Gasdermin D triggers cardiolipin-driven mitochondrial damage and pyroptosis.

In a remarkable recent study, Miao et al. reveal that gasdermin D N-terminal (GSDMD-NT) instigates mitochondrial damage in pyroptosis by forming pores in inner and outer mitochondrial membranes (OMMs). The authors highlight the key role of mitochondrial cardiolipin in the action of GSDMD-NT, and significantly advance our understanding of this inflammatory cell death mechanism.

Co-encapsulation of human serum albumin and superparamagnetic iron oxide in PLGA nanoparticles: part I. Effect of process variables on the mean size.

PLGA (poly d,l-lactic-co-glycolic acid) nanoparticles (NPs) encapsulating magnetite nanoparticles (MNPs) along with a model drug human serum albumin (HSA) were prepared by double emulsion solvent evaporation method. This Part I will focus on size and size distribution of prepared NPs, whereas encapsulation efficiency will be discussed in Part II. It was found that mean hydrodynamic particle size was influenced by five important process variables. To explore their effects, a five-factorial, three-level experimental design and statistical analysis were carried out using STATISTICA® software. Effect of process variables on the mean size of nanoparticles was investigated and finally conditions to minimize size of NPs were proposed. GAMS™/MINOS software was used for optimization. The mean hydrodynamic size of nanoparticles ranged from 115 to 329 nm depending on the process conditions. Smallest possible mean particle size can be achieved by using low polymer concentration and high dispersion energy (enough sonication time) along with small aqueous/organic volume ratio.

Co-encapsulation of human serum albumin and superparamagnetic iron oxide in PLGA nanoparticles: part II. Effect of process variables on protein model drug encapsulation efficiency.

This study investigates encapsulation efficiency of model drug, encapsulated by magnetic poly d,l-lactic-co-glycolic acid (PLGA) nanoparticles (NPs). This is the following part of our preceding paper, which is referred in this paper as Part I. Magnetic nanoparticles and model drug human serum albumin (HSA)-loaded PLGA NPs were prepared by the double emulsion solvent evaporation method. Among five important process variables, concentration of PLGA and concentration of HSA in the inner aqueous phase along with their cross-effect had the strongest influence on the encapsulation efficiency. Encapsulation efficiency of nanoparticles ranged from 18% to 97% depending on the process conditions. Higher encapsulation efficiencies can be achieved by using low HSA and high PLGA concentrations. The optimization process, carried out by exact mathematical tools using GAMSTM/MINOS software makes it easier to find out optimum process conditions to achieve comparatively high encapsulation efficiency (e.g. 92.3%) for relatively small-sized PLGA NPs (e.g. 155 nm).

Targeting metabolic circuitry to supercharge CD8+ T cell antitumor responses.

Tumors compromise T cell functionality through various mechanisms, including the induction of a nutrient-scarce microenvironment, leading to lipid accumulation and metabolic reprogramming. Hunt et al. elucidate acetyl-CoA carboxylase's crucial role in regulating lipid metabolism in CD8+ T cells, uncovering a novel metabolic strategy to potentiate antitumor immune responses.

Beyond the danger signal: RNA aggregates orchestrate immunotherapy.

Mendez-Gomez et al. recently demonstrated the transformative potential of RNA-lipid particle aggregates (RNA-LPAs) in immunotherapy. By reprogramming the tumor microenvironment (TME) and potentiating antitumor immunity, RNA-LPAs target primary tumors and elicit robust systemic immunity. This innovative platform holds promise for translating preclinical success into tangible clinical benefits.

Iron oxide nanoparticles in magnetic drug targeting and ferroptosis-based cancer therapy.

Iron oxide (IO) nanoparticles (NPs) have gained significant attention in the field of biomedicine, particularly in drug targeting and cancer therapy. Their potential in magnetic drug targeting (MDT) and ferroptosis-based cancer therapy is highly promising. IO NPs serve as an effective drug delivery system (DDS), utilizing external magnetic fields (EMFs) to target cancer cells while minimizing damage to healthy organs. Additionally, IO NPs can generate reactive oxygen species (ROS) and induce ferroptosis, resulting in cytotoxic effects on cancer cells. This article explores how IO NPs can potentially revolutionize cancer research, focusing on their applications in MDT and ferroptosis-based therapy.

Overcoming blood-brain barrier for targeted delivery of lysosome-targeting chimeras.

In a recent Chem article, Liu et al.1 introduced polydopamine-based lysosome-targeting chimeras (KPLYs). In in vitro cellular models, KPLYs adeptly cross the blood-brain barrier to target and eliminate ß-amyloid aggregates. They also reduce inflammation and modulate microglial activity.

Hyperthermia-embolization-immunotherapy: a potent trio in advancing cancer treatment.

Yang et al. recently demonstrated the high potential of liquid metal microspheres (LM MSs) in cancer therapy. By amplifying the effects of magnetic hyperthermia and embolization, LM MSs not only target primary tumors, but also potentiate immune defenses. This dual-action approach effectively curtails distant tumor growth, marking a pivotal advancement in cancer immunotherapy.

Alternate-day fasting exacerbates doxorubicin cardiotoxicity in cancer chemotherapy.

Doxorubicin (Dox) is a highly potent chemotherapy drug. Despite its efficacy, Dox's clinical application is limited due to its association with significant complications, namely cardiotoxicity and the risk of heart failure. Recent intriguing findings by Ozcan et al. indicate that alternate-day fasting (ADF) significantly exacerbates the cardiotoxicity of Dox.

Estimated pulse wave velocity is associated with all-cause and cardio-cerebrovascular disease mortality in stroke population: Results from NHANES (2003-2014).

Background: Arterial stiffness is a significant determinant and evaluation of cardio-cerebrovascular disease and all-cause mortality risk in the stroke population. Estimated pulse wave velocity (ePWV) is a well-established indirect measure of arterial stiffness. We examined the association of ePWV with all-cause and cardio-cerebrovascular disease (CCD) mortality in the stroke population in a large sample of US adults. Methods: The study design was a prospective cohort study with data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2014, between the ages of 18-85 years, with follow-up through December 31, 2019. 1,316 individuals with stroke among 58,759 participants were identified and ultimately, 879 stroke patients were included in the analysis. ePWV was calculated from a regression equation using age and mean blood pressure according to the following formula: ePWV = 9.587 - (0.402 × age) + [4.560 × 0.001 × (age2)] - [2.621 × 0.00001 × (age2) × MBP] + (3.176 × 0.001 × age × MBP) - (1.832 × 0.01 × MBP). Survey-weighted Cox regression models were used to assess the association between ePWV and all-cause and CCD mortality risk. Results: The high ePWV level group had a higher increased risk of all-cause mortality and CCD mortality compared to the low ePWV level group after fully adjusting for covariates. With an increase in ePWV of 1 m/s, the risk of all-cause and CCD mortality increased by 44%-57% and 47%-72% respectively. ePWV levels were linearly correlated with the risk of all-cause mortality (P for nonlinear = 0.187). With each 1 m/s increase in ePWV, the risk of all-cause mortality increased by 44% (HR 1.44, 95% CI: 1.22-1.69; P < 0.001). When ePWV was <12.1 m/s, an increase in ePWV per 1 m/s was associated with a 119% (HR 2.19, 95% CI: 1.43-3.36; P < 0.001) increase in CCD mortality risk; when ePWV was ≥12.1 m/s, an increase in ePWV per 1 m/s was not associated with in CCD mortality risk. Conclusion: ePWV is an independent risk factor for all-cause and CCD mortality in stroke patients. Higher levels of ePWV are associated with higher all-cause mortality and CCD mortality in stroke patients.

Association of arterial stiffness with all-cause and cause-specific mortality in the diabetic population: A national cohort study.

Background: Estimated pulse wave velocity (ePWV) has been proposed as a potential alternative to carotid-femoral pulse wave velocity to assess the degree of aortic stiffness, and may predict cardiovascular disease (CVD) outcomes and mortality in the general population. However, whether arterial stiffness estimated by ePWV predicts all-cause and cause-specific mortality in patients with diabetes mellitus (DM) has not been reported. Methods: This was a prospective cohort study with data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 and followed up until the end of December 2019. 5,235U.S. adults with DM (age≥20years) were included in the study. Arterial stiffness was estimated by ePWV. Survey-weighted Cox proportional hazards models were performed to assess the hazard ratios (HRs), and 95% confidence intervals (CIs) for the associations of ePWV with all-cause and cause-specific mortality. Meanwhile, the generalized additive model was used to visually assess the dose-dependent relationship between ePWV and mortality. As a complementary analysis, the relationship between mean blood pressure (MBP) and risk of mortality was also examined. Multiple imputations accounted for missing data. Results: For the 5,235 DM patients, the weighted mean age was 57.4 years, and 51.07% were male. During a median follow-up period of 115 months (interquartile range 81-155 months; 53,159 person-years), 1,604 all-cause deaths were recorded. In the fully adjusted Cox regression model, every 1 m/s increase in ePWV was associated with 56% (HR 1.56; 95% CI, 1.44 to 1.69) increase in the risk of all-cause. In addition, a nonlinear relationship between ePWV and all-cause mortality was observed (P for non-linear=0.033). Similar results were obtained after subgroup analysis and multiple imputations. Besides, the risk of most cause-specific mortality, except for accident and renal disease-specific mortality, increased from 53% to 102% for every 1 m/s increase in ePWV. Conclusions: In the diabetic population, ePWV is independently associated with all-cause and most cause-specific mortality risks. ePWV may be a useful tool for assessing mortality risk.

Engineered Magnetic Polymer Nanoparticles Can Ameliorate Breast Cancer Treatment Inducing Pyroptosis-Starvation along with Chemotherapy.

Nanotechnology has shown a revolution in cancer treatments, including breast cancers. However, there remain some challenges and translational hurdles. Surgery, radiotherapy, and chemotherapy are the primary treatment methods for breast cancer, although drug combinations showed promising results in preclinical studies. Herein we report the development of a smart drug delivery system (DDS) to efficiently treat breast cancer by pyroptosis-starvation-chemotherapeutic combination. Cancer-starvation agent glucose oxidase was chemically attached to synthesized iron oxide nanoparticles which were entrapped inside poly(lactic-co-glycolic acid) along with apoptosis-associated speck-like protein containing a caspase recruitment domain plasmid and paclitaxel (PTX). An emulsion solvent evaporation method was used to prepare the DDS. The surface of the DDS was modified with chitosan to which aptamer was attached to achieve site-specific targeting. Hence, the prepared DDS could be targeted to a tumor site by both external magnet and aptamer to obtain an enhanced accumulation of drugs at the tumor site. The final size of the aptamer-decorated DDS was less than 200 nm, and the encapsulation efficiency of PTX was 76.5 ± 2.5%. Drug release from the developed DDS was much higher at pH 5.5 than at pH 7.4, ensuring the pH sensitivity of the DDS. Due to efficient dual targeting of the DDS, in vitro viability of 4T1 cells was reduced to 12.1 ± 1.6%, whereas the nontargeted group and free PTX group could reduce the viability of cells to 29.2 ± 2.4 and 46.2 ± 1.6%, respectively. Our DDS showed a synergistic effect in vitro and no severe side effects in vivo. This DDS has strong potential to treat various cancers.

Sponge-Like Macroporous Hydrogel with Antibacterial and ROS Scavenging Capabilities for Diabetic Wound Regeneration.

Hydrogels with soft and wet properties have been intensively investigated for chronic disease tissue repair. Nevertheless, tissue engineering hydrogels containing high water content are often simultaneously suffered from low porous size and low water-resistant capacities, leading to undesirable surgery outcomes. Here, a novel sponge-like macro-porous hydrogel (SM-hydrogel) with stable macro-porous structures and anti-swelling performances is developed via a facile, fast yet robust approach induced by Ti3 C2 MXene additives. The MXene-induced SM-hydrogels (80% water content) with 200-300 µm open macropores, demonstrating ideal mass/nutrient infiltration capability at ≈20-fold higher water/blood-transport velocity over that of the nonporous hydrogels. Moreover, the highly strong interactions between MXene and polymer chains endow the SM-hydrogels with excellent anti-swelling capability, promising equilibrium SM-hydrogels with identical macro-porous structures and toughened mechanical performances. The SM-hydrogel with versatile functions such as facilitating mass transport, antibacterial (bacterial viability in (Acrylic acid-co-Methacrylamide dopamine) copolymer-Ti3 C2 MXene below 25%), and reactive oxygen species scavenging capacities (96% scavenging ratio at 120 min) synergistically promotes diabetic wound healing (compared with non-porous hydrogels the wound closure rate increased from 39% to 81% within 7 days). Therefore, the durable SM-hydrogels exhibit connective macro-porous structures and bears versatile functions induced by MXene, demonstrating its great potential for wound tissue engineering.

Dual targeting smart drug delivery system for multimodal synergistic combination cancer therapy with reduced cardiotoxicity.

This study first reports the development of a smart drug delivery system (DDS) for multimodal synergistic cancer therapy combining chemo-photothermal-starvation approaches. A magnetic photothermal agent was synthesized by preparing iron oxide (IO) nanoparticles (NPs) with covalently attached indocyanine green (ICG) and glucose oxidase (GOx) (ICGOx@IO). Synthesized ICGOx@IO NPs were co-encapsulated with doxorubicin (Dox) and EGCG ((-)-epigallocatechin-3-gallate) inside PLGA (poly(lactic-co-glycolic acid)) NPs using multiple emulsion solvent evaporation method. Such formulation gave the advantage of triggered drug release by near-infrared (NIR) laser irradiation (808 nm at 1 W/cm2). RGD peptide was attached to the surface of PLGA NPs and the final hydrodynamic size was around 210 nm. Dual targeting by peptide and 240 mT external magnet significantly improved cellular uptake. Cellular uptake was observed using FACS, electron and optical microscopy. Dual targeting along with laser irradiation could reduce in vitro cell viability by 90 ± 2% (Dox-equivalent dose: 10 µg/ml) and complete tumor ablation was achieved in vivo due to synergetic therapeutic effect. Another attractive feature of the DDS was the significant reduction of cardiotoxicity of doxorubicin by EGCG. This new platform is thus expected to hold strong promise for future multimodal combination therapy of cancers. STATEMENT OF SIGNIFICANCE: Doxorubicin is one of the most studied and effective chemotherapeutic agents whose application is hindered due to its cardiotoxicity. In this study, we used (-)-Epigallocatechin-3-gallate (EGCG) to overcome that limitation. However, drug delivery to tumor sites with no/minimum accumulation in healthy organs is always challenging. Although peptide-based targeting is very popular, the effectiveness of receptor/ligand binding active targeting is sometimes questioned which motivated us to apply dual targeting approach. Multimodal therapies can exhibit synergistic effects and subsequently reduce the required dose of drug over monotherapy. We aimed to achieve chemo-photothermal-starvation combination therapy in this study and such achievement is yet to be reported. Our developed system also has the advantage of triggered drug release by near-infrared (NIR) laser irradiation.

Preliminary in vivo magnetofection data using magnetic calcium phosphate nanoparticles immobilizing DNA and iron oxide nanocrystals.

The data reported herein are in association with our research article entitled "Rapid one-pot fabrication of magnetic calcium phosphate nanoparticles immobilizing DNA and iron oxide nanocrystals using injection solutions for magnetofection and magnetic targeting" (Shubhra et al. 2017) [1]. This article reports morphological and gene delivery (in vitro and preliminary in vivo) data of those calcium phosphate (CaP) naonparticles (NPs) with various iron oxide (IO) contents, named as CaP-Fe(1), CaP-Fe(2), CaP-Fe(3), CaP-Fe(4), and CaP-Fe(5), which were prepared via coprecipitation in supersaturated CaP solutions with nominal Fe concentrations 6.97, 13.94, 27.87, 55.74, and 139.35 µg/mL, respectively. Morphological data of four different NPs: CaP-Fe(1), CaP-Fe(2), CaP-Fe(4), and CaP-Fe(5) are shown here. Data of the luciferase reporter gene expression assay show the effects of the coprecipitation time and the dosage of the CaP-Fe(3) NPs on gene expression levels of CHO-K1 cells transfected by the NPs without external magnetic field. It is demonstrated using digital and microscopic images that the CaP-Fe(3) NPs localize near the periphery of the external magnet that was placed under the cell culture plate. Using the CaP-Fe(3) NPs, animal experiments were conducted to obtain preliminary in vivo magnetofection data.