Search Results (816)

We report the development of highly luminescent, bovine serum albumin (BSA)-stabilized gold–silver bimetallic nanoclusters (Au-AgNCs@BSA) as a novel platform for high-sensitivity, ratiometric intracellular temperature sensing. Precise and non-invasive temperature sensing at the nanoscale is crucial for applications ranging from intracellular thermogenesis monitoring to localized hyperthermia therapies. Traditional luminescent thermometric platforms often suffer from limitations such as high cytotoxicity and low photostability. Here, we synthesized Au-AgNCs@BSA via a one-pot aqueous reaction, achieving significantly enhanced photoluminescence quantum yields (PL QYs, up to 18%) and superior thermal responsiveness compared to monometallic counterparts. The dual-emissive Au-AgNCs@BSA exhibit a linear ratiometric fluorescence response to temperature fluctuations within the physiological range (20–50 °C), enabling accurate and concentration-independent thermometry in live cells. Time-resolved PL and Arrhenius analyses reveal two distinct emissive states and a high thermal activation energy (E_a = 199 meV), indicating strong temperature dependence. Silver doping increases radiative decay rates while maintaining low non-radiative losses, thus amplifying fluorescence intensity and thermal sensitivity. Owing to their small size, excellent photostability, and low cytotoxicity, these nanoclusters were applied to non-invasive intracellular temperature mapping, presenting a promising luminescent nanothermometer for real-time cellular thermogenesis monitoring and advanced bioimaging applications. Full article

The paradigm-shift idea of murburn concept is no hypothesis but developed directly from fundamental facts of cellular/ecological existence. Murburn involves spontaneous and stochastic interactions (mediated by murzymes) amongst the molecules and unbound ions of cells. It leads to effective charge separation (ECS) and formation/recruitment of diffusible reactive species (DRS, like radicals whose reactions enable ATP-synthesis and thermogenesis) and emission of radiations (UV/Vis to ELF). These processes also lead to a chemo-electromagnetic matrix (CEM), ascertaining that living cell/organism react/function as a coherent unit. Murburn concept propounds the true utility of oxygen: generating DRS (with catalytic and electrical properties) on the way to becoming water, the life solvent, and ultimately also leading to phase-based macroscopic homeostatic outcomes. Such a layout enables cells to become simple chemical engines (SCEs) with powering, coherence, homeostasis, electro-mechanical and sensing–response (PCHEMS; life’s short-term “intelligence”) abilities. In the current review, we discuss the coacervate nature of cells and dwell upon the ways and contexts in which various radiations (either incident or endogenously generated) could interact in the new scheme of cellular function. Presenting comparative evidence/arguments and listing of systems with murburn models, we argue that the new perceptions explain life processes better and urge the community to urgently adopt murburn bioenergetics and adapt to its views. Further, we touch upon some distinct scientific and sociological contexts with respect to the outreach of murburn concept. It is envisaged that greater awareness of murburn could enhance the longevity and quality of life and afford better approaches to therapies. Full article

In boron neutron capture therapy (BNCT), the intracellular localization and concentration of boron-10 atoms significantly influence therapeutic efficacy. Although various boronic-acid-targeted fluorescent probes have been developed to evaluate BNCT agents, most of these probes emit at short wavelengths and are, therefore, incompatible with common nuclear-staining reagents such as Hoechst 33342 and 4′,6-diamidino-2-phenylindole (DAPI). While our previously reported probe, BS-631, emitted fluorescence above 500 nm, it exhibited limitations in terms of reaction rate and fluorescence intensity. To address these issues, we developed a boronic-acid-targeted fluorescent probe with a longer emission wavelength, rapid reactivity, and strong fluorescence intensity. Herein, we designed and synthesized BTTQ, a probe based on a 2-(2-hydroxyphenyl)benzothiazole core structure. BTTQ exhibited immediate fluorescence upon reaction with 4-borono-L-phenylalanine (BPA), with an emission wavelength of 567 nm and a sufficiently high fluorescence quantum yield for detection. BTTQ quantitatively detected BPA with high sensitivity (quantification limit of 10.27 µM), suitable for evaluating BNCT agents. In addition, BTTQ exhibited selective fluorescence for BPA over metal cations. Importantly, BTTQ enabled fluorescence microscopic imaging of intracellular BPA distribution in living cells co-stained with Hoechst 33342. These results suggest that BTTQ is a promising fluorescent probe for the evaluation of future BNCT agents. Full article

Toxoplasma gondii is an intracellular protozoan found worldwide that is capable of infecting nearly all warm-blooded animals, including humans. Its parasitic success lies in its capacity to create chronic infections while avoiding immune detection, altering host immune responses, and disrupting programmed cell death pathways. This review examines the complex relationship between T. gondii and host immunity, focusing on how the parasite influences innate and adaptive immune responses to survive in immune-privileged tissues. We present recent findings on the immune modulation specific to various parasite strains, the immunopathology caused by imbalanced inflammation, and how the parasite undermines host cell death mechanisms such as apoptosis, necroptosis, and pyroptosis. These immune evasion tactics enable prolonged intracellular survival and pose significant challenges for treatment and vaccine development. We also review advancements in therapeutic strategies, including host-directed approaches, nanoparticle drug delivery, and CRISPR-based technologies, along with progress in vaccine development from subunit and DNA vaccines to live-attenuated candidates. This review emphasizes the importance of T. gondii as a model for chronic infections and points out potential avenues for developing innovative therapies and vaccines aimed at toxoplasmosis and similar intracellular pathogens. Full article

Cancer remains a leading global health burden, profoundly affecting patient survival and quality of life. Current treatments—including chemotherapy, radiotherapy, immunotherapy, and surgery—are often limited by toxicity or insufficient specificity. Conventional chemotherapy, for instance, indiscriminately attacks rapidly dividing cells, causing severe side effects. In contrast, peptide-based therapeutics offer a paradigm shift, combining high tumour-targeting precision with minimal off-target effects. Their low immunogenicity, multi-pathway modulation capabilities, and adaptability for diagnostics and therapy make them ideal candidates for advancing oncology care. Innovative peptide platforms now enable three transformative applications: (1) precision molecular diagnostics (e.g., ¹⁸F-PSMA-1007 for prostate cancer detection), (2) targeted therapies (e.g., BT5528 and SAR408701 targeting tumour-specific antigens), and (3) theranostic systems (e.g., RAYZ-8009 and ¹⁷⁷Lu-FAP-2286 integrating imaging and radiotherapy). Despite their promise, peptides face challenges like metabolic instability and short half-lives. Recent advances in structural engineering (e.g., cyclization and D-amino acid incorporation) and delivery systems (e.g., nanoparticles and PEGylation) have significantly enhanced their clinical potential. This review highlights peptide-based agents in development, showcasing their ability to improve early cancer detection, reduce metastasis, and enhance therapeutic efficacy with fewer adverse effects. Examples like CLP002 underscore their role in personalised medicine. By overcoming current limitations, peptide drugs are poised to redefine cancer management, offering safer, more effective alternatives to conventional therapies. Their integration into clinical practice could mark a critical milestone in achieving precision oncology. Full article

CLL is the most prevalent adult leukemia in Western countries, characterized by the accumulation of monoclonal B lymphocytes. Over the past decade, the therapeutic landscape for CLL has undergone significant transformations, primarily due to the introduction of targeted small molecular therapies like BTK inhibitors and BCL-2 inhibitors, that have improved patient outcomes drastically. Despite significant advances, long-term disease management remains challenging for patients with double-refractory CLL, where responses with subsequent therapies are short-lived. Resistance to these therapies can arise through several mechanisms like kinase-altering BTK mutations, alterations in the BCL-2 pathway, and adaptations within the tumor microenvironment, necessitating the exploration of new therapeutic options. This review provides an in-depth overview of the promising novel treatment approaches under investigation in CLL, focusing on advanced cellular therapies (CAR T-cell therapy), T-cell engagers, new monoclonal antibodies, and various next-generation small molecule inhibitors including BTK degraders, PI3K inhibitors, MALT1 inhibitors, c-MYC inhibitors, CDK9 inhibitors, and agents targeting angiogenesis and DNA damage repair. In this review, we will discuss the novel therapeutic targets and agents as well as ongoing trials, emphasizing the potential of these treatments to overcome resistance and meet the unmet needs of patients, particularly those with double-refractory CLL. Full article

Pancreatic cancer cells exhibit a remarkable ability to tolerate nutrient deprivation, a phenomenon termed “austerity,” which enables their survival within the hypovascular tumor microenvironment. Conventional anticancer therapies frequently fail to effectively target these resilient neoplastic cells, posing a significant challenge to the therapeutic management of pancreatic cancer. Consequently, targeting austerity, the ability of cancer cells to tolerate nutrient starvation, represents a promising anti-austerity strategy for developing novel pancreatic cancer therapeutics. In this study, we investigated calliviminone A (CVM-A), a phloroglucinol–meroterpenoid isolated from Callistemon citrinus leaves, for its anti-austerity activity against PANC-1 human pancreatic cancer cells. Calliviminone A exhibited potent preferential cytotoxicity in nutrient-deprived medium (NDM) with a PC₅₀ of 0.57 µM, while showing minimal toxicity in nutrient-rich Dulbecco’s Modified Eagle’s medium (IC₅₀ = 45.2 µM), indicating a favorable therapeutic index. Real-time live-cell imaging revealed that CVM-A induced significant morphological changes, including cell shrinkage and membrane blebbing, leading to cell death within 24 h of NDM. Furthermore, under normal nutrient conditions in Dulbecco’s Modified Eagle’s Medium (DMEM), CVM-A significantly inhibited PANC-1 cell migration (up to 47% reduction at 20 µM) and colony formation (over 80% suppression at 25 µM), suggesting its antimetastatic potential. Western blot studies demonstrated that CVM-A downregulated key survival components of the PI3K/Akt/mTOR signaling pathway, completely inhibiting Akt and p-Akt at 2.5 µM in NDM, and suppressing insulin-induced Akt activation. These findings highlight CVM-A as a promising lead compound for developing novel anticancer therapies that target the adaptive survival mechanisms and metastatic potential of pancreatic cancer in nutrient-deprived microenvironments. Full article

Radiation therapy, a highly effective cancer treatment that targets cancer cells, may produce challenging side effects, including radiation-induced skin tissue injuries. The wound healing process involves complex cellular responses, with key phases including hemostasis, inflammation, proliferation, and remodeling. However, radiation-induced injuries disrupt this process, resulting in delayed healing, excessive scarring, and compromised tissue integrity. This review explores innovative approaches related to wound healing in post-radiotherapy defects, focusing on the integration of adipose-derived stem cells (ADSCs) in protein/polysaccharide bioengineered scaffolds. Such scaffolds, like hydrogels, sponges, or 3D-printed/bioprinted materials, provide a biocompatible and biomimetic environment that supports cell-to-cell and cell-to-matrix interactions. Various proteins and polysaccharides are discussed for beneficial properties and limitations, and their compatibility with ADSCs in wound healing applications. The potential of ADSCs-polymeric scaffold combinations in radiation-induced wound healing is investigated, alongside the mechanisms of cell proliferation, inflammation reduction, angiogenesis promotion, collagen formation, integrin binding, growth factor signaling, and activation of signaling pathways. New strategies to improve the therapeutic efficacy of ADSCs by integration in adaptive polymeric materials and designed scaffolds are highlighted, providing solutions for radiation-induced wounded skin, personalized care, faster tissue regeneration, and, ultimately, enhanced quality of the patients’ lives. Full article

Checkpoint inhibitor therapy revolutionized the treatment of patients with melanoma. However, in patients where melanoma exhibits resistance to checkpoint inhibitor therapy, the treatment options are limited. Oncolytic viruses are a unique form of immunotherapy that uses live viruses to infect and lyse tumor cells to release the elusive neoantigen picked up by the antigen-presenting cells, thus increasing the chances of an immune response against cancer. Coupled with checkpoint inhibitors, intratumoral injections of the oncolytic virus can help an enhanced immune response, especially in a tumor that displays resistance to checkpoint inhibitors. However, oncolytic viruses are not bereft of challenges and face several obstacles in the tumor microenvironment. From the historical use of wild viruses to the sophisticated use of genetically modified viruses in the current era, oncolytic virus therapy has evolved tremendously in the last two decades. Increasing the ability of the virus to select the malignant cells over the non-malignant ones, circumventing the antiviral immune response from the body, and enhancing the oncolytic properties of the viral platform by attaching various ligands are some of the several improvements made in the last three decades. In this manuscript, we trace the journey of the development of oncolytic virus therapy, especially in the context of melanoma. We review the clinical trials of talimogene laherparepvec in patients with melanoma. We also review the data available from the clinical trials of vusolimogene oderparepvec in patients with melanoma. Finally, we review the use of various oncolytic viruses and their challenges in clinical development. This manuscript aims to create a comprehensive literature review for clinicians to understand and implement oncolytic virus therapy in patients diagnosed with melanoma. Full article

We aimed to simulate tau abnormalities—specifically hyperphosphorylation and aggregation—that are hallmarks of tauopathies, including Alzheimer’s disease, to evaluate tau-targeting therapies. To model pathological p-tau accumulation at early disease stages, we exposed mouse cortical cultures to redox-active iron from hemin (Hm), a breakdown product of hemoglobin, or challenged them with the excitatory neurotransmitter glutamate. Using the AT8 phospho-specific antibody, we demonstrate that a subtoxic concentration of Hm (3 µM) promotes pathological p-tau accumulation in a subpopulation of cultured cortical neurons and their proximal neurites. Uric acid (UA; 0.1–200 µM), the metabolic end-product of purines in humans, prevented p-tau build-up. Neither xanthine, the immediate precursor of UA, nor allantoin, its oxidized product, reproduced this effect. Live cell imaging studies revealed that UA operates by repressing iron-driven lipid peroxidation. DOT (3 µM), a brain-permeant tetracycline (TC) without antibiotic activity, mimicked UA’s anti-tau and antioxidant effects. Interestingly, both UA and DOT remained effective in preventing p-tau accumulation induced by glutamate (10 µM). To simulate tau aggregation at more advanced disease stages, we conducted a Thioflavin-T aggregation assay. Our findings revealed that UA and DOT prevented tau aggregation seeded by heparin. However, only DOT remained effective when heparin-assembled tau fibrils were used as the seeding material. In summary, our results indicate that UA-elevating agents may hold therapeutic utility for tauopathies. The non-purine compound DOT could serve as an effective alternative to UA-related therapies. Full article

Science has made significant progress in detecting reactive oxygen species (ROS) in tobacco smoke, which is an important step for precision cancer therapy. An important advance is also the understanding that superoxide can be produced by electrophilic molecules. The dual action of hydrogen peroxide, directly or via electrophilic molecules, in the development of oxidative stress allows for the identification of target proteins that can potentially stop unwanted signals in cancer development. However, despite advances in proteomics, reliable inhibitors to stop ROS-associated cancer progression have not yet been proposed for the treatment of tobacco cigarette smokers. This is likely due to an imperfect understanding of the diversity of molecular mechanisms of anti-ROS action. Fluorescent protein detection in living cells, called in-gel, offers a direct route to a better understanding of the rapid interaction of ROS and electrophilic compounds with targeted proteins. It seemed that the traditional paradigm of pharmaceutical innovation “one drug, one disease” did not solve the problem of tobacco smoking causing cancer. However, among the various therapeutic treatments for tobacco smokers, the best way to combat cancer today is smoking cessation, which fits into the “one-cure” paradigm. Full article

AIDS-related malignant lymphomas (ARLs) are the lymphomas that develop in association with HIV infection. According to the introduction of combination antiretroviral therapy (cART), the life expectancy of People Living with HIV (PLWH) has markedly improved; however, approximately one-third of PLWH have passed away from the complications of malignancies, even in well-controlled PLWH. HIV itself is not tumorigenic, and most of these tumors are due to co-infection with oncogenic viruses. γ-herpes viruses (Epstein–Barr virus: EBV and Kaposi sarcoma-associated herpesvirus: KSHV) are the most significant risk factors for ARLs. Immunodeficiency, chronic inflammation, accelerated aging, and genetic instability caused by HIV infection, as well as HIV accessory molecules, are thought to promote lymphomagenesis. The prognosis of ARLs is comparable to that of non-HIV cases in the cART era. Intensive chemotherapy with autologous stem cell transplantation is also available for relapsed/refractory ARLs. Since the early stage of HIV infection has no symptoms, significant numbers of HIV-infected individuals have not noticed HIV infection until the onset of AIDS (so-called Ikinari AIDS). Since the ratio of these patients is more than 30% in Japan, hematologists should carefully consider the possibility of HIV infection in cases of lymphoma. Even in an era of cART, ARL remains a critical complication in PLWH, warranting continuous surveillance. Full article

Positron emission tomography (PET) imaging targeting glypican-3 (GPC3) holds promise for improving the detection and characterization of hepatocellular carcinoma (HCC). Preclinical and early clinical studies have largely utilized high-molecular-weight antibodies radiolabeled with isotopes such as ⁸⁹Zr and ¹²⁴I, demonstrating high affinity and tumor uptake but suffering from prolonged circulation times and suboptimal signal-to-background ratios. To address these limitations, interest has shifted toward low-molecular-weight vectors—synthetic peptides and small antibody fragments—labeled with shorter-lived radionuclides (e.g., ⁶⁸Ga and ¹⁸F) to enable rapid pharmacokinetics and same-day imaging protocols. Emerging platforms such as affibodies and aptamers offer further advantages in target affinity and reduced immunogenicity. However, clinical translation requires rigorous validation: larger, histologically confirmed cohorts, head-to-head comparison with CT/MRI, and correlation with hard clinical endpoints. Moreover, leveraging GPC3 expression as a biomarker could guarantee a deeper knowledge of tumor biology—differentiation grade and vascular invasion risk—and guide theranostic strategies. While β-emitters (⁹⁰Y, ¹⁷⁷Lu) have been explored for GPC3-directed therapy, their efficacy is influenced by oxygenation and cell-cycle status, whereas α-emitters (²²⁵Ac) may overcome these constraints, albeit with challenges in radionuclide selection and daughter nuclide management. Finally, dual-targeting probes combining GPC3 and prostate-specific membrane antigen (PSMA) have demonstrated superior uptake and retention in murine models, suggesting a versatile approach for future clinical diagnostics and therapy planning. Full article

Cancer is a leading cause of death globally, claiming millions of lives each year. Despite the availability of numerous anticancer drugs, the need for new treatment options remains essential. Many current therapies come with significant toxicity, lead to various side effects, or do not consistently deliver the expected therapeutic results. Purines and pyrimidines are fundamental building blocks of nucleic acids and play crucial roles in cellular metabolism and signaling. Recent advances in medicinal chemistry have led to the development and synthesis of various derivatives that exhibit selective cytotoxic effects against cancer cells while minimizing toxicity to healthy tissues. Purine and pyrimidine scaffolds, due to their well-established biological roles and structural versatility, have emerged as key pharmacophoric fragments in anticancer drug discovery. In recent years, the rational design of hybrid molecules incorporating these heterocycles has shown promise in overcoming drug resistance, improving target selectivity, and enhancing pharmacological profiles. Purine and pyrimidines scaffolds hold significant potential as foundations for novel antitumor drugs, with established representatives in cancer treatment, including 5-fluorouracil, cladribine, capecitabine, and several others. In addition, the article discusses the challenges and future developments of purine and pyrimidine derivatives and hybrid molecules as antitumor drugs and emphasizes the need for continued research to optimize their effectiveness and reduce side effects. Overall, the innovative use of these compounds represents a major advance in targeted cancer therapy and holds promise for improving the therapeutic efficacy of malignant diseases. Full article

Human immunodeficiency virus (HIV) is responsible for acquired immunodeficiency syndrome (AIDS), a condition characterized by the depletion of CD4+ T lymphocytes, which predisposes individuals to opportunistic infections and, ultimately, death. Although antiretroviral therapy (ART) has substantially improved clinical outcomes, certain limitations persist. Notably, 15–30% of individuals undergoing ART achieve viral suppression but fail to restore adequate CD4+ T cell counts, being defined as immunological non-responders (INR) and remaining at increased risk of disease progression to AIDS. The impaired immune recovery in INRs is attributed to insufficient production and/or excessive destruction of CD4+ T lymphocytes, which can be modulated by autophagy process. This evolutionarily conserved mechanism is fundamental to lymphocyte development and activation as well as to programmed cell death pathways such as apoptosis, necroptosis, ferroptosis, and pyroptosis. These pathways are essential for understanding the impaired immune reconstitution observed in people living with HIV, whose inability to maintain immune homeostasis contributes to accelerated disease progression. This review explores the interplay between autophagy, HIV, and cell death mechanisms, highlighting its relevance in immunological recovery under ART and its potential as a therapeutic target. Full article