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Nirmatrelvir/ritonavir (N/r) has received emergency use authorization for mild-to-moderate COVID-19 treatment in adult and pediatric patients (aged and weighing at least 12 years and 40 kg, respectively) presenting positive direct SARS-CoV-2 viral testing results and a high risk of disease progression to severe COVID-19. However, information remains limited concerning the corresponding drug safety, efficacy, and pharmacokinetics in patients with severe renal impairment. In this study, we present the case of a 91-year-old Chinese man who, despite exhibiting recurrent positive SARS-CoV-2 results and progression to severe COVID-19, was treated with N/r. Due to severe renal impairment and concurrent administration of continuous renal replacement therapy (continuous venovenous hemofiltration) during medication, we aimed to determine the serum N/r drug concentration in the patient. Our analysis revealed Cmax values of 12.42 and 2.001 μg/mL for nirmatrelvir and ritonavir, respectively. Despite the particularly high serum N/r concentration in this patient, the clinical and laboratory test analyses confirmed that the treatment was safe and effective. Nevertheless, N/r should be used with caution and at lower doses in patients with severe renal impairment to avoid potential high N/r concentration-related adverse reactions and events.

The biotoxicity and chemotherapeutic resistance of cisplatin (CDDP) pose a challenge for tumor therapy. Practically, the change in the therapeutic response of tumor from resistance to sensitivity are impressive but challenging. To this end, we propose a strategy of “one stone, three birds” by designing a CuPt nanoalloy to simultaneously eliminate GSH, relieve hypoxia, and promote ROS production for effectively reversing the platinum (IV) (Pt(IV), (c,c,t-[Pt(NH3)2Cl2(OOCCH2CH2COOH)2)) resistance. Notably, the CuPt nanoalloy exhibits ternary catalytic capabilities including mimicking GSH oxidase, catalase and peroxidase. With the subsequent disguise of tumor cell membrane, the CuPt nanoalloy is conferred with homologous targeting ability, making it actively recognize tumor cells and then effectively internalized by tumor cells. Upon entering tumor cell, it gives rise to GSH depletion, hypoxia relief, and oxidative stress enhancement by catalyzing the reaction of GSH and H2O2, which mitigates the vicious milieu and ultimately reinforces the tumor response to Pt(IV) treatment. In vivo results prove that combination therapy of mCuPt and Pt(IV) realizes the most significant suppression on A549 cisplatin-resistant tumor. This study provides a potential strategy to design novel nanozyme for conquering resistant tumor.

Tetrabromobisphenol A (TBBPA) is one of the most prevalently used brominated flame retardants. Due to its persistence, it is predominantly found in environmental matrices and has the potential to generate multi-generational toxicity. However, knowledge of its adaptive response or long-term residual effect in multi-generations, and molecular mechanisms remain understudied. In the current study, the model animal nematode Caenorhabditis elegans (C. elegans) was exposed to TBBPA at environmentally realistic concentrations (0.1–1000 μg L−1) for four consecutive generations (G0 to G3). Degenerative age-related multiple endpoints including lifespan, locomotion behaviors, growth, reproduction, oxidative stress-related biochemical responses, cell apoptosis, and stress related gene expressions were assessed in the continuous exposure generations (G0 and G3) and the discontinuously exposed generations (T3 and T′3). The results showed that changes in degenerative age-related response monitored four generations varied in direction and magnitude depending on the TBBPA concentrations, and the response intensify ranked as G0 > T′3/G3 > T3. TBBPA at 1 μg L−1 dosage was detected as the lowest observed effect concentration in multi-biomarkers. The underlying mechanism of aging phenotypes was that reactive oxygen species accumulation led to cell apoptosis regulated by gene ape-1, and confirmed catalase enzyme and superoxide dismutase activity played a crucial role in the detoxification process of TBBPA at the molecular level. This study provided insights into the underlying mechanism of TBBPA-interfered longevity and its environmental multi-generational potential risks.