pathways of chromosomal instability, microsatellite instability, and CpG island methylator phenotype. When detected early, CRC is potentially curable, and its treatment is based on the pathological characteristics of the tumor and factors related to the patient, as well as on drug efficacy and toxicity studies. Therefore, the aim of this study was to review the pathogenesis and molecular subtypes of CRC and to describe the main targets of disease-directed therapy used in patients refractory to current treatments. Full article

Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the “new use” of the “old drug” menadione in CRC treatment. Full article

Background and Clinical Significance: Breast cancer is a heterogeneous disease with different spread of metastases. In particular, skin metastases are common in HER2-positive metastatic breast cancer (mBC). However, anti-HER2 therapies have shown limited activity in this context. Recently, Trastuzumab Deruxtecan (T-DXd), a novel potent anti-HER2 antibody–drug conjugate (ADC), has revolutionized the therapeutic armamentarium of HER2 mBC with unprecedented evidence of efficacy in pretreated patients. However, the activity of this drug in patients with skin involvement is largely unknown. Case Presentation: Here, we report a case of extensive cutaneous involvement in a heavily pretreated patient who achieved a long-lasting complete response to T-DXd, which, unexpectedly, remained sustained for more than three years following treatment discontinuation. Conclusions: Skin toxicity is not a common adverse event with this agent, and, as demonstrated in the present case, it might not be drug-related, and additional causes might be ruled out before treatment discontinuation. However, the possibility of discontinuing anti-Her2 treatment in a patient who has achieved a complete response could represent a field of research, potentially using liquid biopsy or other new technologies. Full article

Background/Objectives: Limited robust data support the use of antibiotic combinations in the treatment of orthopedic infections. However, in certain situations, the combination of antibiotics seems to be beneficial. This review aims to outline the circumstances under which a combination of antibiotics may be utilized in the treatment of orthopedic infections. Methods: We reviewed the existing guidelines on orthopedic infections and focused on situations where antibiotic combinations are recommended or proposed optionally. We chose vitro and animal studies that provide evidence for the effectiveness of several widely recommended combinations. Results: The combinations serve multiple purposes: they provide empirical coverage while awaiting microbiological results, offer targeted treatment for difficult-to-treat infections, and facilitate oral treatment primarily for staphylococcal infections. The objectives include enhancing bacterial coverage against Gram-positive and Gram-negative bacteria, achieving synergistic effects with bactericidal agents, and reducing the risk of antibiotic resistance. The review outlines specific combinations for fracture-related infections, periprosthetic joint infections, spinal infections, and anterior cruciate ligament reconstruction infections, emphasizing the importance of tailoring antibiotic choices based on local epidemiology and patient history. The review also addresses potential drawbacks of combination therapy, such as toxicity, higher costs, and drug interactions, underscoring the complexity of managing orthopedic infections effectively. Conclusions: According to the guidelines, several different proposals are made, depending in part on the countries’ epidemiology. In a well-defined situation, various authors propose either monotherapy or a combination of antibiotics. When a combination is suggested, the choice of antibiotics is based on the expected effect: broadening the spectrum, enhancing bactericidal activity, achieving a synergistic effect, or reinforcing biofilm activity to optimize the treatment. Full article

Animal venoms are complex biochemical secretions rich in highly potent and selective bioactive molecules, including peptides, enzymes, and small organic compounds. Once associated primarily with toxicity, these venoms are now recognized as a promising source of therapeutic agents for a wide range of medical conditions. This review provides a comprehensive analysis of the pharmacological potential of venom-derived compounds, highlighting their mechanisms of action, such as ion channel modulation, receptor targeting, and enzyme inhibition. Successful venom-derived drugs like captopril and ziconotide exemplify the translational potential of this biological arsenal. We discuss therapeutic applications in cardiovascular diseases, chronic pain, cancer, thrombosis, and infectious diseases, as well as emerging peptide candidates in clinical development. Technological advancements in omics, structural biology, and synthetic peptide engineering have significantly enhanced the discovery and optimization of venom-based therapeutics. Despite challenges related to stability, immunogenicity, and ecological sustainability, the integration of AI-driven drug discovery and personalized medicine is expected to accelerate progress in this field. By synthesizing current findings and future directions, this review underscores the transformative potential of animal venoms in modern pharmacotherapy and drug development. We also discuss current therapeutic limitations and how venom-derived compounds may address unmet needs in specific disorders. Full article

Dark sweet cherries (DSC) phytochemicals have emerged as a promising dietary strategy to combat triple-negative breast cancer (TNBC). This study explored the effects of DSC extract rich in anthocyanins (ACN) as a chemopreventive agent and as a complement to doxorubicin (DOX) in treating TNBC tumors and metastasis using a 4T1 syngeneic animal model. Initiating ACN intake as a chemopreventive one week before 4T1 cell implantation significantly delayed tumor growth without any signs of toxicity. Both DOX treatment and the combination of DOX-ACN effectively delayed tumor growth rate, but DOX-ACN allowed for body weight gain, which was hindered by DOX alone. As a chemopreventive, ACN downregulated metastasis- and immune-suppression-related genes, including STAT3, Snail1, mTOR, SIRT1, TGFβ1, IKKβ, and those unaffected by DOX alone, such as HIF, Cd44, and Rgcc32. Correlations between mRNA levels seen in control and DOX groups were absent in ACN and/or DOX-ACN groups, indicating that Cd44, mTOR, Rgcc32, SIRT1, Snail1, and TGFβ1 may be ACN targets. The DOX-ACN treatment showed a trend toward enhanced efficacy involving CREB, PI3K, Akt-1, and Vim compared to DOX alone. Particularly, ACN significantly suppressed lung metastasis compared to the other groups. ACN also decreased the frequency and incidence of metastasis in the liver, heart, kidneys, and spleen, while their metastatic area (%) and number of breast cancer (BC) metastatic tumor nodules were lowered without reaching significance. Further research is needed to explore the efficacy of combining ACN with drug therapy in the context of drug resistance. Full article

Green tea, derived from the unoxidized leaves of Camellia sinensis (L.) Kuntze, is one of the least processed types of tea and is rich in antioxidants and polyphenols. Among these, catechins—particularly epigallocatechin gallate (EGCG)—play a key role in regulating cell signaling pathways associated with various chronic conditions, including cardiovascular diseases, neurodegenerative disorders, metabolic diseases, and cancer. This review presents a comprehensive analysis of recent clinical studies focused on the therapeutic benefits and potential risks of interventions involving green tea extracts or EGCG. A systematic literature survey identified 17 relevant studies, classified into five key areas related to catechin interventions: toxicity and detoxification, drug pharmacokinetics, cognitive functions, anti-inflammatory and antioxidant properties, and obesity and metabolism. Findings from these clinical studies suggest that the health benefits of green tea catechins outweigh the potential risks. The review highlights the importance of subject genotyping for enzymes involved in catechin metabolism to aid in interpreting liver injury biomarkers, the necessity of assessing drug–catechin interactions in clinical contexts, and the promising effects of topical EGCG in reducing inflammation. This analysis underscores the need for further research to refine therapeutic applications while ensuring the safe and effective use of green tea catechins. Full article

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

Microorganisms serve as a vital source of natural anticancer agents, with many of their secondary metabolites already employed in clinical oncology. In recent years, salt-adapted microbes, including halophilic and halotolerant species from marine, salt lake, and other high-salinity environments, have gained significant attention. Their unique adaptation mechanisms and diverse secondary metabolites offer promising potential for novel anticancer drug discovery. This review consolidated two decades of research alongside current global cancer statistics to evaluate the therapeutic potential of salt-adapted microorganisms. Halophilic and halotolerant species demonstrate significant promise, with their bioactive metabolites exhibiting potent inhibitory effects against major cancer cell lines, particularly in lung and breast cancer. Evidence reveals structurally unique secondary metabolites displaying enhanced cytotoxicity compared to conventional anticancer drugs. Collectively, salt-adapted microorganisms represent an underexplored yet high-value resource for novel anticancer agents, offering potential solutions to chemotherapy resistance and treatment-related toxicity. Full article

Forensic entomotoxicology is a subdiscipline that utilizes necrophagous insects as bioindicators for detecting drugs and toxicants in decomposed remains, particularly in cases where conventional biological matrices are no longer available. Toxic substances can profoundly alter insect development, physiology, and community succession, potentially impacting the accuracy of postmortem interval (PMI) estimation. This review systematically summarizes the effects of various xenobiotics, including pesticides, illicit drugs, sedatives, heavy metals, and antibiotics on larval growth, physiological traits, and gut microbial composition in forensically relevant flies. However, most studies to date have relied primarily on phenotypic observations, with limited insight into underlying molecular mechanisms. Significant interspecies and dose-dependent variability also exists in the absorption, metabolism, and physiological responses to xenobiotics. We highlight recent advances in multi-omics technologies that facilitate the identification of molecular biomarkers associated with xenobiotic exposure, particularly within the insect detoxification system. Key components such as cytochrome P450 monooxygenases (P450s), glutathione S-transferases (GSTs), and ATP-binding cassette (ABC) transporters play essential roles in xenobiotic metabolism and insecticide resistance. Additionally, the insect fat body serves as a central hub for detoxification, hormonal regulation, and energy metabolism. It integrates signals related to xenobiotic exposure and modulates larval development, making it a promising model for future mechanistic studies in insect toxicology. Altogether, this review offers a comprehensive and reliable framework for understanding the complex interactions between toxic substance exposure, insect ecology, and decomposition in forensic investigations. Full article

Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral drug delivery system, KGM-CUR/PSM microspheres, to achieve precise drug release in CRC and enhance tumor-specific drug accumulation, which leverages high ROS levels in CRC and the β-mannanase overexpression in colorectal tissues. Methods: In this study, we synthesized a ROS-responsive prodrug polymer (PSM) by conjugating polyethylene glycol monomethyl ether (mPEG) and mesalazine (MSL) via a thioether bond. CUR was then encapsulated into PSM using thin-film hydration to form tumor microenvironment-responsive micelles (CUR/PSM). Subsequently, konjac glucomannan (KGM) was employed to fabricate KGM-CUR/PSM microspheres, enabling targeted delivery for colorectal cancer therapy. The ROS/enzyme dual-response properties were confirmed through in vitro drug release studies. Cytotoxicity, cellular uptake, and cell migration were assessed in SW480 cells. In vivo efficacy was evaluated in AOM/DSS-induced CRC mice, monitoring tumor growth, inflammatory markers (TNF-α, IL-1β, IL-6, MPO), and gut microbiota composition. Results: In vitro drug release studies demonstrated that KGM-CUR/PSM microspheres exhibited ROS/enzyme-responsive release profiles. CUR/PSM micelles demonstrated significant anti-CRC efficacy in cytotoxicity assays, cellular uptake studies, and cell migration assays. In AOM/DSS-induced CRC mice, KGM-CUR/PSM microspheres significantly improved survival and inhibited CRC tumor growth, and effectively reduced the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and myeloperoxidase (MPO). Histopathological and microbiological analyses revealed near-normal colon architecture and microbial diversity in the KGM-CUR/PSM group, confirming the system’s ability to disrupt the “inflammation-microbiota-tumor” axis. Conclusions: The KGM-CUR/PSM microspheres demonstrated a synergistic enhancement of anti-tumor efficacy by inducing apoptosis, alleviating inflammation, and modulating the intestinal microbiota, which offers a promising stimuli-responsive drug delivery system for future clinical treatment of CRC. Full article

Increasing evidence demonstrates the mutualistic connection between the microbiome and acute myeloid leukemia (AML) treatment. Drugs disrupt the microbial balance and, conversely, changes in the microbiome influence therapy. A new field, pharmacomicrobiomics, examines the role of the microbiome in pharmacokinetics, pharmacodynamics, and drug toxicity. The multimodal therapeutic management of AML, along with disease-related immunosuppression, infection, and malnutrition, creates the unique microbial profile of AML patients, in which every delicate modification plays a crucial role in pharmacotherapy. While both preclinical and real-world data have confirmed a bilateral connection between standard chemotherapy and the microbiome, the impact of novel targeted therapies and immunotherapy remains unknown. Multi-omics technologies have provided qualitative and mechanistic insights into specific compositional and functional microbial signatures associated with the outcomes of AML therapy, but require a large-scale investigation to draw reliable conclusions. In this review, we outline the role of the microbiome within the therapeutic landscape of AML, focusing on the determinants of post-treatment dysbiosis and its effects on the therapeutic response and toxicity. We explore emerging strategies for microbiota modulation, highlighting their safety and efficacy. Advances in microbiome-based approaches are an inevitable step toward precision medicine in AML. However, clinical research in a well-defined group of immunocompromised patients is needed to study their variable effects on human health and determine safety issues. Full article

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal malignancies of the female reproductive system. Glucose oxidase (GOx) has emerged as a potential therapeutic agent in cancer treatment by inducing tumor starvation through glucose depletion. Nonetheless, its clinical application is constrained due to its systemic toxicity, immunogenicity, poor in vivo stability, and short half-life. These challenges can be addressed through nanotechnology; in particular, biogenic mesoporous silica nanoparticles (MSNs) offer promise as drug delivery systems (DDSs) that enhance therapeutic efficacy while minimizing side effects. Methods: Biogenic MSNs were extracted from the Equisetum myriochaetum plant via acid digestion, functionalized with 3-aminopropiltrietoxysilane (APTES) and glutaraldehyde (GTA), and loaded with GOx. The free and immobilized MSNs were characterized using FTIR, DLS, XRD, SEM/EDX, and BET techniques. A colorimetric approach was employed to quantify the enzymatic activity of both the free and immobilized GOx. The MTT assay was employed to assess the viability of SKOV3 cells. The obtained IC₅₀ concentration of the nanoformulation was administered to SKOV3 cells to analyze the expression of cancer-related genes using RT-qPCR. Results: IC₅₀ values of 60.77 ng/mL and 111.6 µg/mL were ascertained for the free and immobilized GOx, respectively. Moreover, a significant downregulation of the oncogene β-catenin (CTNNB1) was detected after 24 h with the nanoformulation. Conclusions: Our findings indicate that GOx-loaded biogenic MSNs may serve as a potential therapeutic agent for ovarian cancer. This is, to the best of our knowledge, the first report exploring the effect of GOx-loaded biogenic MSNs on SKOV3 cells. Full article

Background: Fungal infections, particularly those caused by Candida species, pose a serious threat to immunocompromised individuals, and therapeutic options are limited due to toxicity and resistance concerns. This in vitro study aimed to explore the feasibility of using liquid fractions of autologous platelet concentrates (APCs), namely concentrated platelet-rich fibrin (c-PRF) and liquid-phase concentrated growth factor (LPCGF), as carriers for antifungal drugs. Methods: The research was conducted in two phases: first, to evaluate the inherent antifungal properties of different APCs; and second, to assess their effectiveness as drug carriers for fluconazole and voriconazole against Candida albicans, Candida glabrata, and Candida krusei. Results: Results showed that APCs alone exhibited no direct antifungal effects. However, when combined with antifungal agents, notable inhibition zones were observed—especially with voriconazole against C. krusei and fluconazole against C. glabrata using c-PRF. Both c-PRF and LPCGF were compatible with the drugs and did not hinder clot formation. Conclusions: These findings suggest that APCs can act as effective vehicles for localized antifungal drug delivery and warrant further investigation for clinical application in treating fungal-related oral diseases. Full article