lamivudine + raltegravir (MK 0518B / Dutrebis / MK0518B)

Biocompatibility and Multifunctional Biological Evaluation of Flower-Shaped Ag₂CO₃ and Ag/Ag₂CO₃ Nanostructures in Diabetic Albino Mice.

Umar Ali A, Roy Dibakar D, Khan Misbah Ullah MU, Imanov Huseyn H et al.

The present study aimed to synthesize Ag₂CO₃ and Ag/Ag₂CO₃ nanostructures and to systematically investigate their physicochemical characteristics, biocompatibility, metabolic effects, wound healing potential, antioxidant activity, and antibacterial efficacy. Both nanostructures were synthesized using a controlled chemical reduction method. X-ray diffraction analysis confirmed the crystalline Ag₂CO₃ phase and the successful incorporation of metallic silver in the Ag/Ag₂CO₃ composite, while zeta potential analysis revealed enhanced colloidal stability for Ag/Ag₂CO₃ (approximately - 38 mV) compared with Ag₂CO₃ (approximately - 28 mV). Biocompatibility and safety evaluation in non-diabetic mice, including complete blood count, liver and renal function tests, and lipid profiling, demonstrated that both nanostructures were well tolerated at the administered doses without evidence of severe toxicity. In alloxan-induced diabetic mice, treatment with Ag₂CO₃ and Ag/Ag₂CO₃ resulted in significant glucose-lowering effects from Day 7 onward. Serum insulin, triiodothyronine (T3), and thyroxine (T4) levels were significantly improved at Days 14 and 28 compared with diabetic controls. Antioxidant assessment after 28 days showed reduced malondialdehyde levels and enhanced activities of superoxide dismutase, catalase, and reduced glutathione. In a diabetic excision wound model with an initial wound area of 1.2 cm2, complete wound healing occurred by Day 19 in diabetic controls, Day 17 in Ag₂CO₃-treated mice, and Day 14 in Ag/Ag₂CO₃-treated mice. Additionally, both nanostructures exhibited concentration-dependent antibacterial activity against Staphylococcus aureus and Escherichia coli, with Ag/Ag₂CO₃ producing inhibition zones of up to approximately 17 mm at 100 µg/mL. Overall, Ag/Ag₂CO₃ nanostructures demonstrated superior multifunctional biomedical performance.

Co-stimulatory signal deficiency impairs cytotoxic T lymphocyte function in tumor immune evasion: molecular mechanisms and therapeutic implications.

Ma Junjie J, Chen Jing J, Miao Tianrun T, Li Yehong Y et al.

The generation and maintenance of effective tumor-specific CTL responses require more than antigen recognition. In most settings, TCR engagement must be accompanied by co-stimulatory input, with the B7-1/B7-2-CD28 axis being one of the best-characterized examples. When this second signal is weak or absent, tumor-reactive CD8+ T cells may recognize tumor antigens but fail to expand, survive, or acquire and sustain cytotoxic activity. Tumors take advantage of this vulnerability by reducing co-stimulatory ligand availability, increasing inhibitory checkpoint signaling, and remodeling the tumor microenvironment in ways that further restrict T-cell activation. Depending on the stage and context of dysfunction, this shift may favor anergy-like dysfunction, impaired persistence and apoptotic attrition, or, under persistent antigen exposure and sustained inhibitory signaling, exhaustion-associated dysfunction, thereby promoting immune escape. This review examines how reduced or functionally restricted B7-CD28 co-stimulation impairs CTL activation, intratumoral reactivation, and persistence, and how checkpoint signaling, suppressive immune cells, metabolic stress, and stromal barriers compound this defect within tumors. We also evaluate strategies intended to restore or bypass inadequate co-stimulatory input, distinguishing established checkpoint-based interventions from co-stimulatory agonists, engineered T-cell therapies, multispecific antibodies, and gene-based approaches that remain preclinical or early translational in many settings. We propose that mechanism-matched therapy should be guided by the phase at which the dominant barrier arises-tumor-reactive CD8+ T-cell priming, intratumoral CTL reactivation, or long-term CTL persistence.

Mitochondria-Targeted Nanozyme Reprograms Dendritic-Cell Immunometabolism via Microenvironment-Responsive CO Release to Treat Periodontitis.

Shan Shangyan S, Liu Chengyu C, Ding Lina L, Zeng Weishu W et al.

Inflammatory diseases are characterized by overactivated immune responses and a disrupted metabolic equilibrium, particularly in dendritic cells (DCs), where mitochondrial reactive oxygen species (mtROS) burst and metabolic reprogramming drives pathological maturation. While modulating immunometabolism is a promising therapeutic avenue, achieving subcellular-targeted delivery of bioactive molecules remains a formidable challenge. Here, we report a mitochondria-targeted nanozyme designed to concurrently scavenge mtROS and reprogram DC metabolism for effective anti-inflammatory therapy in periodontitis. This system is constructed based on Prussian blue nanoparticles (PB NPs) loaded with manganese carbonyl, a high oxidative stress-responsive carbon monoxide (CO) donor, and further modified with triphenylphosphine for mitochondrial targeting. This nanozyme efficiently accumulates in the mitochondria of activated DCs, where it efficiently scavenges mtROS and concurrently delivers controlled CO release, synergistically modulating DC function. Metabolomics analysis reveals that CO suppresses DC maturation by reprogramming cellular metabolism, including inhibiting the tricarboxylic acid cycle, modulating glycolysis, and disrupting fatty acid synthesis. Consequently, the synergistic action of PB NPs and CO effectively reverses the pro-inflammatory phenotype of DCs, reshapes the immune microenvironment, and ultimately alleviates periodontal inflammation in vivo. This work presents a promising strategy for curing inflammatory diseases by targeting metabolic reprogramming at the subcellular level.

No pollutant acts alone: environmental co-exposure and the cardiovascular exposome.

Münzel Thomas T, Daiber Andreas A, Landrigan Philip J PJ