Cisplatin and oleanolic acid Co-loaded pH-sensitive CaCO3 nanoparticles for synergistic chemotherapy.

Despite being one of the most potent anticancer agents, cisplatin (CDDP) clinical usage is limited owing to the acquired resistance and severe adverse effects including nephrotoxicity. The current work has offered a unique approach by designing a pH-sensitive calcium carbonate drug delivery system for CDDP and oleanolic acid (OA) co-delivery, with an enhanced tumor efficacy and reduced unwanted effects. Micro emulsion method was employed to generate calcium carbonate cores (CDDP encapsulated) followed by lipid coating along with the OA loading resulting in the generation of lipid-coated cisplatin/oleanolic acid calcium carbonate nanoparticles (CDDP/OA-LCC NPs). In vitro biological assays confirmed the synergistic apoptotic effect of CDDP and OA against HepG2 cells. It was further verified in vivo through the tumor-bearing nude mice model where NPs exhibited enhanced satisfactory antitumor efficacy in contrast to free drug solutions. In vivo pharmacokinetic study demonstrated that a remarkable long circulation time with a constant therapeutic concentration for both drugs could be achieved via this drug delivery system. In addition, the in vivo imaging study revealed that DiR-loaded NPs were concentrated more in tumors for a longer period of time as compared to other peritoneal tissues in tumor bearing mice, demonstrating the site specificity of the delivery system. On the other hand, hematoxylin and eosin (H&E) staining of Kunming mice kidney tissue sections revealed that OA greatly reduced CDDP induced nephrotoxicity in the formulation. Overall, these results confirmed that our pH-sensitive dual loaded drug delivery system offers a handy direction for effective and safer combination chemotherapy.

ChK1 activation induces reactive astrogliosis through CIP2A/PP2A/STAT3 pathway in Alzheimer's disease.

Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is upregulated and causes reactive astrogliosis, synaptic degeneration, and cognitive deficits in Alzheimer's disease (AD). However, the mechanism underlying the increased CIP2A expression in AD brains remains unclear. We here demonstrated that the DNA damage-related Checkpoint kinase 1 (ChK1) is activated in AD human brains and 3xTg-AD mice. ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induces reactive astrogliosis, degeneration of neurons, and exacerbation of AD through the CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 may be a potential therapeutic approach for AD treatment.

Memory and Learning Complaints in Relation to Depression among Elderly People with Multimorbidity.

Although current models of care are generally well-suited to providing treatment for individual medical conditions, the emergence of multimorbidity is becoming a serious concern for practitioners and policy researchers, particularly in developing countries. The challenges of tackling multimorbidity are further compounded when the multimorbidity co-occurs with psychiatric conditions such as cognitive and depressive disorders. Understanding the relationships between multimorbidity and psychiatric illnesses is therefore of considerable clinical importance. In the present study, we cross-sectionally examined whether multimorbidity has an association with perceived cognition-including memory, learning complaints, and depression-among elderly population in South Africa. Study subjects were 422 men and women aged 50 years and older. The prevalence of arthritis, asthma, cancer, diabetes, heart disease, chronic lung disease, hypertension, and stroke was respectively 31.5, 7.3, 1.7, 10.2, 1.2, 1.7, 52.1, and 31.5%, and that of multimorbidity was 30.8%. In the multivariate analysis, women with multimorbidity were 4.33 times (OR = 4.33, 95%CI = 2.96⁻14.633) more likely to report memory complaints. The odds of diagnosed depression were 1.4 times (OR = 1.4, 95%CI = 1.045⁻5.676), and the odds of self-reported depression were 1.7 times (OR = 1.7, 95%CI = 1.41⁻2.192) higher among women who had multimorbidity compared with those who had no morbid conditions. However, the association was not significant among men. Overall, the findings suggest that the occurrence of multimorbidity warrants special attention, especially regarding its compounding effects on psychological health. The findings need to be replicated through longitudinal studies that consider a broader range of chronic conditions.