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.

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.

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.

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.

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.

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.

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.

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.

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.

Calcium phosphate nanoparticles prepared from infusion fluids for stem cell transfection: process optimization and cytotoxicity analysis.

This is the first study to report the use of infusion fluids for particle-mediated gene delivery with DNA-immobilized calcium phosphate (CaP) nanoparticles (NPs). In conventional CaP systems, CaP NPs are fabricated in labile supersaturated CaP solutions which are prepared from chemical reagents. In the present study, we fabricated CaP NPs via coprecipitation in labile supersaturated CaP solutions that were prepared from infusion fluids (even the water used was of injectable quality) instead of chemical reagents and demonstrated their gene delivery capabilities for the hard to transfect pluripotent stem cell (C3H10T1/2) along with the easy to transfect CHO-K1 cell. To achieve a high gene delivery capability by keeping the high safety level of our system intact, we varied the process parameters: coprecipitation temperature and time, along with the Ca and P concentrations of the CaP solution, without using additive agents (e.g. surfactants) other than infusion fluids and plasmids. The optimization of these process parameters led to a higher gene delivery capability compared with that of a commercial CaP system for both types of cells. MTT and protein assays showed that both our system and the commercial CaP system were not cytotoxic to both types of cells. Our CaP system has the advantages of high biological safety (due to injectable source materials), high serum-resistance, and relatively high and controllable gene delivery capability, depending on the process parameters. Thus, the present system warrants consideration for gene delivery applications.

Controlled superficial assembly of DNA-amorphous calcium phosphate nanocomposite spheres for surface-mediated gene delivery.

Surface-mediated gene delivery systems have many potential applications in tissue engineering. We recently fabricated an assembly consisting of DNA-amorphous calcium phosphate (DNA-ACP) nanocomposite spheres on a polymer substrate via coprecipitation in a labile supersaturated calcium phosphate (CaP) solution and demonstrated the assembly's high gene delivery efficacy. In this study, we conducted a detailed investigation of the coprecipitation process in solution and revealed that the negatively charged DNA molecules were immobilized in the ACP spheres during the initial stage of coprecipitation and functioned as both sphere-dispersing and size-regulating agents. As a result, the DNA-ACP nanocomposites grew into size-regulated submicrospheres in solution and assembled onto the substrate via gravity sedimentation. The assembled nanocomposite spheres were chemically anchored to the substrate surface through an intermediate layer of CaP-based nanoparticles that was formed heterogeneously at the substrate surface. The coprecipitation conditions, i.e., coprecipitation time and Ca and P concentrations in solution, greatly affected the state of assembly of the nanocomposite spheres, thereby influencing the gene expression level of the cells cultured on the substrate. Increasing the number density and decreasing the size of the nanocomposite spheres did not always increase the assembly's gene delivery efficacy (per surface area of the substrate) due to adverse effects on cellular viability. As demonstrated herein, controlling the coprecipitation conditions is important for designing a cell-stimulating and biocompatible scaffold surface consisting of an assembly of DNA-ACP nanocomposite spheres.

Surface modified thin film from silk and gelatin for sustained drug release to heal wound.

In this study a unique thin film was designed from a silk and gelatin blend which was capable of delivering drug to heal a wound in a rat model. The mechanical properties of the studied film were quite attractive, showing the good strength required for wound-healing applications. The use of a higher content of either silk or gelatin was not advantageous for drug loading or drug-delivery applications. Modification of film using polyethylene glycol (PEG) was quite effective and not only showed better uptake results for wound fluid but also exhibited an excellent in vitro release profile and faster in vivo healing. In addition, results showed that PEG modification was able to reduce the speed of degradation of the film. The initial burst release was extremely high for unmodified films and released more than 60% within the first 8 hours which was significantly reduced by surface modification using PEG. Ciprofloxacin-loaded modified films were able to heal the wound within one week, whereas unmodified films were not able to heal within the same period of time. The in vitro results suggest that the films are very promising for drug-delivery application and PEG modification is very effective for that purpose.

Surface modification of HSA containing magnetic PLGA nanoparticles by poloxamer to decrease plasma protein adsorption.

Lifetime prolongation for hydrophobic drug carriers has been the focus of interest for many years. Poloxamer (Pluronic F68, PF68) has been employed in this study for modifying the surface of magnetic poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with human serum albumin (HSA) model drug. Surface characteristics of untreated and PF68 treated NPs were analyzed by size, zeta potential and electrophoretic mobility studies. UV-vis spectroscopic analysis, isothermal titration calorimetry (ITC) and dynamic light scattering methods were used to investigate serum protein (bovine serum albumin, BSA) adsorption. Results showed the successful surface attachment of PF68. Among different concentrations (0.1-1%, wt/vol) of PF68 studied, 0.5% was found to be the most useful, since a higher concentration can issue in micelle formation. 50% less BSA tended to be adsorbed on the treated NPs in comparison to the untreated ones.