Doxorubicin Research Articles

Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu2+ depletes intracellular GSH and is reduced to Cu+ simultaneously, which reacts with local H2O2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

A smart-responsive Y-shaped DNA scaffold drug conjugate achieving precise and synergetic tumor chemo-gene therapy via promoting tumor apoptosis and activating the anti-tumor immunity

Constructing precise delivery systems to enhance the antitumor efficacy of drugs represents a pressing clinical practice need. The characteristics of suitable physiological stability, flexible tunable size, and highly programmable architecture make functional DNA scaffolds an ideal solution to this requirement. Here, we designed DNA oligonucleotide probes Y1, Y2 and Y3 to construct a smart-responsive Y-shaped DNA scaffold drug conjugate (sYDD). This sYDD incorporates two AS1411 aptamers, an apurinic/apyrimidinic (AP) site, a B-cell lymphoma-2 (Bcl-2) antisense oligonucleotide (ASO) and a doxorubicin (DOX)-carrying sequence. The Bcl-2 ASO and DOX within sYDD could be responsively released in tumor cells that exhibited high expression of apurinic/apyrimidinic endonuclease 1 (APE1) and microRNA-21 (miR-21). And the in vitro and in vivo experiments demonstrated that sYDD exhibited substantial antitumor efficiency. Moreover, the flow cytometry and RNA sequencing results proved that the proposed sYDD effectively activated immune responses. This strategy provides an alternative approach for designing synergistic chemo-gene drug conjugates, which facilitates the development of precision tumor treatment modalities.

Carbenoxolone upregulates TRAIL\\TRAILR2 expression and enhances the anti-neoplastic effect of doxorubicin in experimentally induced hepatocellular carcinoma in rats

AimsThis study investigates the in vivo anticancer activity of carbenoxolone (CBX) and its role in fighting hepatocellular carcinoma (HCC) progression and alleviating resistance against doxorubicin (DOX). Moreover, the molecular mechanism of action of CBX is explored. MethodsHCC was induced in Sprague Dawley rats via biweekly administration of thioacetamide (TAA) (200 mg/kg) intraperitoneally (i.p.) for 16 weeks after administering a single dose of diethylnitrosamine (DEN) (200 mg/kg, i.p.). A prophylactic model was established by treating rats with i.p. CBX (20 mg/kg/day) for 4 weeks starting on week 13 post-TAA injection. A therapeutic model was established by treating rats with CBX, DOX, or their combination for 7 weeks following 16 weeks of TAA administration. Serum Alpha-fetoprotein (AFP) and biochemical markers of hepatic functions were assessed. Histopathological examinations of hepatic tissues were performed. Immunohistochemical and qRT-PCR analyses were applied to assess the differential expressions of TRAIL/TRAILR2, Bcl-2, TGF-β1, and caspases 3,8, and 9. ResultsCBX markedly improved hepatic functions, reduced serum AFP levels, and alleviated TAA-induced hepatic histopathological alterations. CBX triggered apoptosis as evident by upregulating apoptotic markers: TRAIL/TRAILR2, caspases 3,8, and 9, and downregulating the antiapoptotic protein Bcl-2. CBX downregulated TGF-β1. Interestingly, CBX/DOX combination mitigated hepatic damage and induced apoptosis in a way that surpassed DOX-only treatment. ConclusionThe current study proposes that CBX is a promising anti-tumor compound, which can work effectively under prophylactic and therapeutic modes. Interestingly, CBX enhanced the anti-tumor effect of DOX. CBX exerted these effects via, in part, stimulating TRAIL-induced apoptosis along with attenuating fibrosis.

Multifunctional nanoplatforms based on alumina-coated mesoporous silica with potential for cancer theranostics applications

Multifunctional nanoplatforms based on mesoporous silica coated with alumina were successfully and sustainably synthesized using sodium silicate extracted from rice husk ash (RHA), demonstrating the potential for cancer theranostics. The hybrid nanostructures produced (C2-600 and C4-600), from two different calcination times, exhibited distinct morphologies, textural parameters, and degrees of mesoscopic organization. As expected, the Al2O3 coating on the mesoporous silica nanoparticles (MSNs) reduced the specific surface area from 720 m2/g to 122 m2/g (C2-600) and 57 m2/g (C4-600), while preserving their mesoporous structure. Additionally, both C2-600 and C4-600 showed relatively good stability across a wide pH interval, with a zeta potential of ζ = -15 mV and hydrodynamic diameter (Dh) ranging from 160 to 670 nm, depending on the pH of the medium. These peculiar characteristics resulted in high encapsulation efficiency (EE ≈ 90%) for the doxorubicin (DOX) anticancer drug, as well as sustained drug release in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.4). Appreciably, C4-600-DOX released approximately 83% of the drug over 96 hours and demonstrated significant biodegradation in simulated biological media. Furthermore, the hybrid nanoplatforms exhibited strong optical absorption between 250 and 420 nm, along with broad and intense photoluminescence (PL) in the near-infrared (NIR) region (680-900 nm), which is highly desirable for NIR-fluorescence diagnostic imaging. Notably, the hybrid nanoplatforms without DOX were non-cytotoxic to fibroblast and Caco-2 cells, while the DOX-loaded nanoplatforms exhibited selectivity and potent anticancer activity, inhibiting approximately 80% of Caco-2 colorectal cancer cells after 72 hours. These findings demonstrate that C2-600 and C4-600 are innovative, multifunctional and biodegradable nanoplatforms with powerful potential as drug carriers and fluorescence imaging agents, making them promising candidates for cancer theranostics.

Growth of dendritic CuS nanostructures for photoacoustic image guided Chemo-Photothermal therapy

Herein, we report a unique method for design and development of carboxyl enriched dendritic CuS nanostructures (CuS NSs) for photoacoustic image guided chemo-photothermal therapy. The dendritic network was grown on the surface of CuS nanoparticles via layer-by-layer assembly of amino acid. XRD and TEM studies established the formation of crystalline well-spherical nanosized hexagonal covellite (CuS) phase. The successful growth of dendritic structure was apparent from the rise in surface charge, hydrodynamic diameter and characteristic vibrational band intensity of peptide bonds. The developed different generations of dendritic CuS NSs (D0-CuS NSs, D1-CuS NSs, D2-CuS NSs and D3-CuS NSs) displayed wide-ranging absorption band in near infrared (NIR) zone and exhibited good photothermal heating efficacy upon irradiation of 980 nm laser light. From in to vitro cellular studies, it has been found that the NIR irradiation effectively enhanced the photothermal toxicity of D3-CuS NSs towards cancer cells. Moreover, these negatively charged water-dispersible D3-CuS NSs were conjugated with positively charged anticancer drug, doxorubicin hydrochloride (DOX) through electrostatic interaction. The DOX loaded D3-CuS NSs (DOX@D3-CuS NSs) revealed pH dependent drug release behaviour and their considerable uptake in breast cancer cells (MCF-7). Further, DOX@D3-CuS NSs exhibited a much higher toxicity towards cancer cells upon NIR light over individual counterparts suggesting their strong ability for chemo-photothermal therapy. Moreover, these biocompatible CuS NSs have shown excellent concentration dependent photoacoustic properties at pulse laser excitation (850 nm) and thus, they can be found potential application in chemo-photothermal therapy.

Copper-coordinated nanomedicine for the concurrent treatment of lung cancer through the induction of cuproptosis and apoptosis

The resistance of tumor cells to apoptosis often leads to chemoresistance and treatment failure in clinic. In this study, we have developed a Cu2+-coordinated lignosulfonate (CLS) /doxorubicin (DOX) biological complex (referred to as LCD) with the aim of overcoming cellular resistance to apoptosis for combined lung cancer therapy. The copper complexes modified by CLS exhibit significant water solubility and excellent in vivo biocompatibility. The proportion of copper in the composite is simultaneously increased. Due to the coordination and π-π stacking effects, the self-assembled LCD exhibits nanometer-scale particle size, a narrow and homogeneous grain distribution, as well as excellent dispersion stability. Furthermore, LCD has the potential to disassemble in the presence of high levels of glutathione (GSH) and low pH, leading to effective drug release. Cu2+-mediated cuproptosis can lead to the down-regulation of FDX1 and DLAT protein expression by reducing mitochondrial membrane potential, resulting in non-apoptotic programmed cell death (PCD) regardless of cellular resistance to apoptosis. Moreover, the released DOX not only exhibits a preference for localizing in the cell nucleus to induce apoptosis for combined chemotherapy, but also generates a substantial amount of H2O2. This H2O2 further produces ROS to induce apoptosis through Fenton reaction with Cu2+. LCD demonstrates significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity through the combined action of cuproptosis and apoptosis. This study may provide a potential avenue for the advancement of self-delivery nanomedicine to overcome resistance to apoptosis in tumor therapy.

GSH-responsive magnetic mesoporous silica nanoparticles for efficient controlled drug delivery in tumor cells

In this study, glutathione (GSH)-responsive magnetic mesoporous silica nanoparticles grafted by disulfide organosilicon (SMNPs) were synthesized, characterized, and evaluated as controlled drug carriers. The nanoparticles exhibited consistent dispersion, considerable drug-loading capacity, and high saturation magnetization. Importantly, they demonstrated the ability to release doxorubicin (DOX) by up to 43% in a reducing tumor microenvironment, highlighting their potential for targeted therapy. In addition, the SMNPs displayed favorable biocompatibility, making them suitable for biomedical applications. Most notably, the SMNPs loaded with DOX effectively killed both HepG2 and HeLa cancer cells, while also showing efficient cellular uptake in HeLa cells. These findings suggest that SMNPs are a promising platform for magnetic-targeted and GSH-responsive delivery of therapeutic agents.

The mechanism and therapeutic strategies in doxorubicin-inducedcardiotoxicity: Role of programmed cell death.

Doxorubicin (DOX) is the most commonly used anthracycline anticancer agent, while its clinical utility is limited by harmful side effects like cardiotoxicity. Numerous studies have elucidated that programmed cell death plays a significant role in DOX-induced cardiotoxicity (DIC). This review summarizes several kinds of programmed cell death, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis. Furthermore, oxidative stress, inflammation, and mitochondrial dysfunction are also important factors in the molecular mechanisms of DIC. Besides, a comprehensive understanding of specific signal pathways of DIC can be helpful to its treatment. Therefore, the related signal pathways are elucidated in this review, including sirtuin deacetylase (silent information regulator 2 [Sir2]) 1 (SIRT1)/nuclear factor erythroid 2-related factor 2, SIRT1/Klotho, SIRT1/Recombinant Sestrin 2, adenosine monophosphate-activated protein kinase, AKT, and peroxisome proliferator-activated receptor. Heat shock proteins function as chaperones, which play an important role in various stressful situations, especially in the heart. Thus, some of heat shock proteins involved in DIC are also included. Hence, the last part of this review focuses on the therapeutic research based on the mechanisms above.

Sensing steroid hormone 17α-hydroxypregnenolone by GPR56 enables protection from ferroptosis-induced liver injury.

G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.

Neurotoxicity of the antineoplastic drugs: "Doxorubicin" as an example.

There is an increased prevalence of cancer, and chemotherapy is widely and routinely utilized to manage the majority of cancers; however, administration of chemotherapeutic drugs has faced limitations concerning the "off-target" cytotoxicity. Chemobrain and impairment of neurocognitive functions have been observed in a significant fraction of cancer patients or survivors and reduce their life quality; this could be ascribed to the ability of chemotherapeutic drugs to alter the structure and function of the brain. Doxorubicin (DOX), an FDA-approved chemotherapeutic drug with therapeutic effectiveness, is commonly used to treat several carcinomas clinically. DOX-triggered neurotoxicity is the most serious adverse reaction after DOX-induced cardiotoxicity which greatly limits its clinical application. DOX-induced neurotoxicity is a net of multiple mechanisms that have been verified in pre-clinical and clinical studies, such as oxidative stress, neuroinflammation, mitochondrial disruption, apoptosis, autophagy, disruption of neurotransmitters, and impairment of neurogenesis. There is a massive need for developing novel therapeutics for both cancer and DOX-associated neurotoxicity; therefore investigating the implicated mechanisms of DOX-induced chemobrain will reveal multi-targets for novel curative strategies. Recently, various neuroprotective mechanisms were employed to mitigate DOX-mediated neurotoxicity. For this purpose, therapeutic interventions using pharmacological compounds were developed to protect healthy "off-target" tissues from DOX-induced toxicity. In addition, nanoplatforms were used to enable target delivery of DOX; to prevent its deposition in non-cancerous tissues. The aim of the current review is to provide some reference value for the future management of DOX-induced neurotoxicity and to summarize the underlying mechanisms of DOX-mediated neurotoxicity and the potential therapeutic interventions.

Mesoporous polydopamine (MPDA)-based drug delivery system for oral chemo-photothermal combinational therapy of orthotopic colon cancer

Oral nano-drug delivery systems offering combination therapy have garnered significant interest in colon cancer treatment due to their precision in targeting tumors and minimizing peripheral tissue exposure. However, challenges such as the complex gastrointestinal environment and effective retention of nanoparticles in the colon have impeded further advancement. We developed a novel oral drug delivery system designed for localized treatment of colon cancer via chemotherapy and photothermal therapy (PTT). This system utilized mesoporous polydopamine (MPDA) as a photothermal carrier for doxorubicin hydrochloride (DOX), with surface modification using folic acid (FA) to enhance systemic tumor targeting. Additionally, to ensure gastrointestinal retention and precise colon localization, the nanoparticles were coated with an enteric-soluble material, ES100, resulting in the formulation MPDA-FA-DOX/ES100. This formulation exhibited high photothermal conversion efficiency, robust photothermal stability, and responsive drug release under near-infrared (NIR) laser stimulation. FA modification significantly enhanced the cellular uptake of nanoparticles by CT26 cells, promoting greater cytotoxic effects through combined chemotherapy and PTT. In vivo, MPDA-FA-DOX/ES100 demonstrated superior accumulation in colon tumor tissues and substantial photothermal effects, and notably, the CT/PTT group demonstrated significant tumor growth inhibition along with excellent biocompatibility. Collectively, these findings highlight the clinical potential of MPDA-FA-DOX/ES100 as an effective platform for localized and synergistic CT/PTT of colon cancer.

Novel CD44-Targeted Albumin Nanoparticles: An Innovative Approach to Improve Breast Cancer Treatment.

This study introduces novel CD44-targeted and redox-responsive nanoparticles (FNPs), proposed as doxorubicin (DOX) delivery devices for breast cancer. A cationized and redox-responsive Human Serum Albumin derivative was synthesized by conjugating Human Serum Albumin with cystamine moieties and then ionically complexing it with HA. The suitability of FNPs for cancer therapy was assessed through physicochemical measurements of size distribution (mean diameter of 240 nm), shape, and zeta potential (15.4 mV). Nanoparticles possessed high DOX loading efficiency (90%) and were able to trigger the drug release under redox conditions of the tumor environment (55% release after 2 h incubation). The use of the carrier increased the cytotoxic effect of DOX by targeting the CD44 protein. It was shown that, upon loading, the cytotoxic effect of DOX was enhanced in relation to CD44 protein expression in both 2D and 3D models. DOX@FNPs significantly decrease cellular metabolism by reducing both oxygen consumption and extracellular acidification rates. Moreover, they decrease the expression of proteins involved in the oxidative phosphorylation pathway, consequently reducing cellular viability and motility, as well as breast cancer stem cells and spheroid formation, compared to free DOX. This new formulation could become pioneering in reducing chemoresistance phenomena and increasing the specificity of DOX in breast cancer patients.

Zn/Cu Bi‐Single‐Atom Nanoplatform: Hexagonal Anti‐Tumor Warrior by ROS Amplification for DOX Resistance Reversal and Immune Activation

AbstractSevere resistance of doxorubicin (DOX) caused by drug efflux and immunosuppression has led to a high treatment failure risk of breast cancer (BC). Compared with the single atom nanozymes, the bi‐single‐atomic nanozymes obtained through sequential single‐atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi‐single‐atom nanozymes (Zn/Cu‐BSAN‐DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H2O2 self‐supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn/Cu‐BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as “hexagonal” anti‐tumor warrior, Zn/Cu‐BSAN‐DOX NPs show great potential for multimodal DOX‐resistant BC therapy, which further expands the new preparation strategy and the clinical anti‐tumor application paradigm of single‐atom nanozymes.

Antisense oligonucleotide facilitate the photothermal therapy of Mxene-based nanoplatform for drug-resistant breast cancer

Breast cancer has become the most common form of cancer worldwide. Chemotherapy failure, primarily due to drug resistance, necessitates the development of new therapeutic strategies. In this study, ultrathin Ti3C2 nanosheets are utilized as photothermal agents and nanocarriers. We developed a multifunctional Ti3C2-based nanoplatform (214.7 nm) through layer-by-layer absorption of HSP90 antisense oligonucleotide (ASO) and doxorubicin (DOX), with surface modification using hyaluronic acid (HA). In a simulated acidic tumor microenvironment in vitro, 90 % of the drug was released within 36 hours. Additionally, Under 808 nm irradiation (2.0 W/cm²), MCF-7/ADM cell viability assays revealed the following results: HA-Ti3C2 (57 %), HA-Ti3C2@ASO (HT@A) (41 %), and HA-Ti3C2@ASO/DOX (HT@AD) (26 %), which shown the synergistic inhibitory effects of this multifunctional nanoplatform. Herein, this nanosystem exhibits enhanced biocompatibility, superior photothermal performance, and stimuli-responsive drug release behavior, making it a promising candidate for effective inhibition of cancer cell proliferation and migration.

FASN contributes to ADM resistance of diffuse large B-cell lymphoma by inhibiting ferroptosis via nf-κB/STAT3/GPX4 axis

ABSTRACT Drug resistance is a critical impediment to efficient therapy of diffuse large B-cell lymphoma (DLBCL) patients. Recent studies have highlighted the association between ferroptosis and drug resistance that has been reported. Fatty acid synthase (FASN) is always related to a poor prognosis. In this study, we investigate the impact of FASN on drug resistance in DLBCL and explore its potential modulation of ferroptosis mechanisms. The clinical correlation of FASN mRNA expression was first analyzed to confirm the role of FASN on drug resistance in DLBCL based on the TCGA database. Next, the impact of FASN on ferroptosis was investigated in vitro and in vivo. Furthermore, a combination of RNA-seq, western blot, luciferase reporter, and ChIP experiments was employed to elucidate the underlying mechanism. The prognosis for patients with DLBCL was worse when FASN was highly expressed, particularly in those undergoing chemotherapy for Adriamycin (ADM). FASN promoted tumor growth and resistance of DLBCL to ADM, both in vitro and in vivo. It is noteworthy that this effect was achieved by inhibiting ferroptosis, since Fer-1 (a ferroptosis inhibitor) treatment significantly recovered the effects of silencing FASN on inhibiting ferroptosis, while Erastin (a ferroptosis inducer) treatment attenuated the impact of overexpressing FASN. Mechanistically, FASN activated NF-κB/STAT3 signaling pathway through phosphorylating the upstream IKKα and IκBα, and the activated STAT3 promoted GPX4 expression by directly binding to GPX4 promoter. FASN inhibits ferroptosis in DLBCL via NF-κB/STAT3/GPX4 signaling pathway, indicating its critical role in mediating ADM resistance of DLBCL.

Fluorescence Label‐Free Doxorubicin Sensor Using Polystyrene Sulfonate as a Synthetic Receptor in Whispering Gallery Mode Microresonators

AbstractThe conventional quantification of Doxorubicin (DXR), a crucial anticancer drug, typically relies on complex and expensive techniques, limiting measurements beyond hospital settings and at different time intervals. Here, a label‐free fluorescence sensor is presented for DXR utilizing Whispering Gallery Mode (WGM) resonators. The resonators are based on fluorescent microparticles coated with a nanometer‐thick polystyrene sulfonate (PSS) layer serving as a synthetic receptor. The sensor demonstrates linear response for both position and width of the resonance peaks within the concentration range of 1–10 µg mL−1 of DXR of clinical interest. It also exhibits good selectivity against other chemotherapy drugs and can operate in complex biological fluids. The findings underscore the potential of WGM resonators as versatile multiparameter sensors for the sensitive and selective detection of small molecules, also in complex biological media.

Novel derivative of nicotinic acid ameliorates doxorubicin-induced cardiac injury via regulation of redox homeostasis

Introduction: Doxorubicin (DOX) is an anthracycline antibiotic with considerable significance in clinics as an anticancer agent, which is limited by its cardiotoxicity, though. A large number of possible therapeutic strategies for reducing cardiotoxicity with doxorubicin have been studied. However, none of them fully meets the requirements of clinical practice. The aim of the study: to evaluate the cardioprotective effects of a new original heterocyclic compound, a pyridine-3-carboxylic acid derivative potassium 5-hydroxynicotinate. Materials and Methods: Cardiac injury was induced by intraperitoneal administration of doxorubicin (DOX) at a dose of 20 mg/kg. After 48 hours, the parameters of left ventricular contractility and StTTI coefficient were assessed on isolated heart in the Langendorff system under the conditions of 480 beats per minute for 11 seconds. Additionally, specific markers of myocardial injury were determined. The lipid peroxidation products and SOD activity were measured as well to challenge whether the compound is able to reduce oxidative stress. Results: The study showed that pretreatment by potassium 5-hydroxynicotinate (35 mg/kg, 48 h) attenuated DOX-induced damage, resulting in a significant decrease in the StТТI coefficient to 3.3 values and in the restoration of the antioxidant activity of enzymes. Conclusion: The obtained data totally demonstrate the protective effects of potassium 5-hydroxynicotinate in DOX-induced cardiomyopathy. A significant role in potassium 5-hydroxynicotinate-mediated cardioprotection is, apparently, related to the reduction of oxidative stress and down-regulation of the level of intracellular calcium.

TongGuanWan Alleviates Doxorubicin- and Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis by Modulating Apoptotic and Fibrotic Pathways.

Heart failure, a major public health issue, often stems from prolonged stress or damage to the heart muscle, leading to cardiac hypertrophy. This can progress to heart failure and other cardiovascular problems. Doxorubicin (DOX), a common chemotherapy drug, and isoproterenol (ISO), a β-adrenergic agonist, both induce cardiac hypertrophy through different mechanisms. This study investigates TongGuanWan (TGW,), a traditional herbal remedy, for its effects on cardiac hypertrophy and fibrosis in DOX-induced H9c2 cells and ISO-induced mouse models. TGW was found to counteract DOX-induced increases in H9c2 cell surface area (n = 8, p < 0.01) and improve biomarkers like ANP (n = 3, p < 0.01)) and BNP (n = 3, p < 0.01). It inhibited the MAPK pathway (n = 4, p < 0.01) and GATA-4/calcineurin/NFAT-3 signaling, reduced inflammation by decreasing NF-κB p65 translocation, and enhanced apoptosis-related factors such as caspase-3 (n = 3, p < 0.01), caspase-9 (n = 3, p < 0.01), Bax (n = 3, p < 0.01), and Bcl-2 (n = 3, p < 0.01). Flow cytometry showed TGW reduced apoptotic cell populations. In vivo, TGW reduced heart (n = 8~10, p < 0.01), and left ventricle weights (n = 6~7), cardiac hypertrophy markers (n = 3, p < 0.01), and perivascular fibrosis in ISO-induced mice, with Western blot analysis confirming decreased levels of fibrosis-related factors like fibronectin, α-SMA (n = 3, p < 0.05), and collagen type I (n = 3, p < 0.05). These findings suggest TGW has potential as a therapeutic option for cardiac hypertrophy and fibrosis.

Reducing the water quenching processes using heavy water in capillary electrophoresis with fluorescence detection

Water, ubiquitous in analytical methods, is renowned for its fluorescence quenching properties, influencing techniques like fluorescence spectrophotometry or techniques with fluorescence detection. This study explores the impact of water (H₂O) substitution for heavy water (D₂O) on the fluorescence behavior of anthraquinones and anthracyclines. Anthraquinones and anthracyclines play crucial roles in pharmacy, serving as essential components in various therapeutic formulations, particularly in cancer treatment and other pharmacological interventions. Capillary electrophoresis (CE) with heavy water as the background electrolyte (BGE) solvent offers superior sensitivity to the separation and detection of these analytes. Experimental results demonstrate the improved detection limits and separation efficiency of selected anthraquinones rhein (RH), aloe-emodin (AE), and anthracyclines doxorubicin (DOX), epirubicin (EPI) and daunorubicine (DAU) in heavy water-based buffers, highlighting the potential of heavy water in advancing analytical chemistry.

NIR Enhanced pH-Responsive Microneedles for Synergetic Therapy of Melanoma.

Melanoma has emerged as a significant threat to human life and health. Microneedle (MN)-mediated transdermal drug delivery (TDD) has garnered attention in melanoma treatment for bypassing the first-pass effect. However, the propensity of melanoma to metastasize presents substantial challenges for MN mediated local treatment. Developing systemic therapies, such as immunotherapy in combination with TDD, is crucial for achieving effective melanoma treatment. Herein, a polyvinyl alcohol (PVA) MN-mediated multifunctional TDD system, designated MN@PDA@1-MT/CUR/DOX@HA (MN@PMCDH), was developed for synergetic chemotherapy/photothermal/immunotherapy of melanoma. PMCDH nanomedicines penetrate deep skin layers through MNs, accumulate at tumor sites guided by hyaluronic acid (HA), and selectively release drugs in response to the acidic tumor microenvironment and near-infrared (NIR) stimulation. Released curcumin (CUR) significantly enhances the efficacy of photothermal therapy (PTT) and chemotherapy, as well as improves the induction of immunogenic cell death (ICD) by increasing melanoma sensitivity to polydopamine (PDA)-mediated photothermal effects and doxorubicin (DOX). Moreover, the incorporation of 1-methyltryptophan (1-MT) to reverse the tumor immunosuppressive microenvironment can further enhance the effects of immunotherapy. In vitro studies revealed that the MN@PMCDH system can effectively induce ICD and inhibit tumor cell growth. Additionally, remarkable deep tumor cell inhibition effects are also achieved in 3D tumor models.